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Ramos-Molina B, Rossell J, Pérez-Montes de Oca A, Pardina E, Genua I, Rojo-López MI, Julián MT, Alonso N, Julve J, Mauricio D. Therapeutic implications for sphingolipid metabolism in metabolic dysfunction-associated steatohepatitis. Front Endocrinol (Lausanne) 2024; 15:1400961. [PMID: 38962680 PMCID: PMC11220194 DOI: 10.3389/fendo.2024.1400961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 06/03/2024] [Indexed: 07/05/2024] Open
Abstract
The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), a leading cause of chronic liver disease, has increased worldwide along with the epidemics of obesity and related dysmetabolic conditions characterized by impaired glucose metabolism and insulin signaling, such as type 2 diabetes mellitus (T2D). MASLD can be defined as an excessive accumulation of lipid droplets in hepatocytes that occurs when the hepatic lipid metabolism is totally surpassed. This metabolic lipid inflexibility constitutes a central node in the pathogenesis of MASLD and is frequently linked to the overproduction of lipotoxic species, increased cellular stress, and mitochondrial dysfunction. A compelling body of evidence suggests that the accumulation of lipid species derived from sphingolipid metabolism, such as ceramides, contributes significantly to the structural and functional tissue damage observed in more severe grades of MASLD by triggering inflammatory and fibrogenic mechanisms. In this context, MASLD can further progress to metabolic dysfunction-associated steatohepatitis (MASH), which represents the advanced form of MASLD, and hepatic fibrosis. In this review, we discuss the role of sphingolipid species as drivers of MASH and the mechanisms involved in the disease. In addition, given the absence of approved therapies and the limited options for treating MASH, we discuss the feasibility of therapeutic strategies to protect against MASH and other severe manifestations by modulating sphingolipid metabolism.
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Affiliation(s)
- Bruno Ramos-Molina
- Group of Obesity, Diabetes & Metabolism, Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain
| | - Joana Rossell
- Group of Endocrinology, Diabetes & Nutrition, Institut de Recerca SANT PAU, Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
| | | | - Eva Pardina
- Department de Biochemistry & Molecular Biology, Facultat de Biologia, Universitat de Barcelona (UB), Barcelona, Spain
| | - Idoia Genua
- Department of Endocrinology & Nutrition, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Marina I. Rojo-López
- Group of Endocrinology, Diabetes & Nutrition, Institut de Recerca SANT PAU, Barcelona, Spain
| | - María Teresa Julián
- Department of Endocrinology & Nutrition, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | - Núria Alonso
- Centro de Investigación Biomédica en Red (CIBER) de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology & Nutrition, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | - Josep Julve
- Group of Endocrinology, Diabetes & Nutrition, Institut de Recerca SANT PAU, Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
| | - Didac Mauricio
- Group of Endocrinology, Diabetes & Nutrition, Institut de Recerca SANT PAU, Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology & Nutrition, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
- Department of Endocrinology & Nutrition, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Faculty of Medicine, University of Vic/Central University of Catalonia (UVIC/UCC), Vic, Spain
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Tanriover C, Copur S, Gaipov A, Ozlusen B, Akcan RE, Kuwabara M, Hornum M, Van Raalte DH, Kanbay M. Metabolically healthy obesity: Misleading phrase or healthy phenotype? Eur J Intern Med 2023; 111:5-20. [PMID: 36890010 DOI: 10.1016/j.ejim.2023.02.025] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 02/16/2023] [Accepted: 02/27/2023] [Indexed: 03/08/2023]
Abstract
Obesity is a heterogenous condition with multiple different phenotypes. Among these a particular subtype exists named as metabolically healthy obesity (MHO). MHO has multiple definitions and its prevalence varies according to study. The potential mechanisms underlying the pathophysiology of MHO include the different types of adipose tissue and their distribution, the role of hormones, inflammation, diet, the intestinal microbiota and genetic factors. In contrast to the negative metabolic profile associated with metabolically unhealthy obesity (MUO), MHO has relatively favorable metabolic characteristics. Nevertheless, MHO is still associated with many important chronic diseases including cardiovascular disease, hypertension, type 2 diabetes, chronic kidney disease as well as certain types of cancer and has the risk of progression into the unhealthy phenotype. Therefore, it should not be considered as a benign condition. The major therapeutic alternatives include dietary modifications, exercise, bariatric surgery and certain medications including glucagon-like peptide-1 (GLP-1) analogs, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and tirzepatide. In this review, we discuss the significance of MHO while comparing this phenotype with MUO.
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Affiliation(s)
- Cem Tanriover
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Sidar Copur
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Abduzhappar Gaipov
- Department of Medicine, Nazarbayev University School of Medicine, Astana, Kazakhstan; Clinical Academic Department of Internal Medicine, CF "University Medical Center", Astana, Kazakhstan
| | - Batu Ozlusen
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Rustu E Akcan
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | | | - Mads Hornum
- Department of Nephrology, Rigshospitalet, Inge Lehmanns Vej 7, Copenhagen 2100, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Daniel H Van Raalte
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Center, Loaction VUMC, Amsterdam, the Netherlands
| | - Mehmet Kanbay
- Department of Medicine, Division of Nephrology, Koc University School of Medicine, Istanbul 34010, Turkey.
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Fritsche L, Hummel J, Wagner R, Löffler D, Hartkopf J, Machann J, Hilberath J, Kantartzis K, Jakubowski P, Pauluschke-Fröhlich J, Brucker S, Hörber S, Häring HU, Roden M, Schürmann A, Solimena M, de Angelis MH, Peter A, Birkenfeld AL, Preissl H, Fritsche A, Heni M. The German Gestational Diabetes Study (PREG), a prospective multicentre cohort study: rationale, methodology and design. BMJ Open 2022; 12:e058268. [PMID: 35168986 PMCID: PMC8852757 DOI: 10.1136/bmjopen-2021-058268] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 01/18/2022] [Indexed: 12/23/2022] Open
Abstract
INTRODUCTION Even well-treated gestational diabetes mellitus (GDM) might still have impact on long-term health of the mother and her offspring, although this relationship has not yet been conclusively studied. Using in-depth phenotyping of the mother and her offspring, we aim to elucidate the relationship of maternal hyperglycaemia during pregnancy and adequate treatment, and its impact on the long-term health of both mother and child. METHODS The multicentre PREG study, a prospective cohort study, is designed to metabolically and phenotypically characterise women with a 75-g five-point oral glucose tolerance test (OGTT) during, and repeatedly after pregnancy. Outcome measures are maternal glycaemia during OGTTs, birth outcome and the health and growth development of the offspring. The children of the study participants are followed up until adulthood with developmental tests and metabolic and epigenetic phenotyping in the PREG Offspring study. A total of 800 women (600 with GDM, 200 controls) will be recruited. ETHICS AND DISSEMINATION The study protocol has been approved by all local ethics committees. Results will be disseminated via conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER The PREG study and the PREG Offspring study are registered with Clinical Trials (ClinicalTrials.gov identifiers: NCT04270578, NCT04722900).
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Affiliation(s)
- Louise Fritsche
- Institute of Diabetes Research and Metabolic Diseases, Helmholtz Center Munich German Research Center for Environmental Health, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
| | - Julia Hummel
- Institute of Diabetes Research and Metabolic Diseases, Helmholtz Center Munich German Research Center for Environmental Health, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
| | - Robert Wagner
- Institute of Diabetes Research and Metabolic Diseases, Helmholtz Center Munich German Research Center for Environmental Health, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
- Department for Diabetology, Endocrinology, and Nephrology, Faculty of Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Dorina Löffler
- Institute of Diabetes Research and Metabolic Diseases, Helmholtz Center Munich German Research Center for Environmental Health, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
- Department for Diabetology, Endocrinology, and Nephrology, Faculty of Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Julia Hartkopf
- Institute of Diabetes Research and Metabolic Diseases, Helmholtz Center Munich German Research Center for Environmental Health, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
| | - Jürgen Machann
- Institute of Diabetes Research and Metabolic Diseases, Helmholtz Center Munich German Research Center for Environmental Health, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
- Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Johannes Hilberath
- Department for Pediatric Gastroenterology and Hepatology, Faculty of Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Konstantinos Kantartzis
- Institute of Diabetes Research and Metabolic Diseases, Helmholtz Center Munich German Research Center for Environmental Health, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
| | - Peter Jakubowski
- Department of Women's Health, Eberhard Karls University Tübingen, Tübingen, Germany
| | | | - Sara Brucker
- Department of Women's Health, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Sebastian Hörber
- Institute of Diabetes Research and Metabolic Diseases, Helmholtz Center Munich German Research Center for Environmental Health, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
- Institute for Clinical Chemistry and Pathobiochemistry, Faculty of Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Hans-Ulrich Häring
- Institute of Diabetes Research and Metabolic Diseases, Helmholtz Center Munich German Research Center for Environmental Health, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
- Department for Diabetology, Endocrinology, and Nephrology, Faculty of Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Michael Roden
- German Center for Diabetes Research, Neuherberg, Germany
- Institute for Clinical Diabetology, Deutsches Diabetes-Zentrum Leibniz-Zentrum für Diabetes-Forschung, Düesseldorf, Germany
| | - Annette Schürmann
- German Center for Diabetes Research, Neuherberg, Germany
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Michele Solimena
- German Center for Diabetes Research, Neuherberg, Germany
- Paul Langerhans Institute Dresden, Dresden University Hospital, Dresden, Germany
| | - Martin Hrabe de Angelis
- German Center for Diabetes Research, Neuherberg, Germany
- Institute of Experimental Genetics, Helmholtz Center Munich (German Research Center for Environmental Health), Neuherberg, Germany
| | - Andreas Peter
- Institute of Diabetes Research and Metabolic Diseases, Helmholtz Center Munich German Research Center for Environmental Health, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
- Institute for Clinical Chemistry and Pathobiochemistry, Faculty of Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Andreas L Birkenfeld
- Institute of Diabetes Research and Metabolic Diseases, Helmholtz Center Munich German Research Center for Environmental Health, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
- Department for Diabetology, Endocrinology, and Nephrology, Faculty of Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Hubert Preissl
- Institute of Diabetes Research and Metabolic Diseases, Helmholtz Center Munich German Research Center for Environmental Health, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
- Department for Diabetology, Endocrinology, and Nephrology, Faculty of Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Andreas Fritsche
- Institute of Diabetes Research and Metabolic Diseases, Helmholtz Center Munich German Research Center for Environmental Health, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
- Department for Diabetology, Endocrinology, and Nephrology, Faculty of Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Martin Heni
- Institute of Diabetes Research and Metabolic Diseases, Helmholtz Center Munich German Research Center for Environmental Health, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
- Department for Diabetology, Endocrinology, and Nephrology, Faculty of Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
- Institute for Clinical Chemistry and Pathobiochemistry, Faculty of Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
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Zak K, Popova V, Orlenko V, Furmanova O, Tronko N. Cytokines in the blood of patients with type 2 diabetes mellitus depending on the level of overweight/obesity (literature review and own data). INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (UKRAINE) 2021; 17:534-551. [DOI: 10.22141/2224-0721.17.7.2021.244969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The paper analyzes the current literature data and the results of our own researches concerning the state of the cytokine network: pro- and anti-inflammatory cytokines (interleukin (IL)1α, IL-1β, IL-4, IL-6, IL-10, IL-17 and tumor necrosis factor (TNF) α), α- and β-chemokines, including IL-8 and IL-16, as well as adipokines (leptin and adiponectin) in the peripheral blood of patients with type 2 diabetes (T2D) with normal and increased body weight/obesity. It has been shown that patients with T2D are characterized by an increased content of proinflammatory cytokines (IL-1, IL-6, IL-17, TNFα), α- and β-chemokines in the peripheral blood, including IL-8 and IL-16, as well as leptin with a decrease in adiponectin content. In lean patients (with body mass index (BMI)<25.5 kg/m2) compared to lean normoglycemic individuals from the control group (BMI<25.5kg/m2), there is a small but significant increase in IL-1β, IL-6, IL-17, TNFα and leptin, which, as BMI increases, significantly increases in severe obesity (BMI>30.0kg/m2), especially in obese women (BMI>35.0kg/m2). Similarly, an increase in proinflammatory cytokines is observed in normoglycemic people, but not as significant as in T2D. Less clear data were obtained when during determination of the anti-inflammatory cytokines IL-4 and IL-10, which is explained by a significant polymorphism of their genes, and both protective and compensatory effects on pro-inflammatory cytokine rise. In T2D patients, especially those with obesity, there is an increase in the leptin level and a decrease in the adiponectin content. The severity of the course and the percentage of mortality are closely associated with the BMI of patients. The effectiveness of the fight against an increase in the incidence of T2D should be primarily aimed at preventing obesity, and in case of already developed T2D— at reducing concomitant obesity. The analysis of the data presented also suggests that a sharp increase in the content of pro-inflammatory cytokines (so called cytokine storm) observed in patients with T2D and obesity infected with COVID-19, is a consequence of the summation and potentiation of already existing inflammatory process.
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Kuraji R, Sekino S, Kapila Y, Numabe Y. Periodontal disease-related nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: An emerging concept of oral-liver axis. Periodontol 2000 2021; 87:204-240. [PMID: 34463983 PMCID: PMC8456799 DOI: 10.1111/prd.12387] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Periodontal disease, a chronic inflammatory disease of the periodontal tissues, is not only a major cause of tooth loss, but it is also known to exacerbate/be associated with various metabolic disorders, such as obesity, diabetes, dyslipidemia, and cardiovascular disease. Recently, growing evidence has suggested that periodontal disease has adverse effects on the pathophysiology of liver disease. In particular, nonalcoholic fatty liver disease, a hepatic manifestation of metabolic syndrome, has been associated with periodontal disease. Nonalcoholic fatty liver disease is characterized by hepatic fat deposition in the absence of a habitual drinking history, viral infections, or autoimmune diseases. A subset of nonalcoholic fatty liver diseases can develop into more severe and progressive forms, namely nonalcoholic steatohepatitis. The latter can lead to cirrhosis and hepatocellular carcinoma, which are end‐stage liver diseases. Extensive research has provided plausible mechanisms to explain how periodontal disease can negatively affect nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, namely via hematogenous or enteral routes. During periodontitis, the liver is under constant exposure to various pathogenic factors that diffuse systemically from the oral cavity, such as bacteria and their by‐products, inflammatory cytokines, and reactive oxygen species, and these can be involved in disease promotion of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Also, gut microbiome dysbiosis induced by enteral translocation of periodontopathic bacteria may impair gut wall barrier function and promote the transfer of hepatotoxins and enterobacteria to the liver through the enterohepatic circulation. Moreover, in a population with metabolic syndrome, the interaction between periodontitis and systemic conditions related to insulin resistance further strengthens the association with nonalcoholic fatty liver disease. However, most of the pathologic links between periodontitis and nonalcoholic fatty liver disease in humans are provided by epidemiologic observational studies, with the causal relationship not yet being established. Several systematic and meta‐analysis studies also show conflicting results. In addition, the effect of periodontal treatment on nonalcoholic fatty liver disease has hardly been studied. Despite these limitations, the global burden of periodontal disease combined with the recent nonalcoholic fatty liver disease epidemic has important clinical and public health implications. Emerging evidence suggests an association between periodontal disease and liver diseases, and thus we propose the term periodontal disease–related nonalcoholic fatty liver disease or periodontal disease–related nonalcoholic steatohepatitis. Continued efforts in this area will pave the way for new diagnostic and therapeutic approaches based on a periodontologic viewpoint to address this life‐threatening liver disease.
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Affiliation(s)
- Ryutaro Kuraji
- Department of Life Science Dentistry, The Nippon Dental University, Tokyo, Japan.,Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan.,Department of Orofacial Sciences, University of California San Francisco School of Dentistry, San Francisco, California, USA
| | - Satoshi Sekino
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Yvonne Kapila
- Department of Orofacial Sciences, University of California San Francisco School of Dentistry, San Francisco, California, USA
| | - Yukihiro Numabe
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
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Peña A, McNeish D, Ayers SL, Olson ML, Vander Wyst KB, Williams AN, Shaibi GQ. Response heterogeneity to lifestyle intervention among Latino adolescents. Pediatr Diabetes 2020; 21:1430-1436. [PMID: 32939893 PMCID: PMC8274397 DOI: 10.1111/pedi.13120] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/06/2020] [Accepted: 09/08/2020] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE To characterize the heterogeneity in response to lifestyle intervention among Latino adolescents with obesity. METHODS We conducted secondary data analysis of 90 Latino adolescents (age 15.4 ± 0.9 y, female 56.7%) with obesity (BMI% 98.1 ± 1.5%) that were enrolled in a 3 month lifestyle intervention and were followed for a year. Covariance pattern mixture models identified response phenotypes defined by changes in insulin sensitivity as measured using a 2 hour oral glucose tolerance test. Baseline characteristics were compared across response phenotypes using one-way ANOVA and chi-square test. RESULTS Three distinct response phenotypes (PH1, PH2, PH3) were identified. PH1 exhibited the most robust response defined by the greatest increase in insulin sensitivity over time (β ± SE, linear 0.52 ± 0.17, P < .001; quadratic -0.03 ± 0.01, P = .001). PH2 showed non-significant changes, while PH3 demonstrated modest short-term increases in insulin sensitivity which were not sustained over time (linear 0.08 ± 0.03, P = .002; quadratic -0.01 ± 0.002, P = .003). At baseline, PH3 (1.1 ± 0.4) was the most insulin resistant phenotype and exhibited the highest BMI% (98.5 ± 1.1%), 2 hours glucose concentrations (144.0 ± 27.5 mg/dL), and lowest beta-cell function as estimated by the oral disposition index (4.5 ± 2.8). CONCLUSION Response to lifestyle intervention varies among Latino youth with obesity and suggests that precision approaches are warranted to meet the prevention needs of high risk youth.
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Affiliation(s)
- Armando Peña
- Center for Health Promotion and Disease Prevention, Arizona State University, Phoenix, AZ,College of Health Solutions, Arizona State University, Phoenix, AZ
| | - Daniel McNeish
- Department of Psychology, Arizona State University, Tempe, AZ
| | - Stephanie L. Ayers
- Southwest Interdisciplinary Research Center, Arizona State University, Phoenix, AZ
| | - Micah L. Olson
- Center for Health Promotion and Disease Prevention, Arizona State University, Phoenix, AZ,College of Health Solutions, Arizona State University, Phoenix, AZ
| | - Kiley B. Vander Wyst
- Center for Health Promotion and Disease Prevention, Arizona State University, Phoenix, AZ
| | - Allison N. Williams
- Center for Health Promotion and Disease Prevention, Arizona State University, Phoenix, AZ
| | - Gabriel Q. Shaibi
- Center for Health Promotion and Disease Prevention, Arizona State University, Phoenix, AZ,College of Health Solutions, Arizona State University, Phoenix, AZ,Department of Pediatric Endocrinology and Diabetes, Phoenix Children’s Hospital, Phoenix, AZ
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Randrianarisoa E, Lehn-Stefan A, Krier J, Böhm A, Heni M, Hrabě De Angelis M, Fritsche A, Häring HU, Stefan N, Staiger H. AMPK Subunits Harbor Largely Nonoverlapping Genetic Determinants for Body Fat Mass, Glucose Metabolism, and Cholesterol Metabolism. J Clin Endocrinol Metab 2020; 105:5568228. [PMID: 31512724 DOI: 10.1210/clinem/dgz020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 07/29/2019] [Accepted: 09/04/2019] [Indexed: 02/13/2023]
Abstract
CONTEXT Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a heterotrimeric enzyme and central regulator of cellular energy metabolism. The impact of single nucleotide polymorphisms (SNPs) in all 7 AMPK subunit genes on adiposity, glucose metabolism, and lipid metabolism has not yet been systematically studied. OBJECTIVE To analyze the associations of common SNPs in all AMPK genes, and of different scores thereof, with adiposity, insulin sensitivity, insulin secretion, blood glucose, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, total cholesterol, and triglycerides. STUDY DESIGN AND METHODS A cohort of 2789 nondiabetic participants from the Tübingen Family study of type 2 diabetes, metabolically characterized by oral glucose tolerance test and genotyped by genome-wide SNP array, was analyzed. RESULTS We identified 6 largely nonoverlapping SNP sets across 4 AMPK genes (PRKAA1, PRKAA2, PRKAG2, PRKAG3) associated with adiposity, insulin sensitivity, insulin secretion, blood glucose, total/LDL cholesterol, or HDL cholesterol, respectively. A genetic score of body-fat-increasing alleles revealed per-allele effect sizes on body mass index (BMI) of +0.22 kg/m2 (P = 2.3 × 10-7), insulin sensitivity of -0.12 × 1019 L2/mol2 (P = 9.9 × 10-6) and 2-hour blood glucose of +0.02 mmol/L (P = 0.0048). Similar effects on blood glucose were observed with scores of insulin-sensitivity-reducing, insulin-secretion-reducing and glucose-raising alleles, respectively. A genetic cholesterol score increased total and LDL cholesterol by 1.17 mg/dL per allele (P = 0.0002 and P = 3.2 × 10-5, respectively), and a genetic HDL score decreased HDL cholesterol by 0.32 mg/dL per allele (P = 9.1 × 10-6). CONCLUSIONS We describe largely nonoverlapping genetic determinants in AMPK genes for diabetes-/atherosclerosis-related traits, which reflect the metabolic pathways controlled by the enzyme. Formation of trait-specific genetic scores revealed additivity of allele effects, with body-fat-raising alleles reaching a marked effect size. (J Clin Endocrinol Metab XX: 0-0, 2019).
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Affiliation(s)
- Elko Randrianarisoa
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, 72076 Tübingen, Germany
- German Center for Diabetes Research (DZD), 72076 Tübingen, Germany
| | - Angela Lehn-Stefan
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, 72076 Tübingen, Germany
- German Center for Diabetes Research (DZD), 72076 Tübingen, Germany
| | - Johannes Krier
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, 72076 Tübingen, Germany
- German Center for Diabetes Research (DZD), 72076 Tübingen, Germany
| | - Anja Böhm
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, 72076 Tübingen, Germany
- German Center for Diabetes Research (DZD), 72076 Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
| | - Martin Heni
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, 72076 Tübingen, Germany
- German Center for Diabetes Research (DZD), 72076 Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
| | - Martin Hrabě De Angelis
- German Center for Diabetes Research (DZD), 72076 Tübingen, Germany
- Institute of Experimental Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany
- Chair of Experimental Genetics, Technical University Munich, 85764 Neuherberg, Germany
| | - Andreas Fritsche
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, 72076 Tübingen, Germany
- German Center for Diabetes Research (DZD), 72076 Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
| | - Hans-Ulrich Häring
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, 72076 Tübingen, Germany
- German Center for Diabetes Research (DZD), 72076 Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
| | - Norbert Stefan
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, 72076 Tübingen, Germany
- German Center for Diabetes Research (DZD), 72076 Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
| | - Harald Staiger
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, 72076 Tübingen, Germany
- German Center for Diabetes Research (DZD), 72076 Tübingen, Germany
- Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
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Goodus MT, McTigue DM. Hepatic dysfunction after spinal cord injury: A vicious cycle of central and peripheral pathology? Exp Neurol 2019; 325:113160. [PMID: 31863731 DOI: 10.1016/j.expneurol.2019.113160] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 11/17/2019] [Accepted: 12/18/2019] [Indexed: 02/06/2023]
Abstract
The liver is essential for numerous physiological processes, including filtering blood from the intestines, metabolizing fats, proteins, carbohydrates and drugs, and regulating iron storage and release. The liver is also an important immune organ and plays a critical role in response to infection and injury throughout the body. Liver functions are regulated by autonomic parasympathetic innervation from the brainstem and sympathetic innervation from the thoracic spinal cord. Thus, spinal cord injury (SCI) at or above thoracic levels disrupts major regulatory mechanisms for hepatic functions. Work in rodents and humans shows that SCI induces liver pathology, including hepatic inflammation and fat accumulation characteristic of a serious form of non-alcoholic fatty liver disease (NAFLD) called non-alcoholic steatohepatitis (NASH). This hepatic pathology is associated with and likely contributes to indices of metabolic dysfunction often noted in SCI individuals, such as insulin resistance and hyperlipidemia. These occur at greater rates in the SCI population and can negatively impact health and quality of life. In this review, we will: 1) Discuss acute and chronic changes in human and rodent liver pathology and function after SCI; 2) Describe how these hepatic changes affect systemic inflammation, iron regulation and metabolic dysfunction after SCI; 3) Describe how disruption of the hepatic autonomic nervous system may be a key culprit in post-injury chronic liver pathology; and 4) Preview ongoing and future research that aims to elucidate mechanisms driving liver and metabolic dysfunction after SCI.
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Affiliation(s)
- Matthew T Goodus
- The Belford Center for Spinal Cord Injury, The Ohio State University, Columbus, OH, USA; Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
| | - Dana M McTigue
- The Belford Center for Spinal Cord Injury, The Ohio State University, Columbus, OH, USA; Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
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9
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Wang X, Sterr M, Ansarullah, Burtscher I, Böttcher A, Beckenbauer J, Siehler J, Meitinger T, Häring HU, Staiger H, Cernilogar FM, Schotta G, Irmler M, Beckers J, Wright CVE, Bakhti M, Lickert H. Point mutations in the PDX1 transactivation domain impair human β-cell development and function. Mol Metab 2019; 24:80-97. [PMID: 30930126 PMCID: PMC6531841 DOI: 10.1016/j.molmet.2019.03.006] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 03/04/2019] [Accepted: 03/13/2019] [Indexed: 01/03/2023] Open
Abstract
OBJECTIVE Hundreds of missense mutations in the coding region of PDX1 exist; however, if these mutations predispose to diabetes mellitus is unknown. METHODS In this study, we screened a large cohort of subjects with increased risk for diabetes and identified two subjects with impaired glucose tolerance carrying common, heterozygous, missense mutations in the PDX1 coding region leading to single amino acid exchanges (P33T, C18R) in its transactivation domain. We generated iPSCs from patients with heterozygous PDX1P33T/+, PDX1C18R/+ mutations and engineered isogenic cell lines carrying homozygous PDX1P33T/P33T, PDX1C18R/C18R mutations and a heterozygous PDX1 loss-of-function mutation (PDX1+/-). RESULTS Using an in vitro β-cell differentiation protocol, we demonstrated that both, heterozygous PDX1P33T/+, PDX1C18R/+ and homozygous PDX1P33T/P33T, PDX1C18R/C18R mutations impair β-cell differentiation and function. Furthermore, PDX1+/- and PDX1P33T/P33T mutations reduced differentiation efficiency of pancreatic progenitors (PPs), due to downregulation of PDX1-bound genes, including transcription factors MNX1 and PDX1 as well as insulin resistance gene CES1. Additionally, both PDX1P33T/+ and PDX1P33T/P33T mutations in PPs reduced the expression of PDX1-bound genes including the long-noncoding RNA, MEG3 and the imprinted gene NNAT, both involved in insulin synthesis and secretion. CONCLUSIONS Our results reveal mechanistic details of how common coding mutations in PDX1 impair human pancreatic endocrine lineage formation and β-cell function and contribute to the predisposition for diabetes.
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Affiliation(s)
- Xianming Wang
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Technische Universität München, Ismaningerstraße 22, 81675 München, Germany
| | - Michael Sterr
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Technische Universität München, Ismaningerstraße 22, 81675 München, Germany
| | - Ansarullah
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Ingo Burtscher
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Anika Böttcher
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Julia Beckenbauer
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Johanna Siehler
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Technische Universität München, Ismaningerstraße 22, 81675 München, Germany
| | - Thomas Meitinger
- Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
| | - Hans-Ulrich Häring
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, 72076 Tübingen, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University of Tübingen, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Harald Staiger
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, 72076 Tübingen, Germany; Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Filippo M Cernilogar
- Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians-University, 82152 Planegg-Martinsried, Germany
| | - Gunnar Schotta
- Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians-University, 82152 Planegg-Martinsried, Germany
| | - Martin Irmler
- Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Johannes Beckers
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Chair of Experimental Genetics, School of Life Sciences Weihenstephan, Technische Universität München, 85354 Freising, Germany
| | - Christopher V E Wright
- Vanderbilt University Program in Developmental Biology, Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37232, USA
| | - Mostafa Bakhti
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Heiko Lickert
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Technische Universität München, Ismaningerstraße 22, 81675 München, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
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10
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Lutz SZ, Hennige AM, Peter A, Kovarova M, Totsikas C, Machann J, Kröber SM, Sperl B, Schleicher E, Schick F, Heni M, Ullrich A, Häring HU, Stefan N. The Gly385(388)Arg Polymorphism of the FGFR4 Receptor Regulates Hepatic Lipogenesis Under Healthy Diet. J Clin Endocrinol Metab 2019; 104:2041-2053. [PMID: 30541128 DOI: 10.1210/jc.2018-01573] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 12/07/2018] [Indexed: 12/12/2022]
Abstract
CONTEXT The effect of a lifestyle intervention to reduce liver fat content in nonalcoholic fatty liver disease in humans is influenced by genetics. We hypothesized that the amino acid exchange in human Gly388Arg (mouse homolog: Gly385Arg) in fibroblast growth factor receptor 4 (FGFR4), which regulates bile acid, lipid, and glucose metabolism, could determine hepatic lipid accumulation and insulin sensitivity. Mechanisms of this substitution were studied in mice under normal chow and high-fat diets. DESIGN In humans, the Gly388Arg polymorphism was studied for its relationship with changes in liver fat content and insulin sensitivity during 9 months of a lifestyle intervention. We also studied a knock-in mouse strain with an Arg385 allele introduced into the murine FGFR4 gene under normal chow and high-fat diets. RESULTS In humans, the FGFR4 Arg388 allele was not associated with liver fat content or insulin sensitivity in subjects who were overweight and obese before lifestyle intervention. However, it was associated with less decrease in liver fat content and less increase in insulin sensitivity during the intervention. In mice receiving normal chow, the FGFR4 Arg385 allele was associated with elevated hepatic triglyceride content, altered hepatic lipid composition, and increased hepatic expression of genes inducing de novo lipogenesis and glycolysis. Body fat mass and distribution, glucose tolerance, and insulin sensitivity were unaltered. The FGFR4 Arg385 allele had no effect on glucose or lipid metabolism under the high-fat diet. CONCLUSION Our data indicate that the FGFR4 Arg388(385) allele affects hepatic lipid and glucose metabolism specifically during healthy caloric intake.
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Affiliation(s)
- Stefan Z Lutz
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
| | - Anita M Hennige
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
| | - Andreas Peter
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
| | - Marketa Kovarova
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
| | - Charisis Totsikas
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
| | - Jürgen Machann
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
- Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, University of Tübingen, Tübingen, Germany
| | - Stefan M Kröber
- Institute of Pathology, University of Tübingen, Tübingen, Germany
| | - Bianca Sperl
- Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Martinsried, Germany
| | - Erwin Schleicher
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
| | - Fritz Schick
- Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, University of Tübingen, Tübingen, Germany
| | - Martin Heni
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
| | - Axel Ullrich
- Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Martinsried, Germany
| | - Hans-Ulrich Häring
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
| | - Norbert Stefan
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
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11
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Abstract
Obesity poses significant public health concerns, including Type 2 diabetes mellitus, cardiovascular disease and stroke. Although deleterious metabolic profiles typically accompany individuals with obesity, various epidemiological studies have identified a subset of patients with a favourable metabolic phenotype referred to as the metabolically healthy obese. Metabolically healthy obesity is a novel concept that stratifies obese individuals according to their respective metabolic status. It has important implications for healthcare policies, particularly the efficient allocation of resources in the targeted treatment of obesity and prevention of metabolic ill-health. However, conflicting evidence in the literature regarding its risk profile questions its clinical relevance. In addition, the lack of a unified definition of metabolically healthy obesity and agreement on its progression further impede its utility as a stratification strategy. This review aims to describe current concepts of metabolically healthy obesity within the literature, evidence of this metabolic phenotype, the clinical implications of patient stratification and limitations of the concept.
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Affiliation(s)
- S Beh
- Institute of Cardiovascular Science, University College London, London, UK
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12
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Kempe-Teufel D, Machicao F, Machann J, Böhm A, Schick F, Fritsche A, Stefan N, Hrabě de Angelis M, Häring HU, Staiger H. A Polygenic Risk Score of Lipolysis-Increasing Alleles Determines Visceral Fat Mass and Proinsulin Conversion. J Clin Endocrinol Metab 2019; 104:1090-1098. [PMID: 30649496 DOI: 10.1210/jc.2018-02042] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 01/07/2019] [Indexed: 01/12/2023]
Abstract
CONTEXT Primary dysregulation of adipose tissue lipolysis caused by genetic variation and independent of insulin resistance could explain unhealthy body fat distribution and its metabolic consequences. OBJECTIVE To analyze common single nucleotide polymorphisms (SNPs) in 48 lipolysis-, but not insulin-signaling-related genes, to form polygenic risk scores of lipolysis-associated SNPs, and to investigate their effects on body fat distribution, glycemia, insulin sensitivity, insulin secretion, and proinsulin conversion. STUDY DESIGN, PARTICIPANTS, AND METHODS SNP array, anthropometric, and metabolic data were available from up to 2789 participants without diabetes of the Tübingen Family study of type 2 diabetes characterized by oral glucose tolerance tests. In a subgroup (n = 942), magnetic resonance measurements of body fat stores were available. RESULTS We identified insulin-sensitivity-independent nominal associations (P < 0.05) of SNPs in 10 genes with plasma free fatty acids (FFAs), in 7 genes with plasma glycerol and in 6 genes with both, plasma FFAs and glycerol. A score formed of the latter SNPs (in ADCY4, CIDEA, GNAS, PDE8B, PRKAA1, PRKAG2) was associated with plasma FFA and glycerol measurements (1.4*10-9 ≤ P ≤ 1.2*10-5), visceral adipose tissue mass (P = 0.0326), and proinsulin conversion (P ≤ 0.0272). The more lipolysis-increasing alleles a subject had, the lower was the visceral fat mass and the lower the proinsulin conversion. CONCLUSIONS We found evidence for a genetic basis of adipose tissue lipolysis resulting from common SNPs in CIDEA, AMP-activated protein kinase subunits, and cAMP signaling components. A genetic score of lipolysis-increasing alleles determined lower visceral fat mass and lower proinsulin conversion.
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Affiliation(s)
- Daniela Kempe-Teufel
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
| | - Fausto Machicao
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute of Experimental Genetics, Helmholtz Center Munich, Neuherberg, Germany
| | - Jürgen Machann
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- Department of Diagnostic and Interventional Radiology, Section on Experimental Radiology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Anja Böhm
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
| | - Fritz Schick
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- Department of Diagnostic and Interventional Radiology, Section on Experimental Radiology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Andreas Fritsche
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
| | - Norbert Stefan
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
| | - Martin Hrabě de Angelis
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute of Experimental Genetics, Helmholtz Center Munich, Neuherberg, Germany
- Chair of Experimental Genetics, Technical University Munich, Neuherberg, Germany
| | - Hans-Ulrich Häring
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
| | - Harald Staiger
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls University Tübingen, Tübingen, Germany
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13
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Hussain MK, Deli FA, Abdul-Rudha KH. Adiponectin receptor 1 gene polymorphisms (rs1342387 & rs12733285) are not associated directly with type 2 diabetes mellitus in Iraqi population. GENE REPORTS 2019. [DOI: 10.1016/j.genrep.2018.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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14
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Gerst F, Jaghutriz BA, Staiger H, Schulte AM, Lorza-Gil E, Kaiser G, Panse M, Haug S, Heni M, Schütz M, Stadion M, Schürmann A, Marzetta F, Ibberson M, Sipos B, Fend F, Fleming T, Nawroth PP, Königsrainer A, Nadalin S, Wagner S, Peter A, Fritsche A, Richter D, Solimena M, Häring HU, Ullrich S, Wagner R. The Expression of Aldolase B in Islets Is Negatively Associated With Insulin Secretion in Humans. J Clin Endocrinol Metab 2018; 103:4373-4383. [PMID: 30202879 PMCID: PMC6915830 DOI: 10.1210/jc.2018-00791] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 09/04/2018] [Indexed: 11/19/2022]
Abstract
CONTEXT Reduced β-cell mass, impaired islet function, and dedifferentiation are considered causal to development of hyperglycemia and type 2 diabetes. In human cohort studies, changes of islet cell-specific expression patterns have been associated with diabetes but not directly with in vivo insulin secretion. OBJECTIVE This study investigates alterations of islet gene expression and corresponding gene variants in the context of in vivo glycemic traits from the same patients. METHODS Fasting blood was collected before surgery, and pancreatic tissue was frozen after resection from 18 patients undergoing pancreatectomy. Islet tissue was isolated by laser capture microdissection. Islet transcriptome was analyzed using microarray and quantitative RT-PCR. Proteins were examined by immunohistochemistry and western blotting. The association of gene variants with insulin secretion was investigated with oral glucose tolerance test (OGTT)-derived insulin secretion measured in a large cohort of subjects at increased risk of type 2 diabetes and with hyperglycemic clamp in a subset. RESULTS Differential gene expression between islets from normoglycemic and hyperglycemic patients was prominent for the glycolytic enzyme ALDOB and the obesity-associated gene FAIM2. The mRNA levels of both genes correlated negatively with insulin secretion and positively with HbA1c. Islets of hyperglycemic patients displayed increased ALDOB immunoreactivity in insulin-positive cells, whereas α- and δ-cells were negative. Exposure of isolated islets to hyperglycemia augmented ALDOB expression. The minor allele of the ALDOB variant rs550915 associated with significantly higher levels of C-peptide and insulin during OGTT and hyperglycemic clamp, respectively. CONCLUSION Our analyses suggest that increased ALDOB expression in human islets is associated with lower insulin secretion.
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Affiliation(s)
- Felicia Gerst
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University of Tuebingen, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
- Internal Medicine IV, University Hospital Tuebingen, Tübingen, Germany
- Correspondence and Reprint Requests: Felicia Gerst, Dr. rer. nat., University Hospital of Tuebingen, Department of Internal Medicine IV and IDM, Otfried-Mueller Street 10, 72076 Tuebingen, Germany. E-mail:
| | - Benjamin A Jaghutriz
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University of Tuebingen, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
- Internal Medicine IV, University Hospital Tuebingen, Tübingen, Germany
| | - Harald Staiger
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University of Tuebingen, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
- Department of Pharmacy and Biochemistry, Institute of Pharmaceutical Sciences, Eberhard Karls University of Tuebingen, Tübingen, Germany
| | - Anke M Schulte
- Diabetes Research, Sanofi-Aventis Deutschland GmbH, Frankfurt-am-Main, Germany
| | - Estela Lorza-Gil
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University of Tuebingen, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
| | - Gabriele Kaiser
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University of Tuebingen, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
- Internal Medicine IV, University Hospital Tuebingen, Tübingen, Germany
| | - Madhura Panse
- German Center for Diabetes Research, Neuherberg, Germany
- Internal Medicine IV, University Hospital Tuebingen, Tübingen, Germany
| | - Sieglinde Haug
- Internal Medicine IV, University Hospital Tuebingen, Tübingen, Germany
| | - Martin Heni
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University of Tuebingen, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
- Internal Medicine IV, University Hospital Tuebingen, Tübingen, Germany
| | - Monika Schütz
- Department of Medical Microbiology and Hygiene, Section of Cellular and Molecular Microbiology, University Hospital Tuebingen, Tübingen, Germany
| | - Mandy Stadion
- German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Annette Schürmann
- German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Flavia Marzetta
- Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Mark Ibberson
- Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Bence Sipos
- Department of General Pathology and Pathological Anatomy, University Hospital Tuebingen, Tübingen, Germany
| | - Falko Fend
- Department of General Pathology and Pathological Anatomy, University Hospital Tuebingen, Tübingen, Germany
| | - Thomas Fleming
- Internal Medicine I, University Hospital Heidelberg, Heidelberg, Germany
| | - Peter P Nawroth
- Internal Medicine I, University Hospital Heidelberg, Heidelberg, Germany
| | - Alfred Königsrainer
- Department of General, Visceral and Transplant Surgery, University Hospital Tuebingen, Tübingen, Germany
| | - Silvio Nadalin
- Department of General, Visceral and Transplant Surgery, University Hospital Tuebingen, Tübingen, Germany
| | - Silvia Wagner
- Department of General, Visceral and Transplant Surgery, University Hospital Tuebingen, Tübingen, Germany
| | - Andreas Peter
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University of Tuebingen, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
- Internal Medicine IV, University Hospital Tuebingen, Tübingen, Germany
| | - Andreas Fritsche
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University of Tuebingen, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
- Internal Medicine IV, University Hospital Tuebingen, Tübingen, Germany
| | | | | | - Hans-Ulrich Häring
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University of Tuebingen, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
- Internal Medicine IV, University Hospital Tuebingen, Tübingen, Germany
| | - Susanne Ullrich
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University of Tuebingen, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
- Internal Medicine IV, University Hospital Tuebingen, Tübingen, Germany
| | - Robert Wagner
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University of Tuebingen, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
- Internal Medicine IV, University Hospital Tuebingen, Tübingen, Germany
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15
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Fritsche L, Sarief M, Wagner R, Stefan N, Lehmann R, Häring HU, Grallert H, Fritsche A, Lechner A. Genetic variation in TCF7L2 rs7903146 and history of GDM negatively and independently impact on diabetes-associated metabolic traits. Diabetes Res Clin Pract 2018; 146:251-257. [PMID: 30419301 DOI: 10.1016/j.diabres.2018.11.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 10/02/2018] [Accepted: 11/02/2018] [Indexed: 12/22/2022]
Abstract
AIMS Gestational diabetes (GDM) is recognized as a major risk factor for the development of type 2 diabetes (T2DM) later in life. Risk allele carriers at TCF7L2 rs7903146 have increased susceptibility for both GDM and T2DM. We hypothesized that carrying TCF7L2 risk alleles would further aggravate the negative impact of a positive history for GDM on metabolic traits related to T2DM later in life. METHODS 210 women with a confirmed history of gestational diabetes and 810 controls without evidence for GDM underwent standardized 75 g oral glucose tolerance tests (OGTT). Liver fat was quantified in a subset of subjects (n = 444) using magnetic resonance spectroscopy. RESULTS 504 women were homozygous or heterozygous risk allele carriers. The risk allele carriers had a higher risk for GDM (p = 0.0076, OR 1.52, 95% CI 1.11-2.06). Multivariable regression analysis demonstrated that both a history of GDM, or carrying a TCF7L2 risk allele resulted in lower insulin secretion, impaired proinsulin processing and higher fasting and 2-hour glucose levels. Liver fat content was not associated with either a history of GDM or a TCF7L2 risk genotype. There was no significant interaction (all p > 0.05) between history of GDM and TCF7L2 risk alleles on all diabetes-associated metabolic traits tested. CONCLUSION The TCF7L2 rs7903146 polymorphism is a risk factor for gestational diabetes. However, the additional presence of TCF7L2 rs7903146 risk alleles does not further aggravate the negative impact of a history of gestational diabetes on metabolic traits related to T2DM.
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Affiliation(s)
- Louise Fritsche
- Division of Endocrinology, Diabetology, Nephrology, Angiology and Clinical Chemistry, Eberhardt Karls University, Tuebingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen (IDM), Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Mirjam Sarief
- German Center for Diabetes Research (DZD), Neuherberg, Germany; Diabetes Research Group, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany; Clinical Cooperation Group Type 2 Diabetes, Helmholtz Center Munich, Neuherberg, Germany
| | - Robert Wagner
- Division of Endocrinology, Diabetology, Nephrology, Angiology and Clinical Chemistry, Eberhardt Karls University, Tuebingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen (IDM), Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Norbert Stefan
- Division of Endocrinology, Diabetology, Nephrology, Angiology and Clinical Chemistry, Eberhardt Karls University, Tuebingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen (IDM), Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Rainer Lehmann
- Division of Endocrinology, Diabetology, Nephrology, Angiology and Clinical Chemistry, Eberhardt Karls University, Tuebingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen (IDM), Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Hans-Ulrich Häring
- Division of Endocrinology, Diabetology, Nephrology, Angiology and Clinical Chemistry, Eberhardt Karls University, Tuebingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen (IDM), Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Harald Grallert
- German Center for Diabetes Research (DZD), Neuherberg, Germany; Diabetes Research Group, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany; Research Unit of Molecular Epidemiology, Institute for Epidemiology II, Helmholtz Center Munich, Neuherberg, Germany
| | - Andreas Fritsche
- Division of Endocrinology, Diabetology, Nephrology, Angiology and Clinical Chemistry, Eberhardt Karls University, Tuebingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen (IDM), Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.
| | - Andreas Lechner
- German Center for Diabetes Research (DZD), Neuherberg, Germany; Diabetes Research Group, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany; Clinical Cooperation Group Type 2 Diabetes, Helmholtz Center Munich, Neuherberg, Germany
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16
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Suwandhi L, Hausmann S, Braun A, Gruber T, Heinzmann SS, Gálvez EJC, Buck A, Legutko B, Israel A, Feuchtinger A, Haythorne E, Staiger H, Heni M, Häring HU, Schmitt-Kopplin P, Walch A, Cáceres CG, Tschöp MH, Rutter GA, Strowig T, Elsner M, Ussar S. Chronic d-serine supplementation impairs insulin secretion. Mol Metab 2018; 16:191-202. [PMID: 30093356 PMCID: PMC6157639 DOI: 10.1016/j.molmet.2018.07.002] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 07/07/2018] [Accepted: 07/16/2018] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE The metabolic role of d-serine, a non-proteinogenic NMDA receptor co-agonist, is poorly understood. Conversely, inhibition of pancreatic NMDA receptors as well as loss of the d-serine producing enzyme serine racemase have been shown to modulate insulin secretion. Thus, we aim to study the impact of chronic and acute d-serine supplementation on insulin secretion and other parameters of glucose homeostasis. METHODS We apply MALDI FT-ICR mass spectrometry imaging, NMR based metabolomics, 16s rRNA gene sequencing of gut microbiota in combination with a detailed physiological characterization to unravel the metabolic action of d-serine in mice acutely and chronically treated with 1% d-serine in drinking water in combination with either chow or high fat diet feeding. Moreover, we identify SNPs in SRR, the enzyme converting L-to d-serine and two subunits of the NMDA receptor to associate with insulin secretion in humans, based on the analysis of 2760 non-diabetic Caucasian individuals. RESULTS We show that chronic elevation of d-serine results in reduced high fat diet intake. In addition, d-serine leads to diet-independent hyperglycemia due to blunted insulin secretion from pancreatic beta cells. Inhibition of alpha 2-adrenergic receptors rapidly restores glycemia and glucose tolerance in d-serine supplemented mice. Moreover, we show that single nucleotide polymorphisms (SNPs) in SRR as well as in individual NMDAR subunits are associated with insulin secretion in humans. CONCLUSION Thus, we identify a novel role of d-serine in regulating systemic glucose metabolism through modulating insulin secretion.
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Affiliation(s)
- Lisa Suwandhi
- RG Adipocytes & Metabolism, Institute for Diabetes & Obesity, Helmholtz Center Munich, 85748 Garching, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Simone Hausmann
- RG Adipocytes & Metabolism, Institute for Diabetes & Obesity, Helmholtz Center Munich, 85748 Garching, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Alexander Braun
- Institute of Groundwater Ecology, Helmholtz Center Munich, 85764 Neuherberg, Germany
| | - Tim Gruber
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Institute for Diabetes & Obesity, Helmholtz Center Munich, 85748 Garching, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Germany
| | - Silke S Heinzmann
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Research Unit Analytical BioGeoChemistry, Department of Environmental Sciences, Helmholtz Center Munich, 85764 Neuherberg, Germany
| | - Eric J C Gálvez
- Research Group Microbial Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Achim Buck
- Research Unit Analytical Pathology, Helmholtz Center Munich, 85764 Neuherberg, Germany
| | - Beata Legutko
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Institute for Diabetes & Obesity, Helmholtz Center Munich, 85748 Garching, Germany
| | - Andreas Israel
- RG Adipocytes & Metabolism, Institute for Diabetes & Obesity, Helmholtz Center Munich, 85748 Garching, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Annette Feuchtinger
- Research Unit Analytical Pathology, Helmholtz Center Munich, 85764 Neuherberg, Germany
| | - Elizabeth Haythorne
- Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, UK
| | - Harald Staiger
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, 72076 Tübingen, Germany
| | - Martin Heni
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, 72076 Tübingen, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen, 72076 Tübingen, Germany
| | - Hans-Ulrich Häring
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, 72076 Tübingen, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen, 72076 Tübingen, Germany
| | - Philippe Schmitt-Kopplin
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Research Unit Analytical BioGeoChemistry, Department of Environmental Sciences, Helmholtz Center Munich, 85764 Neuherberg, Germany
| | - Axel Walch
- Research Unit Analytical Pathology, Helmholtz Center Munich, 85764 Neuherberg, Germany
| | - Cristina García Cáceres
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Institute for Diabetes & Obesity, Helmholtz Center Munich, 85748 Garching, Germany
| | - Matthias H Tschöp
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Institute for Diabetes & Obesity, Helmholtz Center Munich, 85748 Garching, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Germany
| | - Guy A Rutter
- Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, UK
| | - Till Strowig
- Research Group Microbial Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Martin Elsner
- Institute of Groundwater Ecology, Helmholtz Center Munich, 85764 Neuherberg, Germany; Analytical Chemistry and Water Chemistry, Technical University of Munich, 81377 Munich, Germany
| | - Siegfried Ussar
- RG Adipocytes & Metabolism, Institute for Diabetes & Obesity, Helmholtz Center Munich, 85748 Garching, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
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17
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ADIPOR2 variant is associated with higher fasting glucose level in non-diabetic Chinese Han population. Int J Diabetes Dev Ctries 2018. [DOI: 10.1007/s13410-018-0620-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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18
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Sluch VM, Banks A, Li H, Crowley MA, Davis V, Xiang C, Yang J, Demirs JT, Vrouvlianis J, Leehy B, Hanks S, Hyman AM, Aranda J, Chang B, Bigelow CE, Rice DS. ADIPOR1 is essential for vision and its RPE expression is lost in the Mfrp rd6 mouse. Sci Rep 2018; 8:14339. [PMID: 30254279 PMCID: PMC6156493 DOI: 10.1038/s41598-018-32579-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Accepted: 09/10/2018] [Indexed: 12/15/2022] Open
Abstract
The knockout (KO) of the adiponectin receptor 1 (AdipoR1) gene causes retinal degeneration. Here we report that ADIPOR1 protein is primarily found in the eye and brain with little expression in other tissues. Further analysis of AdipoR1 KO mice revealed that these animals exhibit early visual system abnormalities and are depleted of RHODOPSIN prior to pronounced photoreceptor death. A KO of AdipoR1 post-development either in photoreceptors or the retinal pigment epithelium (RPE) resulted in decreased expression of retinal proteins, establishing a role for ADIPOR1 in supporting vision in adulthood. Subsequent analysis of the Mfrprd6 mouse retina demonstrated that these mice are lacking ADIPOR1 in their RPE layer alone, suggesting that loss of ADIPOR1 drives retinal degeneration in this model. Moreover, we found elevated levels of IRBP in both the AdipoR1 KO and the Mfrprd6 models. The spatial distribution of IRBP was also abnormal. This dysregulation of IRBP hypothesizes a role for ADIPOR1 in retinoid metabolism.
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Affiliation(s)
- Valentin M Sluch
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States.
| | - Angela Banks
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
| | - Hui Li
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
| | - Maura A Crowley
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
| | - Vanessa Davis
- Global Scientific Operations, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
| | - Chuanxi Xiang
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
| | - Junzheng Yang
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
| | - John T Demirs
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
| | - Joanna Vrouvlianis
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
| | - Barrett Leehy
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
| | - Shawn Hanks
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
| | - Alexandra M Hyman
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
| | - Jorge Aranda
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
| | - Bo Chang
- The Jackson Laboratory, Bar Harbor, Maine, United States
| | - Chad E Bigelow
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States
| | - Dennis S Rice
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States.
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19
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Gottmann P, Ouni M, Saussenthaler S, Roos J, Stirm L, Jähnert M, Kamitz A, Hallahan N, Jonas W, Fritsche A, Häring HU, Staiger H, Blüher M, Fischer-Posovszky P, Vogel H, Schürmann A. A computational biology approach of a genome-wide screen connected miRNAs to obesity and type 2 diabetes. Mol Metab 2018; 11:145-159. [PMID: 29605715 PMCID: PMC6001404 DOI: 10.1016/j.molmet.2018.03.005] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 02/28/2018] [Accepted: 03/09/2018] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE Obesity and type 2 diabetes (T2D) arise from the interplay between genetic, epigenetic, and environmental factors. The aim of this study was to combine bioinformatics and functional studies to identify miRNAs that contribute to obesity and T2D. METHODS A computational framework (miR-QTL-Scan) was applied by combining QTL, miRNA prediction, and transcriptomics in order to enhance the power for the discovery of miRNAs as regulative elements. Expression of several miRNAs was analyzed in human adipose tissue and blood cells and miR-31 was manipulated in a human fat cell line. RESULTS In 17 partially overlapping QTL for obesity and T2D 170 miRNAs were identified. Four miRNAs (miR-15b, miR-30b, miR-31, miR-744) were recognized in gWAT (gonadal white adipose tissue) and six (miR-491, miR-455, miR-423-5p, miR-132-3p, miR-365-3p, miR-30b) in BAT (brown adipose tissue). To provide direct functional evidence for the achievement of the miR-QTL-Scan, miR-31 located in the obesity QTL Nob6 was experimentally analyzed. Its expression was higher in gWAT of obese and diabetic mice and humans than of lean controls. Accordingly, 10 potential target genes involved in insulin signaling and adipogenesis were suppressed. Manipulation of miR-31 in human SGBS adipocytes affected the expression of GLUT4, PPARγ, IRS1, and ACACA. In human peripheral blood mononuclear cells (PBMC) miR-15b levels were correlated to baseline blood glucose concentrations and might be an indicator for diabetes. CONCLUSION Thus, miR-QTL-Scan allowed the identification of novel miRNAs relevant for obesity and T2D.
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Affiliation(s)
- Pascal Gottmann
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, 14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany.
| | - Meriem Ouni
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, 14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany.
| | - Sophie Saussenthaler
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, 14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany.
| | - Julian Roos
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, 89075, Ulm, Germany.
| | - Laura Stirm
- German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the Eberhard Karls University Tübingen, 72076, Tübingen, Germany.
| | - Markus Jähnert
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, 14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany.
| | - Anne Kamitz
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, 14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany.
| | - Nicole Hallahan
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, 14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany.
| | - Wenke Jonas
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, 14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany.
| | - Andreas Fritsche
- German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the Eberhard Karls University Tübingen, 72076, Tübingen, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Angiology, and Clinical Chemistry, University Hospital Tübingen, 72076, Tübingen, Germany.
| | - Hans-Ulrich Häring
- German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the Eberhard Karls University Tübingen, 72076, Tübingen, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Angiology, and Clinical Chemistry, University Hospital Tübingen, 72076, Tübingen, Germany.
| | - Harald Staiger
- German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the Eberhard Karls University Tübingen, 72076, Tübingen, Germany; Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls University Tübingen, 72076, Tübingen, Germany.
| | - Matthias Blüher
- Department of Medicine, University of Leipzig, 04103, Leipzig, Germany.
| | - Pamela Fischer-Posovszky
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, 89075, Ulm, Germany.
| | - Heike Vogel
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, 14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany.
| | - Annette Schürmann
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, 14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany.
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20
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Randrianarisoa E, Stefan N, Fritsche A, Reis-Damaschk N, Hieronimus A, Balletshofer B, Machann J, Siegel-Axel D, Häring HU, Rittig K. Periaortic Adipose Tissue Compared With Peribrachial Adipose Tissue Mass as Markers and Possible Modulators of Cardiometabolic Risk. Angiology 2018; 69:854-860. [PMID: 29444588 DOI: 10.1177/0003319718755581] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Increased perivascular fat mass contributes to cardiometabolic risk (CMR). High peribrachial adipose tissue (PBAT) associates with insulin resistance independently of established CMR parameters. It is unknown to what extent periaortic adipose tissue (PAAT) may have a similar impact. In 95 participants, precise quantification of total adipose tissue, PBAT, PAAT, visceral adipose tissue (VAT), and liver fat (LF) content was performed by whole-body magnetic resonance imaging. Insulin sensitivity was determined by oral glucose tolerance test and carotid intima-media thickness (cIMT) by high-resolution ultrasound. In univariate analyses, PAAT correlated with PBAT (β = .65, P < .0001). A negative correlation of PAAT (β = -.35, P = .0002) and PBAT (β = -.43, P < .0001) with insulin sensitivity was observed. While in a stepwise forward regression analysis the relationship of PAAT with insulin sensitivity was no longer significant after adjustment for VAT, LF content, and other CMR factors ( P = 0.42), PBAT still correlated with insulin sensitivity ( r2 = .35, P = .01). The association between PAAT and cIMT (β = .49, P < .0001) remained significant after adjustment for these variables ( r2 = .42, P = .0001). Although PAAT and PBAT strongly correlate, PAAT is not associated with insulin resistance, but with cIMT. Therefore, PAAT and PBAT may act differently as possible modulators of insulin resistance and subclinical atherosclerosis.
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Affiliation(s)
- Elko Randrianarisoa
- 1 Division of Endocrinology and Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, Department of Internal Medicine IV, University Hospital of Tübingen, Tübingen, Germany.,2 Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,3 German Center for Diabetes Research (DZD), Tübingen, Germany
| | - Norbert Stefan
- 1 Division of Endocrinology and Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, Department of Internal Medicine IV, University Hospital of Tübingen, Tübingen, Germany.,2 Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,3 German Center for Diabetes Research (DZD), Tübingen, Germany
| | - Andreas Fritsche
- 1 Division of Endocrinology and Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, Department of Internal Medicine IV, University Hospital of Tübingen, Tübingen, Germany.,2 Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,3 German Center for Diabetes Research (DZD), Tübingen, Germany
| | | | - Anja Hieronimus
- 1 Division of Endocrinology and Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, Department of Internal Medicine IV, University Hospital of Tübingen, Tübingen, Germany.,2 Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,3 German Center for Diabetes Research (DZD), Tübingen, Germany
| | - Bernd Balletshofer
- 1 Division of Endocrinology and Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, Department of Internal Medicine IV, University Hospital of Tübingen, Tübingen, Germany
| | - Jürgen Machann
- 2 Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,3 German Center for Diabetes Research (DZD), Tübingen, Germany.,4 Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany
| | - Dorothea Siegel-Axel
- 1 Division of Endocrinology and Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, Department of Internal Medicine IV, University Hospital of Tübingen, Tübingen, Germany.,2 Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,3 German Center for Diabetes Research (DZD), Tübingen, Germany
| | - Hans-Ulrich Häring
- 1 Division of Endocrinology and Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, Department of Internal Medicine IV, University Hospital of Tübingen, Tübingen, Germany.,2 Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,3 German Center for Diabetes Research (DZD), Tübingen, Germany
| | - Kilian Rittig
- 1 Division of Endocrinology and Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, Department of Internal Medicine IV, University Hospital of Tübingen, Tübingen, Germany
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Rozman J, Rathkolb B, Oestereicher MA, Schütt C, Ravindranath AC, Leuchtenberger S, Sharma S, Kistler M, Willershäuser M, Brommage R, Meehan TF, Mason J, Haselimashhadi H, Hough T, Mallon AM, Wells S, Santos L, Lelliott CJ, White JK, Sorg T, Champy MF, Bower LR, Reynolds CL, Flenniken AM, Murray SA, Nutter LMJ, Svenson KL, West D, Tocchini-Valentini GP, Beaudet AL, Bosch F, Braun RB, Dobbie MS, Gao X, Herault Y, Moshiri A, Moore BA, Kent Lloyd KC, McKerlie C, Masuya H, Tanaka N, Flicek P, Parkinson HE, Sedlacek R, Seong JK, Wang CKL, Moore M, Brown SD, Tschöp MH, Wurst W, Klingenspor M, Wolf E, Beckers J, Machicao F, Peter A, Staiger H, Häring HU, Grallert H, Campillos M, Maier H, Fuchs H, Gailus-Durner V, Werner T, Hrabe de Angelis M. Identification of genetic elements in metabolism by high-throughput mouse phenotyping. Nat Commun 2018; 9:288. [PMID: 29348434 PMCID: PMC5773596 DOI: 10.1038/s41467-017-01995-2] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Accepted: 10/30/2017] [Indexed: 12/20/2022] Open
Abstract
Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome.
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Affiliation(s)
- Jan Rozman
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
| | - Birgit Rathkolb
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
- Ludwig-Maximilians-Universität München, Gene Center, Institute of Molecular Animal Breeding and Biotechnology, Feodor-Lynen Strasse 25, 81377, Munich, Germany
| | - Manuela A Oestereicher
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
| | - Christine Schütt
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
| | - Aakash Chavan Ravindranath
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
- Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
| | - Stefanie Leuchtenberger
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
| | - Sapna Sharma
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
- Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
| | - Martin Kistler
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
| | - Monja Willershäuser
- Chair of Molecular Nutritional Medicine, Technical University of Munich, TUM School of Life Sciences Weihenstephan, 85354, Freising, Germany
- EKFZ - Else Kröner-Fresenius Center for Nutritional Medicine, Technical University of Munich, 85354, Freising, Germany
- ZIEL - Institute for Food & Health, Technical University of Munich, 85354, Freising, Germany
| | - Robert Brommage
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
| | - Terrence F Meehan
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
| | - Jeremy Mason
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
| | - Hamed Haselimashhadi
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
| | - Tertius Hough
- Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Oxfordshire, OX11 0RD, UK
| | - Ann-Marie Mallon
- Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Oxfordshire, OX11 0RD, UK
| | - Sara Wells
- Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Oxfordshire, OX11 0RD, UK
| | - Luis Santos
- Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Oxfordshire, OX11 0RD, UK
| | - Christopher J Lelliott
- The Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
| | - Jacqueline K White
- The Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA
| | - Tania Sorg
- CELPHEDIA, PHENOMIN, Institut Clinique de la Souris (ICS), 1 Rue Laurent Fries, 67404, Illkirch-Graffenstaden, France
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Parc d'innovation, 1 Rue Laurent Fries - BP 10142, 67404, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, 67404, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U964, 67404, Illkirch, France
- Université de Strasbourg, 67404, Illkirch, France
| | - Marie-France Champy
- CELPHEDIA, PHENOMIN, Institut Clinique de la Souris (ICS), 1 Rue Laurent Fries, 67404, Illkirch-Graffenstaden, France
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Parc d'innovation, 1 Rue Laurent Fries - BP 10142, 67404, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, 67404, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U964, 67404, Illkirch, France
- Université de Strasbourg, 67404, Illkirch, France
| | - Lynette R Bower
- Mouse Biology Program, University of California, One Shields Avenue, Davis, CA, 95616, USA
| | - Corey L Reynolds
- Department of Molecular and Human Genetics, Baylor College of Medicine, 7702 Main St, Houston Medical Center, Houston, TX, 77030-4406, USA
| | - Ann M Flenniken
- The Centre for Phenogenomics, 25 Orde St, Toronto, M5T 3H7, ON, Canada
- The Hospital for Sick Children, 600 University Avenue, Toronto, ON, M5G 1X5, Canada
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, 600 University Avenue, Toronto, ON, M5G 1X5, Canada
| | - Stephen A Murray
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA
| | - Lauryl M J Nutter
- The Centre for Phenogenomics, 25 Orde St, Toronto, M5T 3H7, ON, Canada
- The Hospital for Sick Children, 600 University Avenue, Toronto, ON, M5G 1X5, Canada
| | - Karen L Svenson
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA
| | - David West
- Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA, 94609, USA
| | - Glauco P Tocchini-Valentini
- Monterotondo Mouse Clinic, Italian National Research Council (CNR), Institute of Cell Biology and Neurobiology, Adriano Buzzati-Traverso Campus, Via E. Ramarini 32, Monterotondo Scalo, RM, 00015, Italy
| | - Arthur L Beaudet
- The Centre for Phenogenomics, 25 Orde St, Toronto, M5T 3H7, ON, Canada
- The Hospital for Sick Children, 600 University Avenue, Toronto, ON, M5G 1X5, Canada
| | - Fatima Bosch
- Center of Animal Biotechnology and Gene Therapy and Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Robert B Braun
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA
| | - Michael S Dobbie
- Australian Phenomics Network, John Curtin School of Medical Research, Australian National University, 131 Garran Road, Canberra, ACT, 2601, Australia
| | - Xiang Gao
- SKL of Pharmaceutical Biotechnology and Model Animal Research Center, Collaborative Innovation Center for Genetics and Development, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, 210061, China
| | - Yann Herault
- CELPHEDIA, PHENOMIN, Institut Clinique de la Souris (ICS), 1 Rue Laurent Fries, 67404, Illkirch-Graffenstaden, France
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Parc d'innovation, 1 Rue Laurent Fries - BP 10142, 67404, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, 67404, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U964, 67404, Illkirch, France
- Université de Strasbourg, 67404, Illkirch, France
| | - Ala Moshiri
- Department of Ophthalmology & Vision Science, School of Medicine, U.C. Davis, 77 Cadillac Drive, Sacramento, 95825, CA, USA
| | - Bret A Moore
- William R. Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, U.C. Davis, One Shields Avenue, Davis, 95616, CA, USA
| | - K C Kent Lloyd
- Mouse Biology Program, University of California, One Shields Avenue, Davis, CA, 95616, USA
| | - Colin McKerlie
- The Centre for Phenogenomics, 25 Orde St, Toronto, M5T 3H7, ON, Canada
- The Hospital for Sick Children, 600 University Avenue, Toronto, ON, M5G 1X5, Canada
| | - Hiroshi Masuya
- RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki, 305-0074, Japan
| | - Nobuhiko Tanaka
- RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki, 305-0074, Japan
| | - Paul Flicek
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
| | - Helen E Parkinson
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
| | - Radislav Sedlacek
- Czech Centre for Phenogenomics, Institute of Molecular Genetics, Prumyslova 595, 252 50, Vestec, Czech Republic
| | - Je Kyung Seong
- Korea Mouse Phenotyping Consortium (KMPC) and BK21 Program for Veterinary Science, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, 599 Gwanangno, Gwanak-gu, Seoul, 151-742, South Korea
| | - Chi-Kuang Leo Wang
- National Laboratory Animal Center, National Applied Research Laboratories (NARLabs), 128 Yen-Chiou-Yuan Rd., Sec. 2, Nankang, Taipei, 11529, Taiwan
| | | | - Steve D Brown
- Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Oxfordshire, OX11 0RD, UK
| | - Matthias H Tschöp
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764, Neuherberg, Germany
- Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333, Munich, Germany
| | - Wolfgang Wurst
- Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany
- Chair of Developmental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany
- Deutsches Institut für Neurodegenerative Erkrankungen (DZNE) Site Munich, Feodor-Lynen-Str. 17, 81377, Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, Feodor-Lynen-Str. 17, 81377, Munich, Germany
| | - Martin Klingenspor
- Chair of Molecular Nutritional Medicine, Technical University of Munich, TUM School of Life Sciences Weihenstephan, 85354, Freising, Germany
- EKFZ - Else Kröner-Fresenius Center for Nutritional Medicine, Technical University of Munich, 85354, Freising, Germany
- ZIEL - Institute for Food & Health, Technical University of Munich, 85354, Freising, Germany
| | - Eckhard Wolf
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
- Ludwig-Maximilians-Universität München, Gene Center, Institute of Molecular Animal Breeding and Biotechnology, Feodor-Lynen Strasse 25, 81377, Munich, Germany
| | - Johannes Beckers
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
- Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Alte Akademie 8, 85354, Freising, Germany
| | - Fausto Machicao
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University of Tübingen, 72076, Tübingen, Germany
| | - Andreas Peter
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University of Tübingen, 72076, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard-Karls-University of Tuebingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany
| | - Harald Staiger
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard-Karls-University of Tuebingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany
- Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls University Tübingen, 72076, Tübingen, Germany
| | - Hans-Ulrich Häring
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University of Tübingen, 72076, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard-Karls-University of Tuebingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany
| | - Harald Grallert
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
- Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
- Clinical Cooperation Group Type 2 Diabetes, Helmholtz Zentrum München and Ludwig-Maximilians Universität München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
| | - Monica Campillos
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
- Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
| | - Holger Maier
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
| | - Helmut Fuchs
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
| | - Valerie Gailus-Durner
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
| | - Thomas Werner
- Internal Medicine Nephrology and Center for Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Martin Hrabe de Angelis
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
- Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Alte Akademie 8, 85354, Freising, Germany.
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22
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Nuñez-Durán E, Aghajan M, Amrutkar M, Sütt S, Cansby E, Booten SL, Watt A, Ståhlman M, Stefan N, Häring HU, Staiger H, Borén J, Marschall HU, Mahlapuu M. Serine/threonine protein kinase 25 antisense oligonucleotide treatment reverses glucose intolerance, insulin resistance, and nonalcoholic fatty liver disease in mice. Hepatol Commun 2017; 2:69-83. [PMID: 29404514 PMCID: PMC5776874 DOI: 10.1002/hep4.1128] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 10/16/2017] [Accepted: 10/30/2017] [Indexed: 12/16/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) contributes to the pathogenesis of type 2 diabetes and cardiovascular disease, and patients with nonalcoholic steatohepatitis (NASH) are also at risk of developing cirrhosis, liver failure, and hepatocellular carcinoma. To date, no specific therapy exists for NAFLD/NASH, which has been recognized as one of the major unmet medical needs of the twenty‐first century. We recently identified serine/threonine protein kinase (STK)25 as a critical regulator of energy homeostasis and NAFLD progression. Here, we investigated the effect of antisense oligonucleotides (ASOs) targeting Stk25 on the metabolic and molecular phenotype of mice after chronic exposure to dietary lipids. We found that Stk25 ASOs efficiently reversed high‐fat diet‐induced systemic hyperglycemia and hyperinsulinemia, improved whole‐body glucose tolerance and insulin sensitivity, and ameliorated liver steatosis, inflammatory infiltration, apoptosis, hepatic stellate cell activation, and nutritional fibrosis in obese mice. Moreover, Stk25 ASOs suppressed the abundance of liver acetyl‐coenzyme A carboxylase (ACC) protein, a key regulator of both lipid oxidation and synthesis, revealing the likely mechanism underlying repression of hepatic fat accumulation by ASO treatment. We also found that STK25 protein levels correlate significantly and positively with NASH development in human liver biopsies, and several common nonlinked single‐nucleotide polymorphisms in the human STK25 gene are associated with altered liver fat, supporting a critical role of STK25 in the pathogenesis of NAFLD in humans. Conclusion: Preclinical validation for the metabolic benefit of pharmacologically inhibiting STK25 in the context of obesity is provided. Therapeutic intervention aimed at reducing STK25 function may provide a new strategy for the treatment of patients with NAFLD, type 2 diabetes, and related complex metabolic diseases. (Hepatology Communications 2018;2:69–83)
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Affiliation(s)
- Esther Nuñez-Durán
- Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Institute of Medicine University of Gothenburg, Sahlgrenska University Hospital Gothenburg Sweden
| | | | - Manoj Amrutkar
- Department of Gastrointestinal and Children Surgery University of Oslo Norway
| | - Silva Sütt
- Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Institute of Medicine University of Gothenburg, Sahlgrenska University Hospital Gothenburg Sweden
| | - Emmelie Cansby
- Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Institute of Medicine University of Gothenburg, Sahlgrenska University Hospital Gothenburg Sweden
| | | | | | - Marcus Ståhlman
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine University of Gothenburg, Sahlgrenska University Hospital Gothenburg Sweden
| | - Norbert Stefan
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich University of Tübingen Tübingen Germany.,German Center for Diabetes Research Tübingen Germany
| | - Hans-Ulrich Häring
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich University of Tübingen Tübingen Germany.,German Center for Diabetes Research Tübingen Germany
| | - Harald Staiger
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich University of Tübingen Tübingen Germany.,German Center for Diabetes Research Tübingen Germany.,Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry Eberhard Karls University Tübingen Tübingen Germany
| | - Jan Borén
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine University of Gothenburg, Sahlgrenska University Hospital Gothenburg Sweden
| | - Hanns-Ulrich Marschall
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine University of Gothenburg, Sahlgrenska University Hospital Gothenburg Sweden
| | - Margit Mahlapuu
- Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Institute of Medicine University of Gothenburg, Sahlgrenska University Hospital Gothenburg Sweden
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Non-alcoholic Fatty Liver Disease in Morbidly Obese Individuals Undergoing Bariatric Surgery: Prevalence and Effect of the Pre-Bariatric Very Low Calorie Diet. Obes Surg 2017; 28:1109-1116. [DOI: 10.1007/s11695-017-2980-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Influence of common polymorphisms in the SLC5A2 gene on metabolic traits in subjects at increased risk of diabetes and on response to empagliflozin treatment in patients with diabetes. Pharmacogenet Genomics 2017; 27:135-142. [PMID: 28134748 DOI: 10.1097/fpc.0000000000000268] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
OBJECTIVE Inhibition of the renal sodium-glucose cotransporter 2 (SGLT2) is a novel concept in the therapy of diabetes mellitus. In this study, we first assessed whether common single nucleotide polymorphisms (SNPs) in the SGLT2-encoding gene SLC5A2 affect diabetes-related metabolic traits in subjects at risk for type 2 diabetes and, second, whether these have pharmacogenetic relevance by interfering with the response to empagliflozin treatment in patients with type 2 diabetes. PATIENTS AND METHODS Samples from a metabolically well-phenotyped cross-sectional study population (total N=2600) at increased risk for type 2 diabetes and pooled pharmacogenetic samples from patients from four phase III trials of empagliflozin (in total: 603 receiving empagliflozin, 305 receiving placebo) were genotyped for five common SNPs (minor allele frequencies ≥5%) present in the SLC5A2 gene locus. RESULTS In the cross-sectional study, none of the SLC5A2 SNPs significantly influenced metabolic traits such as body fat, insulin sensitivity/resistance, insulin release, HbA1c, plasma glucose, or systolic blood pressure when multiple testing was taken into account (all P≥0.0083). Further, no relevant effect on response to treatment with empagliflozin on HbA1c, fasting glucose, weight, or systolic blood pressure was observed for the SNPs tested in the pharmacogenetic study. CONCLUSION Common genetic variants in the SLC5A2 gene neither affects diabetes-related metabolic traits nor have a clinically relevant impact on response to treatment with the SGLT2 inhibitor empagliflozin.
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Baumeier C, Schlüter L, Saussenthaler S, Laeger T, Rödiger M, Alaze SA, Fritsche L, Häring HU, Stefan N, Fritsche A, Schwenk RW, Schürmann A. Elevated hepatic DPP4 activity promotes insulin resistance and non-alcoholic fatty liver disease. Mol Metab 2017; 6:1254-1263. [PMID: 29031724 PMCID: PMC5641684 DOI: 10.1016/j.molmet.2017.07.016] [Citation(s) in RCA: 111] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 07/26/2017] [Accepted: 07/31/2017] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE Increased hepatic expression of dipeptidyl peptidase 4 (DPP4) is associated with non-alcoholic fatty liver disease (NAFLD). Whether this is causative for the development of NAFLD is not yet clarified. Here we investigate the effect of hepatic DPP4 overexpression on the development of liver steatosis in a mouse model of diet-induced obesity. METHODS Plasma DPP4 activity of subjects with or without NAFLD was analyzed. Wild-type (WT) and liver-specific Dpp4 transgenic mice (Dpp4-Liv-Tg) were fed a high-fat diet and characterized for body weight, body composition, hepatic fat content and insulin sensitivity. In vitro experiments on HepG2 cells and primary mouse hepatocytes were conducted to validate cell autonomous effects of DPP4 on lipid storage and insulin sensitivity. RESULTS Subjects suffering from insulin resistance and NAFLD show an increased plasma DPP4 activity when compared to healthy controls. Analysis of Dpp4-Liv-Tg mice revealed elevated systemic DPP4 activity and diminished active GLP-1 levels. They furthermore show increased body weight, fat mass, adipose tissue inflammation, hepatic steatosis, liver damage and hypercholesterolemia. These effects were accompanied by increased expression of PPARγ and CD36 as well as severe insulin resistance in the liver. In agreement, treatment of HepG2 cells and primary hepatocytes with physiological concentrations of DPP4 resulted in impaired insulin sensitivity independent of lipid content. CONCLUSIONS Our results give evidence that elevated expression of DPP4 in the liver promotes NAFLD and insulin resistance. This is linked to reduced levels of active GLP-1, but also to auto- and paracrine effects of DPP4 on hepatic insulin signaling.
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Affiliation(s)
- Christian Baumeier
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Luisa Schlüter
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany
| | - Sophie Saussenthaler
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Thomas Laeger
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Maria Rödiger
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Stella Amelie Alaze
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany
| | - Louise Fritsche
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Hans-Ulrich Häring
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Norbert Stefan
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Andreas Fritsche
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Robert Wolfgang Schwenk
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Annette Schürmann
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
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Böhm A, Wagner R, Machicao F, Holst JJ, Gallwitz B, Stefan N, Fritsche A, Häring HU, Staiger H. DPP4 gene variation affects GLP-1 secretion, insulin secretion, and glucose tolerance in humans with high body adiposity. PLoS One 2017; 12:e0181880. [PMID: 28750074 PMCID: PMC5531535 DOI: 10.1371/journal.pone.0181880] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 07/08/2017] [Indexed: 11/23/2022] Open
Abstract
Objective Dipeptidyl-peptidase 4 (DPP-4) cleaves and inactivates the insulinotropic hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide, collectively termed incretins. DPP-4 inhibitors entered clinical practice as approved therapeutics for type-2 diabetes in 2006. However, inter-individual variance in the responsiveness to DPP-4 inhibitors was reported. Thus, we asked whether genetic variation in the DPP4 gene affects incretin levels, insulin secretion, and glucose tolerance in participants of the TÜbingen Family study for type-2 diabetes (TÜF). Research design and methods Fourteen common (minor allele frequencies ≥0.05) DPP4 tagging single nucleotide polymorphisms (SNPs) were genotyped in 1,976 non-diabetic TÜF participants characterized by oral glucose tolerance tests and bioimpedance measurements. In a subgroup of 168 subjects, plasma incretin levels were determined. Results We identified a variant, i.e., SNP rs6741949, in intron 2 of the DPP4 gene that, after correction for multiple comparisons and appropriate adjustment, revealed a significant genotype-body fat interaction effect on glucose-stimulated plasma GLP-1 levels (p = 0.0021). Notably, no genotype-BMI interaction effects were detected (p = 0.8). After stratification for body fat content, the SNP negatively affected glucose-stimulated GLP-1 levels (p = 0.0229), insulin secretion (p = 0.0061), and glucose tolerance (p = 0.0208) in subjects with high body fat content only. Conclusions A common variant, i.e., SNP rs6741949, in the DPP4 gene interacts with body adiposity and negatively affects glucose-stimulated GLP-1 levels, insulin secretion, and glucose tolerance. Whether this SNP underlies the reported inter-individual variance in responsiveness to DPP-4 inhibitors, at least in subjects with high body fat content, remains to be shown.
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Affiliation(s)
- Anja Böhm
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
| | - Robert Wagner
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
| | - Fausto Machicao
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
| | - Jens Juul Holst
- Section of Translational Metabolic Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Baptist Gallwitz
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Norbert Stefan
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
| | - Andreas Fritsche
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- Department of Internal Medicine, Division of Nutritional and Preventive Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Hans-Ulrich Häring
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- Interfaculty Center for Pharmacogenomics and Pharma Research at the Eberhard Karls University Tübingen, Tübingen, Germany
| | - Harald Staiger
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- Interfaculty Center for Pharmacogenomics and Pharma Research at the Eberhard Karls University Tübingen, Tübingen, Germany
- Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- * E-mail:
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Zha D, Wu X, Gao P. Adiponectin and Its Receptors in Diabetic Kidney Disease: Molecular Mechanisms and Clinical Potential. Endocrinology 2017; 158:2022-2034. [PMID: 28402446 DOI: 10.1210/en.2016-1765] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2016] [Accepted: 04/04/2017] [Indexed: 12/14/2022]
Abstract
Diabetic kidney disease (DKD) is a major complication for diabetic patients. Adiponectin is an insulin sensitizer and anti-inflammatory adipokine and is mainly secreted by adipocytes. Two types of adiponectin receptors, AdipoR1 and AdipoR2, have been identified. In both type 1 and type 2 diabetes (T2D) patients with DKD, elevated adiponectin serum levels have been observed, and adiponectin serum level is a prognostic factor of end-stage renal disease. Renal insufficiency and tubular injury possibly play a contributory role in increases in serum and urinary adiponectin levels in diabetic nephropathy by either increasing biodegradation or elimination of adiponectin in the kidneys, or enhancing production of adiponectin in adipose tissue. Increases in adiponectin levels resulted in amelioration of albuminuria, glomerular hypertrophy, and reduction of inflammatory response in kidney tissue. The renoprotection of adiponectin is associated with improvement of the endothelial dysfunction, reduction of oxidative stress, and upregulation of endothelial nitric oxide synthase expression through activation of adenosine 5'-monophosphate-activated protein kinase by AdipoR1 and activation of peroxisome proliferator-activated receptor (PPAR)-α signaling pathway by AdipoR2. Several single nucleotide polymorphisms in the AdipoQ gene, including the promoter, are associated with increased risk of the development of T2D and DKD. Renin-angiotensin-aldosterone system blockers, adiponectin receptor agonists, and PPAR agonists (e.g., tesaglitazar, thiazolidinediones, fenofibrate), which increase plasma adiponectin levels and adiponectin receptors expression, may be potential therapeutic drugs for the treatment of DKD.
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Affiliation(s)
- Dongqing Zha
- Division of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China
| | - Xiaoyan Wu
- Division of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China
| | - Ping Gao
- Division of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China
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Common variation in the sodium/glucose cotransporter 2 gene SLC5A2 does neither affect fasting nor glucose-suppressed plasma glucagon concentrations. PLoS One 2017; 12:e0177148. [PMID: 28472182 PMCID: PMC5417681 DOI: 10.1371/journal.pone.0177148] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 04/21/2017] [Indexed: 11/19/2022] Open
Abstract
AIM Inhibition of sodium/glucose cotransporter 2 (SGLT2), the key transport protein in renal glucose reabsorption, promotes glucose excretion and represents a new concept in the therapy of type-2 diabetes. In addition, SGLT2 inhibition elevates circulating glucagon concentrations and enhances hepatic glucose production. Since SGLT2 is expressed in human pancreatic α-cells and regulates glucagon release, we tested whether common variants of the SGLT2 gene SLC5A2 associate with altered plasma glucagon concentrations in the fasting state and upon glucose challenge. METHODS A study population of 375 healthy subjects at increased risk for type-2 diabetes, phenotyped by a 5-point oral glucose tolerance test (OGTT) and genotyped for recently described SLC5A2 tagging single nucleotide polymorphisms (SNPs), was selected for plasma glucagon measurements. RESULTS After adjustment for gender, age, body mass index, and insulin sensitivity, the four tagging SNPs (rs9924771, rs3116150, rs3813008, rs9934336), tested separately or as genetic score, were neither significantly nor nominally associated with plasma glucagon concentrations at any time during the OGTT, with the inverse AUC of glucagon or the glucagon fold-change during the OGTT (p ≥ 0.2, all). Testing for genotype-related differences in the time course of the glucagon response using MANOVA did also not reveal any significant or nominal associations (p ≥ 0.5, all). CONCLUSION We could not obtain statistically significant evidence for a role of common SLC5A2 variants in the regulation of glucagon release in the fasting state or upon glucose challenge. Moreover, the reported nominal effects of individual SLC5A2 variants on fasting and post-challenge glucose levels may probably not be mediated by altered glucagon release.
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Holland WL, Xia JY, Johnson JA, Sun K, Pearson MJ, Sharma AX, Quittner-Strom E, Tippetts TS, Gordillo R, Scherer PE. Inducible overexpression of adiponectin receptors highlight the roles of adiponectin-induced ceramidase signaling in lipid and glucose homeostasis. Mol Metab 2017; 6:267-275. [PMID: 28271033 PMCID: PMC5323887 DOI: 10.1016/j.molmet.2017.01.002] [Citation(s) in RCA: 132] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 12/27/2016] [Accepted: 01/05/2017] [Indexed: 02/06/2023] Open
Abstract
Objective Adiponectin and the signaling induced by its cognate receptors, AdipoR1 and AdipoR2, have garnered attention for their ability to promote insulin sensitivity and oppose steatosis. Activation of these receptors promotes the deacylation of ceramide, a lipid metabolite that appears to play a causal role in impairing insulin signaling. Methods Here, we have developed transgenic mice that overexpress AdipoR1 or AdipoR2 under the inducible control of a tetracycline response element. These represent the first inducible genetic models that acutely manipulate adiponectin receptor signaling in adult mouse tissues, which allows us to directly assess AdipoR signaling on glucose and lipid metabolism. Results Overexpression of either adiponectin receptor isoform in the adipocyte or hepatocyte is sufficient to enhance ceramidase activity, whole body glucose metabolism, and hepatic insulin sensitivity, while opposing hepatic steatosis. Importantly, metabolic improvements fail to occur in an adiponectin knockout background. When challenged with a leptin-deficient genetic model of type 2 diabetes, AdipoR2 expression in adipose or liver is sufficient to reverse hyperglycemia and glucose intolerance. Conclusion These observations reveal that adiponectin is critical for AdipoR-induced ceramidase activation which enhances hepatic glucose and lipid metabolism via rapidly acting “cross-talk” between liver and adipose tissue sphingolipids.
Adiponectin receptor signaling in adipose prompts beneficial effects on whole-body glucose and lipid metabolism. The small molecule adiponectin receptor antagonist AdipoRon lowers hepatic ceramides. Depletion of ceramides in adipocytes results in diminished hepatic ceramide accumulation. Depletion of ceramides in hepatocytes results in diminished adipose sphingolipid accumulation. Adiponectin is essential for the beneficial effects of adiponectin receptors on glucose, ceramide, and lipid metabolism.
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Affiliation(s)
- William L Holland
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA.
| | - Jonathan Y Xia
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA
| | - Joshua A Johnson
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA
| | - Kai Sun
- Center for Metabolic and Degenerative Diseases, Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Mackenzie J Pearson
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA
| | - Ankit X Sharma
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA
| | - Ezekiel Quittner-Strom
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA
| | - Trevor S Tippetts
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA
| | - Ruth Gordillo
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA
| | - Philipp E Scherer
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA; Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA
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Heni M, Kullmann S, Ahlqvist E, Wagner R, Machicao F, Staiger H, Häring HU, Almgren P, Groop LC, Small DM, Fritsche A, Preissl H. Interaction between the obesity-risk gene FTO and the dopamine D2 receptor gene ANKK1/TaqIA on insulin sensitivity. Diabetologia 2016; 59:2622-2631. [PMID: 27600277 DOI: 10.1007/s00125-016-4095-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 08/11/2016] [Indexed: 12/19/2022]
Abstract
AIMS/HYPOTHESIS Variations in FTO are the strongest common genetic determinants of adiposity, and may partly act by influencing dopaminergic signalling in the brain leading to altered reward processing that promotes increased food intake. Therefore, we investigated the impact of such an interaction on body composition, and peripheral and brain insulin sensitivity. METHODS Participants from the Tübingen Family study (n = 2245) and the Malmö Diet and Cancer study (n = 2921) were genotyped for FTO SNP rs8050136 and ANKK1 SNP rs1800497. Insulin sensitivity in the caudate nucleus, an important reward area in the brain, was assessed by fMRI in 45 participants combined with intranasal insulin administration. RESULTS We found evidence of an interaction between variations in FTO and an ANKK1 polymorphism that associates with dopamine (D2) receptor density. In cases of reduced D2 receptor availability, as indicated by the ANKK1 polymorphism, FTO variation was associated with increased body fat and waist circumference and reduced peripheral insulin sensitivity. Similarly, altered central insulin sensitivity was observed in the caudate nucleus in individuals with the FTO obesity-risk allele and diminished D2 receptors. CONCLUSIONS/INTERPRETATION The effects of variations in FTO are dependent on dopamine D2 receptor density (determined by the ANKK1 polymorphism). Carriers of both risk alleles might, therefore, be at increased risk of obesity and diabetes.
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Affiliation(s)
- Martin Heni
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Straße 47, 72076, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
| | - Stephanie Kullmann
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Straße 47, 72076, Tübingen, Germany.
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.
| | - Emma Ahlqvist
- Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
| | - Robert Wagner
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Straße 47, 72076, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
| | - Fausto Machicao
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Straße 47, 72076, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
| | - Harald Staiger
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Straße 47, 72076, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls Universität Tübingen, Tübingen, Germany
- Interfaculty Centre for Pharmacogenomics and Pharma Research, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Hans-Ulrich Häring
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Straße 47, 72076, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Interfaculty Centre for Pharmacogenomics and Pharma Research, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Peter Almgren
- Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
| | - Leif C Groop
- Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
- Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
| | - Dana M Small
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
- The John B. Pierce Laboratory, New Haven, CT, USA
| | - Andreas Fritsche
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Straße 47, 72076, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
| | - Hubert Preissl
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Straße 47, 72076, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls Universität Tübingen, Tübingen, Germany
- Interfaculty Centre for Pharmacogenomics and Pharma Research, Eberhard Karls University Tübingen, Tübingen, Germany
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
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Abstract
Fundamental questions remain unresolved in diabetes: What is the actual mechanism of glucose toxicity? Why is there insulin resistance in type 2 diabetes? Why do diets rich in sugars or saturated fatty acids increase the risk of developing diabetes? Studying the C. elegans homologs of the anti-diabetic adiponectin receptors (AdipoR1 and AdipoR2) has led us to exciting new discoveries and to revisit what may be termed “The Membrane Theory of Diabetes”. We hypothesize that excess saturated fatty acids (obtained through a diet rich in saturated fats or through conversion of sugars into saturated fats via lipogenesis) leads to rigid cellular membranes that in turn impair insulin signalling, glucose uptake and blood circulation, thus creating a vicious cycle that contributes to the development of overt type 2 diabetes. This hypothesis is supported by our own studies in C. elegans and by a wealth of literature concerning membrane composition in diabetics. The purpose of this review is to survey this literature in the light of the new results, and to provide an admittedly membrane-centric view of diabetes.
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Ebrahimi E, Shirali S, Afrisham R. Effect and Mechanism of Herbal Ingredients in Improving Diabetes Mellitus Complications. Jundishapur J Nat Pharm Prod 2016. [DOI: 10.17795/jjnpp-31657] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Effect and Mechanism of Herbal Ingredients in Improving Diabetes Mellitus Complications. Jundishapur J Nat Pharm Prod 2016. [DOI: 10.5812/jjnpp.31657] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Abstract
This article describes phenotypes observed in a prediabetic population (i.e. a population with increased risk for type 2 diabetes) from data collected at the University hospital of Tübingen. We discuss the impact of genetic variation on insulin secretion, in particular the effect on compensatory hypersecretion, and the incretin-resistant phenotype of carriers of the gene variant TCF7L2 is described. Imaging studies used to characterise subphenotypes of fat distribution, metabolically healthy obesity and metabolically unhealthy obesity are described. Also discussed are ectopic fat stores in liver and pancreas that determine the phenotype of metabolically healthy and unhealthy fatty liver and the recently recognised phenotype of fatty pancreas. The metabolic impact of perivascular adipose tissue and pancreatic fat is discussed. The role of hepatokines, particularly that of fetuin-A, in the crosstalk between these organs is described. Finally, the role of brain insulin resistance in the development of the different prediabetes phenotypes is discussed.
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Affiliation(s)
- Hans-Ulrich Häring
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University of Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.
- Institute of Diabetes Research and Metabolic Diseases (IDM), University of Tübingen, Tübingen, Germany.
- German Center for Diabetes Research (DZD), Neuherberg, Germany.
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Wang X, Chen S, Burtscher I, Sterr M, Hieronimus A, Machicao F, Staiger H, Häring HU, Lederer G, Meitinger T, Lickert H. Generation of a human induced pluripotent stem cell (iPSC) line from a patient with family history of diabetes carrying a C18R mutation in the PDX1 gene. Stem Cell Res 2016; 17:292-295. [PMID: 27879214 DOI: 10.1016/j.scr.2016.08.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 08/03/2016] [Indexed: 11/26/2022] Open
Abstract
Homozygous loss-of-function mutations in the gene coding for the homeobox transcription factor PDX1 leads to pancreatic agenesis, whereas certain heterozygous point mutations are associated with Maturity-Onset Diabetes of the Young 4 (MODY4) and Type 2 Diabetes Mellitus (T2DM). To understand the pathomechanism of MODY4 and T2DM, we have generated iPSCs from a woman with a C18R heterozygous mutation in the transactivation domain of PDX1. The resulting PDX1 C18R iPSCs generated by episomal reprogramming are integration-free, have a normal karyotype and are pluripotent in vitro and in vivo. Taken together, this iPSC line will be useful to study diabetes pathomechanisms.
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Affiliation(s)
- Xianming Wang
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Technische Universität München, Ismaninger straße 22, 81675 München, Germany
| | - Shen Chen
- iPS and Cancer Research Unit, Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Ingo Burtscher
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Michael Sterr
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Anja Hieronimus
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, 72076 Tübingen, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Fausto Machicao
- Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Harald Staiger
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, 72076 Tübingen, Germany; Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Hans-Ulrich Häring
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, 72076 Tübingen, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Gabriele Lederer
- Institute of Human Genetics, Technische Universität München, 81675 München, Germany
| | - Thomas Meitinger
- Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 München, Germany
| | - Heiko Lickert
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Technische Universität München, Ismaninger straße 22, 81675 München, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
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Identification of proliferative and mature β-cells in the islets of Langerhans. Nature 2016; 535:430-4. [PMID: 27398620 DOI: 10.1038/nature18624] [Citation(s) in RCA: 261] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 06/01/2016] [Indexed: 02/08/2023]
Abstract
Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of β-cells. Pancreatic β-cells differ in size, glucose responsiveness, insulin secretion and precursor cell potential; understanding the mechanisms that underlie this functional heterogeneity might make it possible to develop new regenerative approaches. Here we show that Fltp (also known as Flattop and Cfap126), a Wnt/planar cell polarity (PCP) effector and reporter gene acts as a marker gene that subdivides endocrine cells into two subpopulations and distinguishes proliferation-competent from mature β-cells with distinct molecular, physiological and ultrastructural features. Genetic lineage tracing revealed that endocrine subpopulations from Fltp-negative and -positive lineages react differently to physiological and pathological changes. The expression of Fltp increases when endocrine cells cluster together to form polarized and mature 3D islet mini-organs. We show that 3D architecture and Wnt/PCP ligands are sufficient to trigger β-cell maturation. By contrast, the Wnt/PCP effector Fltp is not necessary for β-cell development, proliferation or maturation. We conclude that 3D architecture and Wnt/PCP signalling underlie functional β-cell heterogeneity and induce β-cell maturation. The identification of Fltp as a marker for endocrine subpopulations sheds light on the molecular underpinnings of islet cell heterogeneity and plasticity and might enable targeting of endocrine subpopulations for the regeneration of functional β-cell mass in diabetic patients.
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Yang G, Liu N, Hu M, Xin X, Han J, Cai Y, Hu Z, Jia C, Zhang M. A Variant in ADIPOR2 Is Associated with Increased Free Fatty Acid Levels in Chinese Population. Metab Syndr Relat Disord 2016; 14:368-71. [PMID: 27348122 DOI: 10.1089/met.2016.0005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
BACKGROUND Elevated free fatty acids (FFAs) are thought to play an important role in the development of insulin resistance. Adiponectin is an adipose tissue-secreted protein known for its effects on the stimulation of fatty acid oxidation. The aim of this study was to investigate the association of adiponectin receptor 2 gene variations with FFAs levels in subjects with normal fasting glucose levels in Chinese Han population. METHODS Four common single nucleotide polymorphisms of ADIPOR2 were genotyped using the TaqMan method to perform association studies with metabolic parameters in 1819 subjects among Chinese Han population. All the subjects were divided into two groups: normal FFAs group (FFAs ≤0.88 mmol/L) and high FFAs group (FFAs >0.88 mmol/L). RESULTS There was a significant association of rs2370055 with higher FFA levels in major T-allele carriers (P = 0.000). There was a significant difference in the distribution of genotypes of polymorphism rs2370055 between normal and high FFA groups. The frequencies of TT and CT genotypes are significantly higher in subjects with high FFA level than those in the normal FFAs group (P = 0.013 and P = 0.004, respectively). After adjustment for age, sex, body mass index, triglyceride, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoproteincholesterol, the TT and CT genotypes are both independent risk factors for high FFAs level. CONCLUSIONS Our findings suggest that variants of ADIPOR2 could be a determinant for higher FFA levels, and among Chinese Han population, carriers of the CT and TT genotypes for rs2370055 even with normal glucose levels may have significantly higher insulin resistance susceptibility.
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Affiliation(s)
- Guihua Yang
- 1 Department of Clinical Laboratory Medicine, Beijing Shijitan Hospital, Peking University Ninth School of Clinical Medicine , Beijing, China .,2 Beijing Shijitan Hospital, Capital Medical University , Beijing, China
| | - Na Liu
- 1 Department of Clinical Laboratory Medicine, Beijing Shijitan Hospital, Peking University Ninth School of Clinical Medicine , Beijing, China .,2 Beijing Shijitan Hospital, Capital Medical University , Beijing, China
| | - Mei Hu
- 1 Department of Clinical Laboratory Medicine, Beijing Shijitan Hospital, Peking University Ninth School of Clinical Medicine , Beijing, China .,2 Beijing Shijitan Hospital, Capital Medical University , Beijing, China
| | - Xuli Xin
- 1 Department of Clinical Laboratory Medicine, Beijing Shijitan Hospital, Peking University Ninth School of Clinical Medicine , Beijing, China .,2 Beijing Shijitan Hospital, Capital Medical University , Beijing, China
| | - Jing Han
- 1 Department of Clinical Laboratory Medicine, Beijing Shijitan Hospital, Peking University Ninth School of Clinical Medicine , Beijing, China .,2 Beijing Shijitan Hospital, Capital Medical University , Beijing, China
| | - Yuyu Cai
- 1 Department of Clinical Laboratory Medicine, Beijing Shijitan Hospital, Peking University Ninth School of Clinical Medicine , Beijing, China .,2 Beijing Shijitan Hospital, Capital Medical University , Beijing, China
| | - Zhiying Hu
- 1 Department of Clinical Laboratory Medicine, Beijing Shijitan Hospital, Peking University Ninth School of Clinical Medicine , Beijing, China .,2 Beijing Shijitan Hospital, Capital Medical University , Beijing, China
| | - Chundi Jia
- 1 Department of Clinical Laboratory Medicine, Beijing Shijitan Hospital, Peking University Ninth School of Clinical Medicine , Beijing, China .,2 Beijing Shijitan Hospital, Capital Medical University , Beijing, China
| | - Man Zhang
- 1 Department of Clinical Laboratory Medicine, Beijing Shijitan Hospital, Peking University Ninth School of Clinical Medicine , Beijing, China .,2 Beijing Shijitan Hospital, Capital Medical University , Beijing, China
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Impacts of Nonsynonymous Single Nucleotide Polymorphisms of Adiponectin Receptor 1 Gene on Corresponding Protein Stability: A Computational Approach. BIOMED RESEARCH INTERNATIONAL 2016; 2016:9142190. [PMID: 27294143 PMCID: PMC4884590 DOI: 10.1155/2016/9142190] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 04/11/2016] [Indexed: 01/05/2023]
Abstract
Despite the reported association of adiponectin receptor 1 (ADIPOR1) gene mutations with vulnerability to several human metabolic diseases, there is lack of computational analysis on the functional and structural impacts of single nucleotide polymorphisms (SNPs) of the human ADIPOR1 at protein level. Therefore, sequence- and structure-based computational tools were employed in this study to functionally and structurally characterize the coding nsSNPs of ADIPOR1 gene listed in the dbSNP database. Our in silico analysis by SIFT, nsSNPAnalyzer, PolyPhen-2, Fathmm, I-Mutant 2.0, SNPs&GO, PhD-SNP, PANTHER, and SNPeffect tools identified the nsSNPs with distorting functional impacts, namely, rs765425383 (A348G), rs752071352 (H341Y), rs759555652 (R324L), rs200326086 (L224F), and rs766267373 (L143P) from 74 nsSNPs of ADIPOR1 gene. Finally the aforementioned five deleterious nsSNPs were introduced using Swiss-PDB Viewer package within the X-ray crystal structure of ADIPOR1 protein, and changes in free energy for these mutations were computed. Although increased free energy was observed for all the mutants, the nsSNP H341Y caused the highest energy increase amongst all. RMSD and TM scores predicted that mutants were structurally similar to wild type protein. Our analyses suggested that the aforementioned variants especially H341Y could directly or indirectly destabilize the amino acid interactions and hydrogen bonding networks of ADIPOR1.
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Böhm A, Weigert C, Staiger H, Häring HU. Exercise and diabetes: relevance and causes for response variability. Endocrine 2016; 51:390-401. [PMID: 26643313 PMCID: PMC4762932 DOI: 10.1007/s12020-015-0792-6] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 10/28/2015] [Indexed: 12/31/2022]
Abstract
Exercise as a key prevention strategy for diabetes and obesity is commonly accepted and recommended throughout the world. Unfortunately, not all individuals profit to the same extent, some exhibit exercise resistance. This phenomenon of non-response to exercise is found for several endpoints, including glucose tolerance and insulin sensitivity. Since these non-responders are of notable quantity, there is the need to understand the underlying mechanisms and to identify predictors of response. This displays the basis to develop personalized training intervention regimes. In this review, we summarize the current knowledge on response variability, with focus on human studies and improvement of glucose homeostasis as outcome.
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Affiliation(s)
- Anja Böhm
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen, Eberhard Karls University Tübingen, 72076, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany
| | - Cora Weigert
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen, Eberhard Karls University Tübingen, 72076, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany
| | - Harald Staiger
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen, Eberhard Karls University Tübingen, 72076, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany
| | - Hans-Ulrich Häring
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen, Eberhard Karls University Tübingen, 72076, Tübingen, Germany.
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, Tübingen, Germany.
- German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany.
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Granulocyte colony-stimulating factor (G-CSF): A saturated fatty acid-induced myokine with insulin-desensitizing properties in humans. Mol Metab 2016; 5:305-316. [PMID: 27069870 PMCID: PMC4812007 DOI: 10.1016/j.molmet.2016.02.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 02/02/2016] [Accepted: 02/08/2016] [Indexed: 01/01/2023] Open
Abstract
Objective Circulating long-chain free fatty acids (FFAs) are important metabolic signals that acutely enhance fatty acid oxidation, thermogenesis, energy expenditure, and insulin secretion. However, if chronically elevated, they provoke inflammation, insulin resistance, and β-cell failure. Moreover, FFAs act via multiple signaling pathways as very potent regulators of gene expression. In human skeletal muscle cells differentiated in vitro (myotubes), we have shown in previous studies that the expression of CSF3, the gene encoding granulocyte colony-stimulating factor (G-CSF), is markedly induced upon FFA treatment and exercise. Methods and results We now report that CSF3 is induced in human myotubes by saturated, but not unsaturated, FFAs via Toll-like receptor 4-dependent and -independent pathways including activation of Rel-A, AP-1, C/EBPα, Src, and stress kinases. Furthermore, we show that human adipocytes and myotubes treated with G-CSF become insulin-resistant. In line with this, a functional polymorphism in the CSF3 gene affects adipose tissue- and whole-body insulin sensitivity and glucose tolerance in human subjects with elevated plasma FFA concentrations. Conclusion G-CSF emerges as a new player in FFA-induced insulin resistance and thus may be of interest as a target for prevention and treatment of type 2 diabetes.
CSF3, the gene encoding G-CSF, is induced in human myotubes by saturated, but not unsaturated, FFAs. CSF3 expression is induced via Toll-like receptor 4-dependent and -independent pathways. Human adipocytes and myotubes treated with G-CSF become insulin-resistant. A CSF3 SNP affects insulin sensitivity and glucose tolerance in human subjects with elevated plasma FFA concentrations. G-CSF emerges as a new player in FFA-induced insulin resistance.
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Machicao F, Peter A, Machann J, Königsrainer I, Böhm A, Lutz SZ, Heni M, Fritsche A, Schick F, Königsrainer A, Stefan N, Häring HU, Staiger H. Glucose-Raising Polymorphisms in the Human Clock Gene Cryptochrome 2 (CRY2) Affect Hepatic Lipid Content. PLoS One 2016; 11:e0145563. [PMID: 26726810 PMCID: PMC4699770 DOI: 10.1371/journal.pone.0145563] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 12/04/2015] [Indexed: 01/22/2023] Open
Abstract
Circadian rhythms govern vital functions. Their disruption provokes metabolic imbalance favouring obesity and type-2 diabetes. The aim of the study was to assess the role of clock genes in human prediabetes. To this end, genotype-phenotype associations of 121 common single nucleotide polymorphisms (SNPs) tagging ARNTL, ARNTL2, CLOCK, CRY1, CRY2, PER1, PER2, PER3, and TIMELESS were assessed in a study population of 1,715 non-diabetic individuals metabolically phenotyped by 5-point oral glucose tolerance tests. In subgroups, hyperinsulinaemic-euglycaemic clamps, intravenous glucose tolerance tests, and magnetic resonance imaging/spectroscopy were performed. None of the tested SNPs was associated with body fat content, insulin sensitivity, or insulin secretion. Four CRY2 SNPs were associated with fasting glycaemia, as reported earlier. Importantly, carriers of these SNPs’ minor alleles revealed elevated fasting glycaemia and, concomitantly, reduced liver fat content. In human liver tissue samples, CRY2 mRNA expression was directly associated with hepatic triglyceride content. Our data may point to CRY2 as a novel switch in hepatic fuel metabolism promoting triglyceride storage and, concomitantly, limiting glucose production. The anti-steatotic effects of the glucose-raising CRY2 alleles may explain why these alleles do not increase type-2 diabetes risk.
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Affiliation(s)
- Fausto Machicao
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
| | - Andreas Peter
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
| | - Jürgen Machann
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Diagnostic and Interventional Radiology, Section on Experimental Radiology, University Hospital Tübingen, Tübingen, Germany
| | - Ingmar Königsrainer
- Department of General, Visceral, and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany
| | - Anja Böhm
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
| | - Stefan Zoltan Lutz
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
| | - Martin Heni
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
| | - Andreas Fritsche
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
- Department of Internal Medicine, Division of Nutritional and Preventive Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Fritz Schick
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Diagnostic and Interventional Radiology, Section on Experimental Radiology, University Hospital Tübingen, Tübingen, Germany
| | - Alfred Königsrainer
- Department of General, Visceral, and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany
| | - Norbert Stefan
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
| | - Hans-Ulrich Häring
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
| | - Harald Staiger
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
- * E-mail:
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Kächele M, Hennige AM, Machann J, Hieronimus A, Lamprinou A, Machicao F, Schick F, Fritsche A, Stefan N, Nürnberg B, Häring HU, Staiger H. Variation in the Phosphoinositide 3-Kinase Gamma Gene Affects Plasma HDL-Cholesterol without Modification of Metabolic or Inflammatory Markers. PLoS One 2015; 10:e0144494. [PMID: 26658747 PMCID: PMC4675530 DOI: 10.1371/journal.pone.0144494] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Accepted: 11/19/2015] [Indexed: 01/22/2023] Open
Abstract
Objective Phosphoinositide 3-kinase γ (PI3Kγ) is a G-protein-coupled receptor-activated lipid kinase mainly expressed in leukocytes and cells of the cardiovascular system. PI3Kγ plays an important signaling role in inflammatory processes. Since subclinical inflammation is a hallmark of atherosclerosis, obesity-related insulin resistance, and pancreatic β-cell failure, we asked whether common genetic variation in the PI3Kγ gene (PIK3CG) contributes to body fat content/distribution, serum adipokine/cytokine concentrations, alterations in plasma lipid profiles, insulin sensitivity, insulin release, and glucose homeostasis. Study Design Using a tagging single nucleotide polymorphism (SNP) approach, we analyzed genotype-phenotype associations in 2,068 German subjects genotyped for 10 PIK3CG SNPs and characterized by oral glucose tolerance tests. In subgroups, data from hyperinsulinaemic-euglycaemic clamps, magnetic resonance spectroscopy of the liver, whole-body magnetic resonance imaging, and intravenous glucose tolerance tests were available, and peripheral blood mononuclear cells (PBMCs) were used for gene expression analysis. Results After appropriate adjustment, none of the PIK3CG tagging SNPs was significantly associated with body fat content/distribution, adipokine/cytokine concentrations, insulin sensitivity, insulin secretion, or blood glucose concentrations (p>0.0127, all; Bonferroni-corrected α-level: 0.0051). However, six non-linked SNPs displayed at least nominal associations with plasma HDL-cholesterol concentrations, two of them (rs4288294 and rs116697954) reaching the level of study-wide significance (p = 0.0003 and p = 0.0004, respectively). More precisely, rs4288294 and rs116697954 influenced HDL2-, but not HDL3-, cholesterol. With respect to the SNPs’ in vivo functionality, rs4288294 was significantly associated with PIK3CG mRNA expression in PBMCs. Conclusions We could demonstrate that common genetic variation in the PIK3CG locus, possibly via altered PIK3CG gene expression, determines plasma HDL-cholesterol concentrations. Since HDL2-, but not HDL3-, cholesterol is influenced by PIK3CG variants, PI3Kγ may play a role in HDL clearance rather than in HDL biogenesis. Even though the molecular pathways connecting PI3Kγ and HDL metabolism remain to be further elucidated, this finding could add a novel aspect to the pathophysiological role of PI3Kγ in atherogenesis.
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Affiliation(s)
- Martin Kächele
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
| | - Anita M. Hennige
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Tübingen, Germany
| | - Jürgen Machann
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Tübingen, Germany
- Department of Diagnostic and Interventional Radiology, Section on Experimental Radiology, University Hospital Tübingen, Tübingen, Germany
| | - Anja Hieronimus
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Tübingen, Germany
| | - Apostolia Lamprinou
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Tübingen, Germany
| | - Fausto Machicao
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Tübingen, Germany
| | - Fritz Schick
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Tübingen, Germany
- Department of Diagnostic and Interventional Radiology, Section on Experimental Radiology, University Hospital Tübingen, Tübingen, Germany
| | - Andreas Fritsche
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Nutritional and Preventive Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Norbert Stefan
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Tübingen, Germany
| | - Bernd Nürnberg
- Department of Experimental and Clinical Pharmacology and Toxicology, Division of Pharmacology and Experimental Therapy, University Hospital Tübingen, Tübingen, Germany
| | - Hans-Ulrich Häring
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Tübingen, Germany
| | - Harald Staiger
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Tübingen, Germany
- * E-mail:
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Ramos-Lopez O, Martinez-Lopez E, Roman S, Fierro NA, Panduro A. Genetic, metabolic and environmental factors involved in the development of liver cirrhosis in Mexico. World J Gastroenterol 2015; 21:11552-11566. [PMID: 26556986 PMCID: PMC4631960 DOI: 10.3748/wjg.v21.i41.11552] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 07/29/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis (LC) is a chronic illness caused by inflammatory responses and progressive fibrosis. Globally, the most common causes of chronic liver disease include persistent alcohol abuse, followed by viral hepatitis infections and nonalcoholic fatty liver disease. However, regardless of the etiological factors, the susceptibility and degree of liver damage may be influenced by genetic polymorphisms that are associated with distinct ethnic and cultural backgrounds. Consequently, metabolic genes are influenced by variable environmental lifestyle factors, such as diet, physical inactivity, and emotional stress, which are associated with regional differences among populations. This Topic Highlight will focus on the genetic and environmental factors that may influence the metabolism of alcohol and nutrients in the setting of distinct etiologies of liver disease. The interaction between genes and environment in the current-day admixed population, Mestizo and Native Mexican, will be described. Additionally, genes involved in immune regulation, insulin sensitivity, oxidative stress and extracellular matrix deposition may modulate the degree of severity. In conclusion, LC is a complex disease. The onset, progression, and clinical outcome of LC among the Mexican population are influenced by specific genetic and environmental factors. Among these are an admixed genome with a heterogenic distribution of European, Amerindian and African ancestry; a high score of alcohol consumption; viral infections; a hepatopathogenic diet; and a high prevalence of obesity. The variance in risk factors among populations suggests that intervention strategies directed towards the prevention and management of LC should be tailored according to such population-based features.
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Dietrich P, Hellerbrand C. Non-alcoholic fatty liver disease, obesity and the metabolic syndrome. Best Pract Res Clin Gastroenterol 2014; 28:637-53. [PMID: 25194181 DOI: 10.1016/j.bpg.2014.07.008] [Citation(s) in RCA: 314] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Revised: 06/25/2014] [Accepted: 07/05/2014] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is now recognized as the most common cause of chronic liver disease worldwide. Its prevalence has increased to more than 30% of adults in developed countries and its incidence is still rising. The majority of patients with NAFLD have simple steatosis but in up to one third of patients, NAFLD progresses to its more severe form nonalcoholic steatohepatitis (NASH). NASH is characterized by liver inflammation and injury thereby determining the risk to develop liver fibrosis and cancer. NAFLD is considered the hepatic manifestation of the metabolic syndrome. However, the liver is not only a passive target but affects the pathogenesis of the metabolic syndrome and its complications. Conversely, pathophysiological changes in other organs such as in the adipose tissue, the intestinal barrier or the immune system have been identified as triggers and promoters of NAFLD progression. This article details the pathogenesis of NAFLD along with the current state of its diagnosis and treatment.
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Affiliation(s)
- Peter Dietrich
- Institute of Pathology, University Regensburg, 93053 Regensburg, Germany
| | - Claus Hellerbrand
- Department of Internal Medicine I, University Hospital Regensburg, 93053 Regensburg, Germany.
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Lutz SZ, Franck O, Böhm A, Machann J, Schick F, Machicao F, Fritsche A, Häring HU, Staiger H. Common genetic variation in the human CTF1 locus, encoding cardiotrophin-1, determines insulin sensitivity. PLoS One 2014; 9:e100391. [PMID: 25025664 PMCID: PMC4099130 DOI: 10.1371/journal.pone.0100391] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 05/23/2014] [Indexed: 12/02/2022] Open
Abstract
Aims/Hypothesis Recently, cardiotrophin-1, a member of the interleukin-6 family of cytokines was described to protect beta-cells from apoptosis, to improve glucose-stimulated insulin secretion and insulin resistance, and to prevent streptozotocin-induced diabetes in mice. Here, we studied whether common single nucleotide polymorphisms (SNPs) in the CTF1 locus, encoding cardiotrophin-1, influence insulin secretion and insulin sensitivity in humans. Methods We genotyped 1,771 German subjects for three CTF1 tagging SNPs (rs1046276, rs1458201, and rs8046707). The subjects were metabolically characterized by an oral glucose tolerance test. Subgroups underwent magnetic resonance (MR) imaging/spectroscopy and hyperinsulinaemic-euglycaemic clamps. Results After appropriate adjustment, the minor allele of CTF1 SNP rs8046707 was significantly associated with decreased in vivo measures of insulin sensitivity. The other tested SNPs were not associated with OGTT-derived sensitivity parameters, nor did the three tested SNPs show any association with OGTT-derived parameters of insulin release. In the MR subgroup, SNP rs8046707 was nominally associated with lower visceral adipose tissue. Furthermore, the SNP rs1458201 showed a nominal association with increased VLDL levels. Conclusions In conclusion, this study, even though preliminary and awaiting further confirmation by independent replication, provides first evidence that common genetic variation in CTF1 could contribute to insulin sensitivity in humans. Our SNP data indicate an insulin-desensitizing effect of cardiotrophin-1 and underline that cardiotrophin-1 represents an interesting target to influence insulin sensitivity.
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Affiliation(s)
- Stefan Z. Lutz
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Tübingen, Germany
| | - Olga Franck
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
| | - Anja Böhm
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Tübingen, Germany
| | - Jürgen Machann
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Tübingen, Germany
- Department of Diagnostic and Interventional Radiology, Section on Experimental Radiology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Fritz Schick
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Tübingen, Germany
- Department of Diagnostic and Interventional Radiology, Section on Experimental Radiology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Fausto Machicao
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Tübingen, Germany
| | - Andreas Fritsche
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Nutritional and Preventive Medicine, University of Tübingen, Tübingen, Germany
| | - Hans-Ulrich Häring
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Tübingen, Germany
- * E-mail:
| | - Harald Staiger
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Tübingen, Germany
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Jung UJ, Choi MS. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci 2014; 15:6184-223. [PMID: 24733068 PMCID: PMC4013623 DOI: 10.3390/ijms15046184] [Citation(s) in RCA: 1291] [Impact Index Per Article: 117.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Revised: 03/27/2014] [Accepted: 04/01/2014] [Indexed: 02/06/2023] Open
Abstract
Accumulating evidence indicates that obesity is closely associated with an increased risk of metabolic diseases such as insulin resistance, type 2 diabetes, dyslipidemia and nonalcoholic fatty liver disease. Obesity results from an imbalance between food intake and energy expenditure, which leads to an excessive accumulation of adipose tissue. Adipose tissue is now recognized not only as a main site of storage of excess energy derived from food intake but also as an endocrine organ. The expansion of adipose tissue produces a number of bioactive substances, known as adipocytokines or adipokines, which trigger chronic low-grade inflammation and interact with a range of processes in many different organs. Although the precise mechanisms are still unclear, dysregulated production or secretion of these adipokines caused by excess adipose tissue and adipose tissue dysfunction can contribute to the development of obesity-related metabolic diseases. In this review, we focus on the role of several adipokines associated with obesity and the potential impact on obesity-related metabolic diseases. Multiple lines evidence provides valuable insights into the roles of adipokines in the development of obesity and its metabolic complications. Further research is still required to fully understand the mechanisms underlying the metabolic actions of a few newly identified adipokines.
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Affiliation(s)
- Un Ju Jung
- Center for Food and Nutritional Genomics Research, Kyungpook National University, 1370 Sankyuk Dong Puk-ku, Daegu 702-701, Korea.
| | - Myung-Sook Choi
- Center for Food and Nutritional Genomics Research, Kyungpook National University, 1370 Sankyuk Dong Puk-ku, Daegu 702-701, Korea.
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Impact of the adipokine adiponectin and the hepatokine fetuin-A on the development of type 2 diabetes: prospective cohort- and cross-sectional phenotyping studies. PLoS One 2014; 9:e92238. [PMID: 24643166 PMCID: PMC3958485 DOI: 10.1371/journal.pone.0092238] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Accepted: 02/20/2014] [Indexed: 01/20/2023] Open
Abstract
Background Among adipokines and hepatokines, adiponectin and fetuin-A were consistently found to predict the incidence of type 2 diabetes, both by regulating insulin sensitivity. Objective To determine to what extent circulating adiponectin and fetuin-A are independently associated with incident type 2 diabetes in humans, and the major mechanisms involved. Methods Relationships with incident diabetes were tested in two cohort studies: within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study (628 cases) and the Nurses' Health Study (NHS; 470 cases). Relationships with body fat compartments, insulin sensitivity and insulin secretion were studied in the Tübingen Lifestyle Intervention Program (TULIP; N = 358). Results Circulating adiponectin and fetuin-A, independently of several confounders and of each other, associated with risk of diabetes in EPIC-Potsdam (RR for 1 SD: adiponectin: 0.45 [95% CI 0.37–0.54], fetuin-A: 1.18 [1.05–1.32]) and the NHS (0.51 [0.42–0.62], 1.35 [1.16–1.58]). Obesity measures considerably attenuated the association of adiponectin, but not of fetuin-A. Subjects with low adiponectin and concomitantly high fetuin-A had the highest risk. Whereas both proteins were independently (both p<1.8×10−7) associated with insulin sensitivity, circulating fetuin-A (r = −0.37, p = 0.0004), but not adiponectin, associated with insulin secretion in subjects with impaired glucose tolerance. Conclusions We provide novel information that adiponectin and fetuin-A independently of each other associate with the diabetes risk. Furthermore, we suggest that they are involved in the development of type 2 diabetes via different mechanisms, possibly by mediating effects of their source tissues, expanded adipose tissue and nonalcoholic fatty liver.
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Single-nucleotide polymorphisms in adiponectin, AdipoR1, and AdipoR2 genes: insulin resistance and type 2 diabetes mellitus candidate genes. Am J Ther 2014; 20:414-21. [PMID: 23656997 DOI: 10.1097/mjt.0b013e318235f206] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
It has already been a decade and a half since the discovery of adiponectin and its role as an insulin sensitizer and only 7 years since its receptors, AdipoR1 and AdipoR2, were described. A single-nucleotide polymorphism (SNP) is a DNA sequence variation that affects only one nucleotide; it may vary from one population to another with different predisposing factors to diseases and other ailments. Once some of the effects of adiponectin and its receptors were known, it was not long until an effort was made to find the associations between specific SNPs of the genes of this hormone and its receptors as genetic risk factors for insulin resistance, type 2 diabetes mellitus, and metabolic syndrome, although these genes were investigated as possible candidates related to the development of these metabolic disorders. All of these possible associations were studied in different populations from France, Finland, the United Kingdom, North America, and Japan, showing hardly concluding results, and because of that it is highly controversial to directly associate one of the genes mentioned above to insulin resistance, type 2 diabetes mellitus, and metabolic syndrome. All of these inconsistencies lead to a review that summarizes the SNPs of the genes of adiponectin, AdipoR1, and AdipoR2 that are mostly related to insulin resistance syndrome, type 2 diabetes mellitus, and metabolic syndrome, although presenting the possible factors that should be taken into account to homogenize the results obtained until now.
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Lustig Y, Barhod E, Ashwal-Fluss R, Gordin R, Shomron N, Baruch-Umansky K, Hemi R, Karasik A, Kanety H. RNA-binding protein PTB and microRNA-221 coregulate AdipoR1 translation and adiponectin signaling. Diabetes 2014; 63:433-45. [PMID: 24130336 DOI: 10.2337/db13-1032] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Adiponectin receptor 1 (AdipoR1) mediates adiponectin's pleiotropic effects in muscle and liver and plays an important role in the regulation of insulin resistance and diabetes. Here, we demonstrate a pivotal role for microRNA-221 (miR-221) and the RNA-binding protein polypyrimidine tract-binding protein (PTB) in posttranscriptional regulation of AdipoR1 during muscle differentiation and in obesity. RNA-immunoprecipitation and luciferase reporter assays illustrated that both PTB and miR-221 bind AdipoR1-3'UTR and cooperatively inhibit AdipoR1 translation. Depletion of PTB or miR-221 increased, while overexpression of these factors decreased, AdipoR1 protein synthesis in both muscle and liver cells. During myogenesis, downregulation of PTB and miR-221 robustly induced AdipoR1 translation, providing a mechanism for enhanced AdipoR1 protein expression and activation in differentiated muscle cells. In addition, since both PTB and miR-221 are upregulated in liver and muscle of genetic and dietary mouse models of obesity, this novel translational mechanism may be at least partly responsible for the reduction in AdipoR1 protein levels in obesity. These findings highlight the importance of translational control in regulating AdipoR1 protein expression and adiponectin signaling. Given that adiponectin is reduced in obesity, induction of AdipoR1 could potentially enhance adiponectin beneficial effects and ameliorate insulin resistance and diabetes.
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Affiliation(s)
- Yaniv Lustig
- Institute of Endocrinology, Chaim Sheba Medical Center, Tel-Hashomer, Israel
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Tao C, Sifuentes A, Holland WL. Regulation of glucose and lipid homeostasis by adiponectin: effects on hepatocytes, pancreatic β cells and adipocytes. Best Pract Res Clin Endocrinol Metab 2014; 28:43-58. [PMID: 24417945 PMCID: PMC4455885 DOI: 10.1016/j.beem.2013.11.003] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Adiponectin has received considerable attention for its potential anti-diabetic actions. The adipokine exerts control of glucose and lipid homeostasis via critical effects within the liver, adipose, and pancreas. By stimulating adipogenesis, opposing inflammation, and influencing rates of lipid oxidation and lipolysis, adiponectin critically governs lipid spillover into non-adipose tissues. Ceramide, a cytotoxic and insulin desensitizing lipid metabolite formed when peripheral tissues are exposed to excessive lipid deposition, is potently opposed by adiponectin. Via adiponectin receptors, AdipoR1 and AdipoR2, adiponectin stimulates the deacylation of ceramide- yielding sphingosine for conversion to sphingosine 1-phosphate (S1P) by sphingosine kinase. The resulting conversion from ceramide to S1P promotes survival of functional beta cell mass, allowing for insulin production to meet insulin demands. Alleviation of ceramide burden on the liver allows for improvements in hepatic insulin action. Here, we summarize how adiponectin-induced changes in these tissues lead to improvements in glucose metabolism, highlighting the sphingolipid signaling mechanisms linking adiponectin to each action. ONE SENTENCE SUMMARY: We review the anti-diabetic actions of adiponectin.
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Affiliation(s)
- Caroline Tao
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA
| | - Angelica Sifuentes
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA
| | - William L Holland
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA.
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