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Iessi IL, Dallaqua B, Sinzato YK, Gallego FQ, Nielsen JH, Volpato GT, Corrente JE, Damasceno DC. Maternal diabetes on fetal endocrine pancreas development in rats. AN ACAD BRAS CIENC 2025; 97:e20240807. [PMID: 40136201 DOI: 10.1590/0001-3765202520240807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 10/27/2024] [Indexed: 03/27/2025] Open
Abstract
To evaluate if an unfavorable maternal environment induced by hyperglycemia, hypoxia, and oxidative stress status impairs the morphological development of pancreatic islets in the fetuses on days 18 and 21 of pregnancy. Wistar rats were injected with streptozotocin for diabetes induction. At adulthood (3 months), all animals underwent an oral glucose tolerance test (OGTT) for glucose assessment as an inclusion criterion. Following, the animals were mated. On day 18 and 21 of pregnancy, the mothers were killed for blood biochemical data and, fetal pancreas was collected for immunohistochemical analysis. On the GD18/21, the diabetic (D) dams showed higher glycemia, erythropoietin and TBARS levels, and a disorganized cell distribution in fetal pancreatic islets compared to control (C) rat mothers. The fetal endocrine pancreas of D dams presented a higher ratio of insulin-stained cells on GD18. No difference in the immunostaining for PDX-1 was observed. Fetuses of D dams showed a lower ratio of cells immunostained for Ki-67 in GD18 and greater cell proliferation in GD21. At the GD21, the D group showed a higher ratio of cells undergoing apoptosis. Maternal hyperglycemia impairs fetal pancreatic islet structure, which causes functional changes contributing to fetal hyperglycemia at birth.
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Affiliation(s)
- Isabela L Iessi
- Universidade Estadual Paulista - UNESP, Programa de Pós-Graduação em Tocoginecologia, Faculdade de Medicina de Botucatu, Laboratório de pesquisa Experimental em Ginecologia e Obstetrícia, Unidade de Pesquisa Experimental - UNIPEX, s/n, Jardim Dona Marta (Rubião Junior), 18610-879 Botucatu, SP, Brazil
| | - Bruna Dallaqua
- Universidade Estadual Paulista - UNESP, Programa de Pós-Graduação em Tocoginecologia, Faculdade de Medicina de Botucatu, Laboratório de pesquisa Experimental em Ginecologia e Obstetrícia, Unidade de Pesquisa Experimental - UNIPEX, s/n, Jardim Dona Marta (Rubião Junior), 18610-879 Botucatu, SP, Brazil
| | - Yuri K Sinzato
- Universidade Estadual Paulista - UNESP, Programa de Pós-Graduação em Tocoginecologia, Faculdade de Medicina de Botucatu, Laboratório de pesquisa Experimental em Ginecologia e Obstetrícia, Unidade de Pesquisa Experimental - UNIPEX, s/n, Jardim Dona Marta (Rubião Junior), 18610-879 Botucatu, SP, Brazil
| | - Franciane Q Gallego
- Universidade Estadual Paulista - UNESP, Programa de Pós-Graduação em Tocoginecologia, Faculdade de Medicina de Botucatu, Laboratório de pesquisa Experimental em Ginecologia e Obstetrícia, Unidade de Pesquisa Experimental - UNIPEX, s/n, Jardim Dona Marta (Rubião Junior), 18610-879 Botucatu, SP, Brazil
| | - Jens H Nielsen
- University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Nørregade 10, PO Box 2177, Denmark
| | - Gustavo T Volpato
- Universidade Federal de Mato Grosso - UFMT, Laboratório de Fisiologia de Sistemas e Toxicologia Reprodutiva, Av. Valdon Varjão, 6390, 78698-000 Barra do Garças, MT, Brazil
| | - José E Corrente
- Universidade Estadual Paulista - UNESP, Faculdade de Medicina de Botucatu, Escritório de Apoio à Pesquisa - EAP, s/n, Jardim Dona Marta (Rubião Junior), 18610-879 Botucatu, SP, Brazil
| | - Débora C Damasceno
- Universidade Estadual Paulista - UNESP, Programa de Pós-Graduação em Tocoginecologia, Faculdade de Medicina de Botucatu, Laboratório de pesquisa Experimental em Ginecologia e Obstetrícia, Unidade de Pesquisa Experimental - UNIPEX, s/n, Jardim Dona Marta (Rubião Junior), 18610-879 Botucatu, SP, Brazil
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Bonnefond A, Florez JC, Loos RJF, Froguel P. Dissection of type 2 diabetes: a genetic perspective. Lancet Diabetes Endocrinol 2025; 13:149-164. [PMID: 39818223 DOI: 10.1016/s2213-8587(24)00339-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 09/11/2024] [Accepted: 10/30/2024] [Indexed: 01/18/2025]
Abstract
Diabetes is a leading cause of global mortality and disability, and its economic burden is substantial. This Review focuses on type 2 diabetes, which makes up 90-95% of all diabetes cases. Type 2 diabetes involves a progressive loss of insulin secretion often alongside insulin resistance and metabolic syndrome. Although obesity and a sedentary lifestyle are considerable contributors, research over the last 25 years has shown that type 2 diabetes develops on a predisposing genetic background, with family and twin studies indicating considerable heritability (ie, 31-72%). This Review explores type 2 diabetes from a genetic perspective, highlighting insights into its pathophysiology and the implications for precision medicine. More specifically, the traditional understanding of type 2 diabetes genetics has focused on a dichotomy between monogenic and polygenic forms. However, emerging evidence suggests a continuum that includes monogenic, oligogenic, and polygenic contributions, revealing their complementary roles in type 2 diabetes pathophysiology. Recent genetic studies provide deeper insights into disease mechanisms and pave the way for precision medicine approaches that could transform type 2 diabetes management. Additionally, the effect of environmental factors on type 2 diabetes, particularly from epigenetic modifications, adds another layer of complexity to understanding and addressing this multifaceted disease.
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Affiliation(s)
- Amélie Bonnefond
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Department of Metabolism, Imperial College London, London, UK.
| | - Jose C Florez
- Center for Genomic Medicine and Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Programs in Metabolism and Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Ruth J F Loos
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Philippe Froguel
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Department of Metabolism, Imperial College London, London, UK.
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Chen HJ, Hu Y, Ma JH. Relationship between imaging changes of the pancreas and islet beta-cell function. World J Radiol 2024; 16:717-721. [PMID: 39801662 PMCID: PMC11718522 DOI: 10.4329/wjr.v16.i12.717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 11/21/2024] [Accepted: 12/20/2024] [Indexed: 12/27/2024] Open
Abstract
Imaging changes in the pancreas can provide valuable information about the status of islet beta-cell function in different pancreatic diseases, such as diabetes, pancreatitis, pancreatic cancer, fatty pancreas, and insulinoma. While imaging cannot directly measure beta-cell function; it can be used as a marker of disease progression and a tool to guide therapeutic interventions. As imaging technologies continue to advance, they will likely play an increasingly important role in diagnosing, monitoring, and managing diabetes.
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Affiliation(s)
- Hong-Jing Chen
- Department of Endocrinology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi 214000, Jiangsu Province, China
| | - Yun Hu
- Department of Endocrinology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi 214000, Jiangsu Province, China
| | - Jian-Hua Ma
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210000, Jiangsu Province, China
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Rivara AC, Russell EM, Carlson JC, Pomer A, Naseri T, Reupena MS, Manna SL, Viali S, Minster RL, Weeks DE, DeLany JP, Kershaw EE, McGarvey ST, Hawley NL. Associations between fasting glucose rate-of-change and the missense variant, rs373863828, in an adult Samoan cohort. PLoS One 2024; 19:e0302643. [PMID: 38829901 PMCID: PMC11146712 DOI: 10.1371/journal.pone.0302643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 04/09/2024] [Indexed: 06/05/2024] Open
Abstract
BACKGROUND The A allele of rs373863828 in CREB3 regulatory factor is associated with high Body Mass Index, but lower odds of type 2 diabetes. These associations have been replicated elsewhere, but to date all studies have been cross-sectional. Our aims were (1) to describe the development of type 2 diabetes and change in fasting glucose between 2010 and 2018 among a longitudinal cohort of adult Samoans without type 2 diabetes or who were not using diabetes medications at baseline, and (2) to examine associations between fasting glucose rate-of-change (mmol/L per year) and the A allele of rs373863828. METHODS We describe and test differences in fasting glucose, the development of type 2 diabetes, body mass index, age, smoking status, physical activity, urbanicity of residence, and household asset scores between 2010 and 2018 among a cohort of n = 401 adult Samoans, selected to have a ~2:2:1 ratio of GG:AG: AA rs373863828 genotypes. Multivariate linear regression was used to test whether fasting glucose rate-of-change was associated with rs373863828 genotype, and other baseline variables. RESULTS By 2018, fasting glucose and BMI significantly increased among all genotype groups, and a substantial portion of the sample developed type 2 diabetes mellitus. The A allele was associated with a lower fasting glucose rate-of-change (β = -0.05 mmol/L/year per allele, p = 0.058 among women; β = -0.004 mmol/L/year per allele, p = 0.863 among men), after accounting for baseline variables. Mean fasting glucose and mean BMI increased over an eight-year period and a substantial number of individuals developed type 2 diabetes by 2018. However, fasting glucose rate-of-change, and type 2 diabetes development was lower among females with AG and AA genotypes. CONCLUSIONS Further research is needed to understand the effect of the A allele on fasting glucose and type 2 diabetes development. Based on our observations that other risk factors increased over time, we advocate for the continued promotion for diabetes prevention and treatment programming, and the reduction of modifiable risk factors, in this setting.
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Affiliation(s)
- Anna C. Rivara
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, United States of America
| | - Emily M. Russell
- Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Jenna C. Carlson
- Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States of America
- Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Alysa Pomer
- Center of Surgery and Public Health, Brigham and Women’s Hospital, Boston, MA, United States of America
| | - Take Naseri
- Family Health Clinic, Apia, Samoa
- Naseri & Associates Health Consultancy Firm, Apia, Samoa
| | | | - Samantha L. Manna
- Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States of America
- Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Satupaitea Viali
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, United States of America
- Oceania University of Medicine, Apia, Samoa
| | - Ryan L. Minster
- Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Daniel E. Weeks
- Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States of America
- Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - James P. DeLany
- Advent Health Orlando, Translational Research Institute, Orlando, FL, United States of America
| | - Erin E. Kershaw
- Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Stephen T. McGarvey
- Department of Epidemiology, International Health Institute, School of Public Health, Brown University, Providence, RI, United States of America
- Department of Anthropology, Brown University, Providence, RI, United States of America
| | - Nicola L. Hawley
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, United States of America
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Kim DS, Song L, Gou W, Kim J, Liu B, Wei H, Muise-Helmericks RC, Li Z, Wang H. GRP94 is an IGF-1R chaperone and regulates beta cell death in diabetes. Cell Death Dis 2024; 15:374. [PMID: 38811543 PMCID: PMC11137047 DOI: 10.1038/s41419-024-06754-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 05/10/2024] [Accepted: 05/16/2024] [Indexed: 05/31/2024]
Abstract
High workload-induced cellular stress can cause pancreatic islet β cell death and dysfunction, or β cell failure, a hallmark of type 2 diabetes mellitus. Thus, activation of molecular chaperones and other stress-response genes prevents β cell failure. To this end, we have shown that deletion of the glucose-regulated protein 94 (GRP94) in Pdx1+ pancreatic progenitor cells led to pancreas hypoplasia and reduced β cell mass during pancreas development in mice. Here, we show that GRP94 was involved in β cell adaption and compensation (or failure) in islets from leptin receptor-deficient (db/db) mice in an age-dependent manner. GRP94-deficient cells were more susceptible to cell death induced by various diabetogenic stress conditions. We also identified a new client of GRP94, insulin-like growth factor-1 receptor (IGF-1R), a critical factor for β cell survival and function that may mediate the effect of GRP94 in the pathogenesis of diabetes. This study has identified essential functions of GRP94 in β cell failure related to diabetes.
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Affiliation(s)
- Do-Sung Kim
- Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Lili Song
- Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Wenyu Gou
- Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Jisun Kim
- Microbiology and Immunology, Medical University of South Carolina, Charleson, SC, 29425, USA
| | - Bei Liu
- Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center-James, Columbus, OH, 43210, USA
| | - Hua Wei
- Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Robin C Muise-Helmericks
- Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Zihai Li
- Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center-James, Columbus, OH, 43210, USA
| | - Hongjun Wang
- Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA.
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA.
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Janssen JAMJL. Overnutrition, Hyperinsulinemia and Ectopic Fat: It Is Time for A Paradigm Shift in the Management of Type 2 Diabetes. Int J Mol Sci 2024; 25:5488. [PMID: 38791525 PMCID: PMC11121669 DOI: 10.3390/ijms25105488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 05/12/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024] Open
Abstract
The worldwide incidence of prediabetes/type 2 has continued to rise the last 40 years. In the same period, the mean daily energy intake has increased, and the quality of food has significantly changed. The chronic exposure of pancreatic β-cells to calorie excess (excessive energy intake) and food additives may increase pancreatic insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing chronic hyperinsulinemia and peripheral insulin resistance. Chronic calorie excess and hyperinsulinemia may promote lipogenesis, inhibit lipolysis and increase lipid storage in adipocytes. In addition, calorie excess and hyperinsulinemia can induce insulin resistance and contribute to progressive and excessive ectopic fat accumulation in the liver and pancreas by the conversion of excess calories into fat. The personal fat threshold hypothesis proposes that in susceptible individuals, excessive ectopic fat accumulation may eventually lead to hepatic insulin receptor resistance, the loss of pancreatic insulin secretion, hyperglycemia and the development of frank type 2 diabetes. Thus, type 2 diabetes seems (partly) to be caused by hyperinsulinemia-induced excess ectopic fat accumulation in the liver and pancreas. Increasing evidence further shows that interventions (hypocaloric diet and/or bariatric surgery), which remove ectopic fat in the liver and pancreas by introducing a negative energy balance, can normalize insulin secretion and glucose tolerance and induce the sustained biochemical remission of type 2 diabetes. This pathophysiological insight may have major implications and may cause a paradigm shift in the management of type 2 diabetes: avoiding/reducing ectopic fat accumulation in the liver and pancreas may both be essential to prevent and cure type 2 diabetes.
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Affiliation(s)
- Joseph A M J L Janssen
- Department of Internal Medicine, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands
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Lu Y, Tian H, Peng H, Wang Q, Bunnell BA, Bazan NG, Hong S. Novel lipid mediator 7 S,14 R-docosahexaenoic acid: biogenesis and harnessing mesenchymal stem cells to ameliorate diabetic mellitus and retinal pericyte loss. Front Cell Dev Biol 2024; 12:1380059. [PMID: 38533089 PMCID: PMC10963555 DOI: 10.3389/fcell.2024.1380059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 02/29/2024] [Indexed: 03/28/2024] Open
Abstract
Introduction: Stem cells can be used to treat diabetic mellitus and complications. ω3-docosahexaenoic acid (DHA) derived lipid mediators are inflammation-resolving and protective. This study found novel DHA-derived 7S,14R-dihydroxy-4Z,8E,10Z,12E,16Z,19Z-docosahexaenoic acid (7S,14R-diHDHA), a maresin-1 stereoisomer biosynthesized by leukocytes and related enzymes. Moreover, 7S,14R-diHDHA can enhance mesenchymal stem cell (MSC) functions in the amelioration of diabetic mellitus and retinal pericyte loss in diabetic db/db mice. Methods: MSCs treated with 7S,14R-diHDHA were delivered into db/db mice i.v. every 5 days for 35 days. Results: Blood glucose levels in diabetic mice were lowered by 7S,14R-diHDHA-treated MSCs compared to control and untreated MSC groups, accompanied by improved glucose tolerance and higher blood insulin levels. 7S,14R-diHDHA-treated MSCs increased insulin+ β-cell ratio and decreased glucogan+ α-cell ratio in islets, as well as reduced macrophages in pancreas. 7S,14R-diHDHA induced MSC functions in promoting MIN6 β-cell viability and insulin secretion. 7S,14R-diHDHA induced MSC paracrine functions by increasing the generation of hepatocyte growth factor and vascular endothelial growth factor. Furthermore, 7S,14R-diHDHA enhanced MSC functions to ameliorate diabetes-caused pericyte loss in diabetic retinopathy by increasing their density in retina in db/db mice. Discussion: Our findings provide a novel strategy for improving therapy for diabetes and diabetic retinopathy using 7S,14R-diHDHA-primed MSCs.
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Affiliation(s)
- Yan Lu
- Neuroscience Center of Excellence, School of Medicine, L.S.U. Health, New Orleans, LA, United States
| | - Haibin Tian
- Neuroscience Center of Excellence, School of Medicine, L.S.U. Health, New Orleans, LA, United States
- Tongji University, Shanghai, China
| | - Hongying Peng
- Biostatistics, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Quansheng Wang
- Neuroscience Center of Excellence, School of Medicine, L.S.U. Health, New Orleans, LA, United States
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Bruce A. Bunnell
- Tulane University School of Medicine, Center for Stem Cell Research and Regenerative Medicine, New Orleans, LA, United States
| | - Nicolas G. Bazan
- Neuroscience Center of Excellence, School of Medicine, L.S.U. Health, New Orleans, LA, United States
- Department of Ophthalmology, School of Medicine, L.S.U. Health, New Orleans, LA, United States
| | - Song Hong
- Neuroscience Center of Excellence, School of Medicine, L.S.U. Health, New Orleans, LA, United States
- Department of Ophthalmology, School of Medicine, L.S.U. Health, New Orleans, LA, United States
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Mohammadnia N, Los J, Opstal TSJ, Fiolet ATL, Eikelboom JW, Mosterd A, Nidorf SM, Budgeon CA, Tijssen JGP, Thompson PL, Tack CJ, Simsek S, Bax WA, Cornel JH, El Messaoudi S. Colchicine and diabetes in patients with chronic coronary artery disease: insights from the LoDoCo2 randomized controlled trial. Front Cardiovasc Med 2023; 10:1244529. [PMID: 37868776 PMCID: PMC10587438 DOI: 10.3389/fcvm.2023.1244529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 09/12/2023] [Indexed: 10/24/2023] Open
Abstract
Introduction Despite optimal treatment, patients with chronic coronary artery disease (CAD) and diabetes mellitus (DM) are at high risk of cardiovascular events, emphasizing the need for new treatment options. The Low-Dose Colchicine 2 (LoDoCo2) trial demonstrated that colchicine reduces cardiovascular risk in patients with chronic CAD. This analysis determines the efficacy of colchicine in patients with chronic CAD and DM as well as the effect of colchicine on the development of new-onset type 2 diabetes mellitus (T2DM). Methods The LoDoCo2 trial randomized 5,522 patients to placebo or colchicine 0.5 mg once daily, with a median follow-up of 28.6 months. The primary composite endpoint was cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven revascularization. The effect of its treatment in patients with and without DM was evaluated by including an interaction term in the model. Results A total of 1,007 participants (18.2%) had T2DM at baseline. The adjusted hazard ratio (HR) [(95% confidence interval (CI)] for the primary endpoint in the T2DM group was 1.52 (1.15-2.01, p < 0.01) compared with the group without T2DM. The HR for the treatment effect on the primary endpoint was 0.87 (0.61-1.25) in participants with T2DM and 0.64 (0.51-0.80) in participants without diabetes (pinteraction = 0.14). The incidence of new-onset T2DM was 1.5% (34 out of 2,270) in the colchicine group and 2.2% (49 out of 2,245) in the placebo group (p = 0.10). Discussion In conclusion, based on the current evidence, the beneficial effects of colchicine on cardiovascular endpoints are consistent regardless of DM status. The potential benefits of colchicine in preventing new-onset DM need further investigation. These findings are only hypothesis-generating and require larger prospective trials to confirm the results.
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Affiliation(s)
| | - Jan Los
- Department of Cardiology, Radboudumc, Nijmegen, Netherlands
| | - Tjerk S. J. Opstal
- Department of Cardiology, Radboudumc, Nijmegen, Netherlands
- Department of Cardiology, Northwest Clinics, Alkmaar, Netherlands
| | - Aernoud T. L. Fiolet
- Department of Cardiology, University Medical Center Utrecht, Utrecht, Netherlands
- Dutch Network for Cardiovascular Research (WCN), Utrecht, Netherlands
| | | | - Arend Mosterd
- Dutch Network for Cardiovascular Research (WCN), Utrecht, Netherlands
- Department of Cardiology, Meander Medical Center, Amersfoort, Netherlands
| | - Stefan M. Nidorf
- Heart and Vascular Research Institute of Western Australia, Perth, WA, Australia
- GenesisCare Western Australia, Perth, WA, Australia
| | - Charley A. Budgeon
- School of Medicine, University of Western Australia, Perth, WA, Australia
| | - Jan G. P. Tijssen
- Department of Cardiology, Amsterdam University Medical Centers, Amsterdam, Netherlands
- Cardialysis BV, Rotterdam, Netherlands
| | - Peter L. Thompson
- Heart and Vascular Research Institute of Western Australia, Perth, WA, Australia
- School of Medicine, University of Western Australia, Perth, WA, Australia
- Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - Cees J. Tack
- Department of Internal Medicine, Radboudumc, Nijmegen, Netherlands
| | - Suat Simsek
- Department of Internal Medicine, Northwest Clinics, Alkmaar, Netherlands
- Department of Internal Medicine, Amsterdam University Medical Centers, Amsterdam, Netherlands
| | - Willem A. Bax
- Department of Internal Medicine, Northwest Clinics, Alkmaar, Netherlands
| | - Jan H. Cornel
- Department of Cardiology, Radboudumc, Nijmegen, Netherlands
- Department of Cardiology, Northwest Clinics, Alkmaar, Netherlands
- Dutch Network for Cardiovascular Research (WCN), Utrecht, Netherlands
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Kurian J, Mavathur Nanjundaiah R. Reinstating acute-phase insulin release among sedentary adults at high risk for type 2 diabetes with Yoga and Walking based lifestyle modification. J Bodyw Mov Ther 2023; 36:300-306. [PMID: 37949576 DOI: 10.1016/j.jbmt.2023.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 07/19/2023] [Accepted: 08/15/2023] [Indexed: 11/12/2023]
Abstract
BACKGROUND We compared the impact of 2 lifestyle modifying physical activities, yoga (YBLM) or walking (WBLM) on impaired beta cell function (IBF) or insulin resistance (IR) in restoring acute phase insulin release (APIR) among prediabetes at high risk for type 2 diabetes (HRDM). METHOD Male and female adults (N = 42, 38.1 ± 4.8 years) with abdominal obesity (Male:103 ± 8.1 cm) Female: 92 ± 11.1 cm), randomized into YBLM (n = 20) and WBLM (n = 22), were monitored for the practice of the intervention, 45 min a day/5 days a week for 12 weeks. Blood sample was collected at 0th minute to estimate the level of Fasting Blood Glucose (FBG), Sr. Insulin and lipid profile and at 10th minute (APIR). IBF, IR and sensitivity (IS) reading were checked in HOMA-2 calculator. RESULT Wilcoxon sign rank t-test denoted an improved APIR among the subjects with IBF (p = 0.008) and not among the subjects with IR (p = 0.332). However, regression analysis yielded an improved APIR among subjects with IBF (F(1,10) = 7.816, p = 0.002) with the management of body weight and lipid profile and IR (F(1,13) = 17.003, p = 0.001) being found influenced with selected lipid components. In all, during the post assessment period, an impressive boost in APIR was manifested among people shifted to Normoglycemia (n = 14, 35.9%). CONCLUSION Intriguingly, we postulate the potential role of YBLM over WBLM in the management of lipid profile and body weight on accelerating APIR either through improved Beta cell compensation or by sensitizing skeletal muscles regulating IR, helping improve glucose tolerance resulting in either remission or management of prediabetes.
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Affiliation(s)
- Jintu Kurian
- Division of Yoga and Life Sciences, Swami Vivekananda Yoga Anusandhana Samsthana (S-VYASA), Jigani, Bangalore, 560105, India.
| | - Ramesh Mavathur Nanjundaiah
- Division of Yoga and Life Sciences, Swami Vivekananda Yoga Anusandhana Samsthana (S-VYASA), Jigani, Bangalore, 560105, India.
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Ferreira G, Santander A, Cardozo R, Chavarría L, Domínguez L, Mujica N, Benítez M, Sastre S, Sobrevia L, Nicolson GL. Nutrigenomics of inward rectifier potassium channels. Biochim Biophys Acta Mol Basis Dis 2023:166803. [PMID: 37406972 DOI: 10.1016/j.bbadis.2023.166803] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 06/27/2023] [Accepted: 06/30/2023] [Indexed: 07/07/2023]
Abstract
Inwardly rectifying potassium (Kir) channels play a key role in maintaining the resting membrane potential and supporting potassium homeostasis. There are many variants of Kir channels, which are usually tetramers in which the main subunit has two trans-membrane helices attached to two N- and C-terminal cytoplasmic tails with a pore-forming loop in between that contains the selectivity filter. These channels have domains that are strongly modulated by molecules present in nutrients found in different diets, such as phosphoinositols, polyamines and Mg2+. These molecules can impact these channels directly or indirectly, either allosterically by modulation of enzymes or via the regulation of channel expression. A particular type of these channels is coupled to cell metabolism and inhibited by ATP (KATP channels, essential for insulin release and for the pathogenesis of metabolic diseases like diabetes mellitus). Genomic changes in Kir channels have a significant impact on metabolism, such as conditioning the nutrients and electrolytes that an individual can take. Thus, the nutrigenomics of ion channels is an important emerging field in which we are attempting to understand how nutrients and diets can affect the activity and expression of ion channels and how genomic changes in such channels may be the basis for pathological conditions that limit nutrition and electrolyte intake. In this contribution we briefly review Kir channels, discuss their nutrigenomics, characterize how different components in the diet affect their function and expression, and suggest how their genomic changes lead to pathological phenotypes that affect diet and electrolyte intake.
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Affiliation(s)
- Gonzalo Ferreira
- Laboratory of Ion Channels, Biological Membranes and Cell Signaling, Dept. of Biophysics, Facultad de Medicina, CP 11800, Universidad de la Republica, Montevideo, Uruguay.
| | - Axel Santander
- Laboratory of Ion Channels, Biological Membranes and Cell Signaling, Dept. of Biophysics, Facultad de Medicina, CP 11800, Universidad de la Republica, Montevideo, Uruguay
| | - Romina Cardozo
- Laboratory of Ion Channels, Biological Membranes and Cell Signaling, Dept. of Biophysics, Facultad de Medicina, CP 11800, Universidad de la Republica, Montevideo, Uruguay
| | - Luisina Chavarría
- Laboratory of Ion Channels, Biological Membranes and Cell Signaling, Dept. of Biophysics, Facultad de Medicina, CP 11800, Universidad de la Republica, Montevideo, Uruguay
| | - Lucía Domínguez
- Laboratory of Ion Channels, Biological Membranes and Cell Signaling, Dept. of Biophysics, Facultad de Medicina, CP 11800, Universidad de la Republica, Montevideo, Uruguay
| | - Nicolás Mujica
- Laboratory of Ion Channels, Biological Membranes and Cell Signaling, Dept. of Biophysics, Facultad de Medicina, CP 11800, Universidad de la Republica, Montevideo, Uruguay
| | - Milagros Benítez
- Laboratory of Ion Channels, Biological Membranes and Cell Signaling, Dept. of Biophysics, Facultad de Medicina, CP 11800, Universidad de la Republica, Montevideo, Uruguay
| | - Santiago Sastre
- Laboratory of Ion Channels, Biological Membranes and Cell Signaling, Dept. of Biophysics, Facultad de Medicina, CP 11800, Universidad de la Republica, Montevideo, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo CP 11800, Uruguay
| | - Luis Sobrevia
- Cellular and Molecular Physiology Laboratory (CMPL), Department of Obstetrics, Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Department of Physiology, Faculty of Pharmacy, Universidad de Sevilla, Seville E-41012, Spain; Medical School (Faculty of Medicine), Sao Paulo State University (UNESP), Brazil; University of Queensland, Centre for Clinical Research (UQCCR), Faculty of Medicine and Biomedical Sciences, University of Queensland, Herston, 4029, Queensland, Australia; Tecnologico de Monterrey, Eutra, The Institute for Obesity Research (IOR), School of Medicine and Health Sciences, Monterrey, Nuevo León, Mexico
| | - Garth L Nicolson
- Department of Molecular Pathology, The Institute for Molecular Medicine, Huntington Beach, CA, USA
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11
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Jain C, Bilekova S, Lickert H. Targeting pancreatic β cells for diabetes treatment. Nat Metab 2022; 4:1097-1108. [PMID: 36131204 DOI: 10.1038/s42255-022-00618-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 07/13/2022] [Indexed: 11/09/2022]
Abstract
Insulin is a life-saving drug for patients with type 1 diabetes; however, even today, no pharmacotherapy can prevent the loss or dysfunction of pancreatic insulin-producing β cells to stop or reverse disease progression. Thus, pancreatic β cells have been a main focus for cell-replacement and regenerative therapies as a curative treatment for diabetes. In this Review, we highlight recent advances toward the development of diabetes therapies that target β cells to enhance proliferation, redifferentiation and protection from cell death and/or enable selective killing of senescent β cells. We describe currently available therapies and their mode of action, as well as insufficiencies of glucagon-like peptide 1 (GLP-1) and insulin therapies. We discuss and summarize data collected over the last decades that support the notion that pharmacological targeting of β cell insulin signalling might protect and/or regenerate β cells as an improved treatment of patients with diabetes.
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Affiliation(s)
- Chirag Jain
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Immunology Discovery, Genentech Inc., South San Francisco, CA, USA
| | - Sara Bilekova
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Heiko Lickert
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany.
- German Center for Diabetes Research (DZD), Neuherberg, Germany.
- Chair of β-Cell Biology, Technische Universität München, School of Medicine, Klinikum Rechts der Isar, München, Germany.
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12
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Li JH, Florez JC. On the Verge of Precision Medicine in Diabetes. Drugs 2022; 82:1389-1401. [PMID: 36123514 PMCID: PMC9531144 DOI: 10.1007/s40265-022-01774-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/29/2022] [Indexed: 11/03/2022]
Abstract
The epidemic of type 2 diabetes (T2D) is a significant global public health challenge and a major cause of morbidity and mortality. Despite the recent proliferation of pharmacological agents for the treatment of T2D, current therapies simply treat the symptom, i.e. hyperglycemia, and do not directly address the underlying disease process or modify the disease course. This article summarizes how genomic discovery has contributed to unraveling the heterogeneity in T2D, reviews relevant discoveries in the pharmacogenetics of five commonly prescribed glucose-lowering agents, presents evidence supporting how pharmacogenetics can be leveraged to advance precision medicine, and calls attention to important research gaps to its implementation to guide treatment choices.
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Affiliation(s)
- Josephine H Li
- Center for Genomic Medicine and Diabetes Unit, Massachusetts General Hospital, Simches Research Building, CPZN 5.250, 185 Cambridge St, Boston, MA, 02114, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Jose C Florez
- Center for Genomic Medicine and Diabetes Unit, Massachusetts General Hospital, Simches Research Building, CPZN 5.250, 185 Cambridge St, Boston, MA, 02114, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, USA.
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
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13
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Rout M, Kour B, Vuree S, Lulu SS, Medicherla KM, Suravajhala P. Diabetes mellitus susceptibility with varied diseased phenotypes and its comparison with phenome interactome networks. World J Clin Cases 2022; 10:5957-5964. [PMID: 35949812 PMCID: PMC9254192 DOI: 10.12998/wjcc.v10.i18.5957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 02/02/2022] [Accepted: 04/22/2022] [Indexed: 02/06/2023] Open
Abstract
An emerging area of interest in understanding disease phenotypes is systems genomics. Complex diseases such as diabetes have played an important role towards understanding the susceptible genes and mutations. A wide number of methods have been employed and strategies such as polygenic risk score and allele frequencies have been useful, but understanding the candidate genes harboring those mutations is an unmet goal. In this perspective, using systems genomic approaches, we highlight the application of phenome-interactome networks in diabetes and provide deep insights. LINC01128, which we previously described as candidate for diabetes, is shown as an example to discuss the approach.
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Affiliation(s)
- Madhusmita Rout
- Department of Pediatrics, University of Oklahoma Health Sciences Centre, Oklahoma City, OK 73104, United States
- Department of Biotechnology and Bioinformatics, Birla Institute of Scientific Research, Jaipur 302001, Rajasthan, India
| | - Bhumandeep Kour
- Department of Biotechnology, Lovely Professional University, Phagwara 144001, Punjab, India
| | - Sugunakar Vuree
- Department of Biotechnology, Lovely Professional University, Phagwara 144001, Punjab, India
| | - Sajitha S Lulu
- Department of Biotechnology, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India
| | - Krishna Mohan Medicherla
- Department of Biotechnology and Bioinformatics, Birla Institute of Scientific Research, Jaipur 302001, Rajasthan, India
| | - Prashanth Suravajhala
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Vallikavu PO, Amritapuri, Clappana, Kollam 690525, Kerala, India
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14
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Hodgson S, Huang QQ, Sallah N, Griffiths CJ, Newman WG, Trembath RC, Wright J, Lumbers RT, Kuchenbaecker K, van Heel DA, Mathur R, Martin HC, Finer S. Integrating polygenic risk scores in the prediction of type 2 diabetes risk and subtypes in British Pakistanis and Bangladeshis: A population-based cohort study. PLoS Med 2022; 19:e1003981. [PMID: 35587468 PMCID: PMC9119501 DOI: 10.1371/journal.pmed.1003981] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 04/06/2022] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Type 2 diabetes (T2D) is highly prevalent in British South Asians, yet they are underrepresented in research. Genes & Health (G&H) is a large, population study of British Pakistanis and Bangladeshis (BPB) comprising genomic and routine health data. We assessed the extent to which genetic risk for T2D is shared between BPB and European populations (EUR). We then investigated whether the integration of a polygenic risk score (PRS) for T2D with an existing risk tool (QDiabetes) could improve prediction of incident disease and the characterisation of disease subtypes. METHODS AND FINDINGS In this observational cohort study, we assessed whether common genetic loci associated with T2D in EUR individuals were replicated in 22,490 BPB individuals in G&H. We replicated fewer loci in G&H (n = 76/338, 22%) than would be expected given power if all EUR-ascertained loci were transferable (n = 101, 30%; p = 0.001). Of the 27 transferable loci that were powered to interrogate this, only 9 showed evidence of shared causal variants. We constructed a T2D PRS and combined it with a clinical risk instrument (QDiabetes) in a novel, integrated risk tool (IRT) to assess risk of incident diabetes. To assess model performance, we compared categorical net reclassification index (NRI) versus QDiabetes alone. In 13,648 patients free from T2D followed up for 10 years, NRI was 3.2% for IRT versus QDiabetes (95% confidence interval (CI): 2.0% to 4.4%). IRT performed best in reclassification of individuals aged less than 40 years deemed low risk by QDiabetes alone (NRI 5.6%, 95% CI 3.6% to 7.6%), who tended to be free from comorbidities and slim. After adjustment for QDiabetes score, PRS was independently associated with progression to T2D after gestational diabetes (hazard ratio (HR) per SD of PRS 1.23, 95% CI 1.05 to 1.42, p = 0.028). Using cluster analysis of clinical features at diabetes diagnosis, we replicated previously reported disease subgroups, including Mild Age-Related, Mild Obesity-related, and Insulin-Resistant Diabetes, and showed that PRS distribution differs between subgroups (p = 0.002). Integrating PRS in this cluster analysis revealed a Probable Severe Insulin Deficient Diabetes (pSIDD) subgroup, despite the absence of clinical measures of insulin secretion or resistance. We also observed differences in rates of progression to micro- and macrovascular complications between subgroups after adjustment for confounders. Study limitations include the absence of an external replication cohort and the potential biases arising from missing or incorrect routine health data. CONCLUSIONS Our analysis of the transferability of T2D loci between EUR and BPB indicates the need for larger, multiancestry studies to better characterise the genetic contribution to disease and its varied aetiology. We show that a T2D PRS optimised for this high-risk BPB population has potential clinical application in BPB, improving the identification of T2D risk (especially in the young) on top of an established clinical risk algorithm and aiding identification of subgroups at diagnosis, which may help future efforts to stratify care and treatment of the disease.
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Affiliation(s)
- Sam Hodgson
- Primary Care Research Centre, University of Southampton, Southampton, United Kingdom
| | - Qin Qin Huang
- Department of Human Genetics, Wellcome Sanger Institute, Hinxton, United Kingdom
| | - Neneh Sallah
- Institute of Health Informatics, University College London, London, United Kingdom
- UCL Genetics Institute, University College London, London, United Kingdom
| | - Genes & Health Research Team
- Wolfson Institute of Population Health, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Chris J. Griffiths
- Wolfson Institute of Population Health, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - William G. Newman
- Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
| | - Richard C. Trembath
- School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - John Wright
- Bradford Institute for Health Research, Bradford, United Kingdom
| | - R. Thomas Lumbers
- Institute of Health Informatics, University College London, London, United Kingdom
- British Heart Foundation Research Accelerator, University College London, London, United Kingdom
| | - Karoline Kuchenbaecker
- UCL Genetics Institute, University College London, London, United Kingdom
- Division of Psychiatry, University College London, London, United Kingdom
| | - David A. van Heel
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Rohini Mathur
- London School of Hygiene & Tropical Medicine, London, United Kingdom
| | - Hilary C. Martin
- Department of Human Genetics, Wellcome Sanger Institute, Hinxton, United Kingdom
| | - Sarah Finer
- Wolfson Institute of Population Health, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
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15
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Gloudemans MJ, Balliu B, Nachun D, Schnurr TM, Durrant MG, Ingelsson E, Wabitsch M, Quertermous T, Montgomery SB, Knowles JW, Carcamo-Orive I. Integration of genetic colocalizations with physiological and pharmacological perturbations identifies cardiometabolic disease genes. Genome Med 2022; 14:31. [PMID: 35292083 PMCID: PMC8925074 DOI: 10.1186/s13073-022-01036-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 03/04/2022] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Identification of causal genes for polygenic human diseases has been extremely challenging, and our understanding of how physiological and pharmacological stimuli modulate genetic risk at disease-associated loci is limited. Specifically, insulin resistance (IR), a common feature of cardiometabolic disease, including type 2 diabetes, obesity, and dyslipidemia, lacks well-powered genome-wide association studies (GWAS), and therefore, few associated loci and causal genes have been identified. METHODS Here, we perform and integrate linkage disequilibrium (LD)-adjusted colocalization analyses across nine cardiometabolic traits (fasting insulin, fasting glucose, insulin sensitivity, insulin sensitivity index, type 2 diabetes, triglycerides, high-density lipoprotein, body mass index, and waist-hip ratio) combined with expression and splicing quantitative trait loci (eQTLs and sQTLs) from five metabolically relevant human tissues (subcutaneous and visceral adipose, skeletal muscle, liver, and pancreas). To elucidate the upstream regulators and functional mechanisms for these genes, we integrate their transcriptional responses to 21 relevant physiological and pharmacological perturbations in human adipocytes, hepatocytes, and skeletal muscle cells and map their protein-protein interactions. RESULTS We identify 470 colocalized loci and prioritize 207 loci with a single colocalized gene. Patterns of shared colocalizations across traits and tissues highlight different potential roles for colocalized genes in cardiometabolic disease and distinguish several genes involved in pancreatic β-cell function from others with a more direct role in skeletal muscle, liver, and adipose tissues. At the loci with a single colocalized gene, 42 of these genes were regulated by insulin and 35 by glucose in perturbation experiments, including 17 regulated by both. Other metabolic perturbations regulated the expression of 30 more genes not regulated by glucose or insulin, pointing to other potential upstream regulators of candidate causal genes. CONCLUSIONS Our use of transcriptional responses under metabolic perturbations to contextualize genetic associations from our custom colocalization approach provides a list of likely causal genes and their upstream regulators in the context of IR-associated cardiometabolic risk.
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Affiliation(s)
- Michael J Gloudemans
- Biomedical Informatics Training Program, Stanford, CA, USA.
- Department of Pathology, Stanford, CA, USA.
| | - Brunilda Balliu
- Department of Computational Medicine, UCLA, Los Angeles, CA, USA
| | - Daniel Nachun
- Department of Genetics, Stanford, CA, USA
- Department of Immunology, Stanford, CA, USA
| | - Theresia M Schnurr
- Department of Medicine, Division of Cardiovascular Medicine and Cardiovascular Institute, Stanford, CA, USA
| | | | - Erik Ingelsson
- Department of Medicine, Division of Cardiovascular Medicine and Cardiovascular Institute, Stanford, CA, USA
| | - Martin Wabitsch
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Endocrinology, Ulm University, Ulm, Germany
| | - Thomas Quertermous
- Department of Medicine, Division of Cardiovascular Medicine and Cardiovascular Institute, Stanford, CA, USA
- Diabetes Research Center, Stanford, CA, USA
| | - Stephen B Montgomery
- Department of Pathology, Stanford, CA, USA.
- Department of Genetics, Stanford, CA, USA.
| | - Joshua W Knowles
- Department of Medicine, Division of Cardiovascular Medicine and Cardiovascular Institute, Stanford, CA, USA.
- Diabetes Research Center, Stanford, CA, USA.
- Prevention Research Center, Stanford, CA, USA.
| | - Ivan Carcamo-Orive
- Department of Medicine, Division of Cardiovascular Medicine and Cardiovascular Institute, Stanford, CA, USA.
- Diabetes Research Center, Stanford, CA, USA.
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16
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Balkhiyarova Z, Luciano R, Kaakinen M, Ulrich A, Shmeliov A, Bianchi M, Chioma L, Dallapiccola B, Prokopenko I, Manco M. Relationship between glucose homeostasis and obesity in early life-a study of Italian children and adolescents. Hum Mol Genet 2022; 31:816-826. [PMID: 34590674 PMCID: PMC8895752 DOI: 10.1093/hmg/ddab287] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 09/15/2021] [Accepted: 09/16/2021] [Indexed: 01/09/2023] Open
Abstract
Epidemic obesity is the most important risk factor for prediabetes and type 2 diabetes (T2D) in youth as it is in adults. Obesity shares pathophysiological mechanisms with T2D and is likely to share part of the genetic background. We aimed to test if weighted genetic risk scores (GRSs) for T2D, fasting glucose (FG) and fasting insulin (FI) predict glycaemic traits and if there is a causal relationship between obesity and impaired glucose metabolism in children and adolescents. Genotyping of 42 SNPs established by genome-wide association studies for T2D, FG and FI was performed in 1660 Italian youths aged between 2 and 19 years. We defined GRS for T2D, FG and FI and tested their effects on glycaemic traits, including FG, FI, indices of insulin resistance/beta cell function and body mass index (BMI). We evaluated causal relationships between obesity and FG/FI using one-sample Mendelian randomization analyses in both directions. GRS-FG was associated with FG (beta = 0.075 mmol/l, SE = 0.011, P = 1.58 × 10-11) and beta cell function (beta = -0.041, SE = 0.0090 P = 5.13 × 10-6). GRS-T2D also demonstrated an association with beta cell function (beta = -0.020, SE = 0.021 P = 0.030). We detected a causal effect of increased BMI on levels of FI in Italian youths (beta = 0.31 ln (pmol/l), 95%CI [0.078, 0.54], P = 0.0085), while there was no effect of FG/FI levels on BMI. Our results demonstrate that the glycaemic and T2D risk genetic variants contribute to higher FG and FI levels and decreased beta cell function in children and adolescents. The causal effects of adiposity on increased insulin resistance are detectable from childhood age.
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Affiliation(s)
- Zhanna Balkhiyarova
- Section of Statistical Multi-Omics, Department of Clinical and Experimental Medicine, University of Surrey, Guildford GU2 7XH, UK
- Institute of Biochemistry and Genetics, Ufa Federal Research Centre Russian Academy of Sciences, Ufa 450008, Russian Federation
- Department of Endocrinology, Bashkir State Medical University, Ufa 450054, Russian Federation
| | - Rosa Luciano
- Research Area for Multifactorial Disease, Bambino Gesù Children’s Hospital, IRCCS, Rome 00146, Italy
- Department of Laboratory Medicine, Bambino Gesù Children’s Hospital, IRCCS, Rome 00146, Italy
| | - Marika Kaakinen
- Section of Statistical Multi-Omics, Department of Clinical and Experimental Medicine, University of Surrey, Guildford GU2 7XH, UK
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK
| | - Anna Ulrich
- Section of Statistical Multi-Omics, Department of Clinical and Experimental Medicine, University of Surrey, Guildford GU2 7XH, UK
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK
| | - Aleksey Shmeliov
- Section of Statistical Multi-Omics, Department of Clinical and Experimental Medicine, University of Surrey, Guildford GU2 7XH, UK
| | - Marzia Bianchi
- Research Area for Multifactorial Disease, Bambino Gesù Children’s Hospital, IRCCS, Rome 00146, Italy
| | - Laura Chioma
- Unit of Endocrinology, Bambino Gesù Children's Hospital, IRCCS, Rome 00146, Italy
| | - Bruno Dallapiccola
- Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome 00146, Italy
| | - Inga Prokopenko
- Section of Statistical Multi-Omics, Department of Clinical and Experimental Medicine, University of Surrey, Guildford GU2 7XH, UK
- Institute of Biochemistry and Genetics, Ufa Federal Research Centre Russian Academy of Sciences, Ufa 450008, Russian Federation
- UMR 8199—EGID, Institut Pasteur de Lille, CNRS, University of Lille, Lille 59000, France
| | - Melania Manco
- Research Area for Multifactorial Disease, Bambino Gesù Children’s Hospital, IRCCS, Rome 00146, Italy
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17
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Wesolowska-Andersen A, Brorsson CA, Bizzotto R, Mari A, Tura A, Koivula R, Mahajan A, Vinuela A, Tajes JF, Sharma S, Haid M, Prehn C, Artati A, Hong MG, Musholt PB, Kurbasic A, De Masi F, Tsirigos K, Pedersen HK, Gudmundsdottir V, Thomas CE, Banasik K, Jennison C, Jones A, Kennedy G, Bell J, Thomas L, Frost G, Thomsen H, Allin K, Hansen TH, Vestergaard H, Hansen T, Rutters F, Elders P, t'Hart L, Bonnefond A, Canouil M, Brage S, Kokkola T, Heggie A, McEvoy D, Hattersley A, McDonald T, Teare H, Ridderstrale M, Walker M, Forgie I, Giordano GN, Froguel P, Pavo I, Ruetten H, Pedersen O, Dermitzakis E, Franks PW, Schwenk JM, Adamski J, Pearson E, McCarthy MI, Brunak S. Four groups of type 2 diabetes contribute to the etiological and clinical heterogeneity in newly diagnosed individuals: An IMI DIRECT study. Cell Rep Med 2022; 3:100477. [PMID: 35106505 PMCID: PMC8784706 DOI: 10.1016/j.xcrm.2021.100477] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 06/21/2021] [Accepted: 11/23/2021] [Indexed: 12/11/2022]
Abstract
The presentation and underlying pathophysiology of type 2 diabetes (T2D) is complex and heterogeneous. Recent studies attempted to stratify T2D into distinct subgroups using data-driven approaches, but their clinical utility may be limited if categorical representations of complex phenotypes are suboptimal. We apply a soft-clustering (archetype) method to characterize newly diagnosed T2D based on 32 clinical variables. We assign quantitative clustering scores for individuals and investigate the associations with glycemic deterioration, genetic risk scores, circulating omics biomarkers, and phenotypic stability over 36 months. Four archetype profiles represent dysfunction patterns across combinations of T2D etiological processes and correlate with multiple circulating biomarkers. One archetype associated with obesity, insulin resistance, dyslipidemia, and impaired β cell glucose sensitivity corresponds with the fastest disease progression and highest demand for anti-diabetic treatment. We demonstrate that clinical heterogeneity in T2D can be mapped to heterogeneity in individual etiological processes, providing a potential route to personalized treatments.
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Affiliation(s)
| | - Caroline A Brorsson
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Andrea Mari
- C.N.R. Institute of Neuroscience, Padova, Italy
| | - Andrea Tura
- C.N.R. Institute of Neuroscience, Padova, Italy
| | - Robert Koivula
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Anubha Mahajan
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Ana Vinuela
- Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
| | | | - Sapna Sharma
- Research Unit Molecular Endocrinology And Metabolism, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Mark Haid
- Research Unit Molecular Endocrinology And Metabolism, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Cornelia Prehn
- Research Unit Molecular Endocrinology And Metabolism, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Anna Artati
- Research Unit Molecular Endocrinology And Metabolism, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Mun-Gwan Hong
- Affinity Proteomics, Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna, Sweden
| | - Petra B Musholt
- R&D Global Development, Translational Medicine & Clinical Pharmacology (TMCP), Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany
| | - Azra Kurbasic
- University of Lund, Clinical Sciences, Malmö, Sweden
| | - Federico De Masi
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Kostas Tsirigos
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Helle Krogh Pedersen
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Valborg Gudmundsdottir
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Cecilia Engel Thomas
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Karina Banasik
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Angus Jones
- University of Exeter Medical School, Exeter, UK
| | - Gwen Kennedy
- The Immunoassay Biomarker Core Laboratory, Shool of Medicine, University of Dundee, Dundee, UK
| | - Jimmy Bell
- Research Centre for Optimal Health, Deparment of Life Sciences, University of Westminster, London, UK
| | - Louise Thomas
- Research Centre for Optimal Health, Deparment of Life Sciences, University of Westminster, London, UK
| | - Gary Frost
- Section for Nutrition Research, Faculty of Medicine, Hammersmith Campus, Imperial College London, London, UK
| | - Henrik Thomsen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kristine Allin
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tue Haldor Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Henrik Vestergaard
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Femke Rutters
- Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, Amsterdam UMC-location VUmc, Amsterdam, the Netherlands
| | - Petra Elders
- Department of General Practice, Amsterdam UMC-location VUmc, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands
| | - Leen t'Hart
- Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, Amsterdam UMC-location VUmc, Amsterdam, the Netherlands
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Amelie Bonnefond
- INSERM UMR 1283, CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille University Hospital, Lille, France
| | - Mickaël Canouil
- INSERM UMR 1283, CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille University Hospital, Lille, France
| | - Soren Brage
- MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK
| | - Tarja Kokkola
- Department of Medicine, University of Eastern Finland, Kuopio, Finland
| | - Alison Heggie
- Institute of Cellular Medicine, Newcastle University, Newcastle, UK
| | - Donna McEvoy
- Diabetes Research Network, Royal Victoria Infirmary, Newcastle, UK
| | | | | | - Harriet Teare
- Centre for Health, Law and Emerging Technologies (HeLEX), Faculty of Law, University of Oxford, Oxford, UK
| | | | - Mark Walker
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, UK
| | | | - Giuseppe N Giordano
- R&D Global Development, Translational Medicine & Clinical Pharmacology (TMCP), Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany
| | - Philippe Froguel
- INSERM UMR 1283, CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille University Hospital, Lille, France
| | - Imre Pavo
- Eli Lilly Regional Operations GmbH, Vienna, Austria
| | - Hartmut Ruetten
- R&D Global Development, Translational Medicine & Clinical Pharmacology (TMCP), Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany
| | - Oluf Pedersen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Emmanouil Dermitzakis
- Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
| | - Paul W Franks
- University of Lund, Clinical Sciences, Malmö, Sweden
| | - Jochen M Schwenk
- Affinity Proteomics, Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna, Sweden
| | - Jerzy Adamski
- Research Unit Molecular Endocrinology And Metabolism, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- Lehrstuhl für Experimentelle Genetik, Technische Universität München, Freising-Weihenstephan, Germany
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore
| | | | - Mark I McCarthy
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
- Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK
| | - Søren Brunak
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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18
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Shum M, Segawa M, Gharakhanian R, Viñuela A, Wortham M, Baghdasarian S, Wolf DM, Sereda SB, Nocito L, Stiles L, Zhou Z, Gutierrez V, Sander M, Shirihai OS, Liesa M. Deletion of ABCB10 in beta-cells protects from high-fat diet induced insulin resistance. Mol Metab 2022; 55:101403. [PMID: 34823065 PMCID: PMC8689243 DOI: 10.1016/j.molmet.2021.101403] [Citation(s) in RCA: 0] [Impact Index Per Article: 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: 09/03/2021] [Revised: 11/18/2021] [Accepted: 11/19/2021] [Indexed: 11/09/2022] Open
Abstract
OBJECTIVE The contribution of beta-cell dysfunction to type 2 diabetes (T2D) is not restricted to insulinopenia in the late stages of the disease. Elevated fasting insulinemia in normoglycemic humans is a major factor predicting the onset of insulin resistance and T2D, demonstrating an early alteration of beta-cell function in T2D. Moreover, an early and chronic increase in fasting insulinemia contributes to insulin resistance in high-fat diet (HFD)-fed mice. However, whether there are genetic factors that promote beta-cell-initiated insulin resistance remains undefined. Human variants of the mitochondrial transporter ABCB10, which regulates redox by increasing bilirubin synthesis, have been associated with an elevated risk of T2D. The effects of T2D ABCB10 variants on ABCB10 expression and the actions of ABCB10 in beta-cells are unknown. METHODS The expression of beta-cell ABCB10 was analyzed in published transcriptome datasets from human beta-cells carrying the T2D-risk ABCB10 variant. Insulin sensitivity, beta-cell proliferation, and secretory function were measured in beta-cell-specific ABCB10 KO mice (Ins1Cre-Abcb10flox/flox). The short-term role of beta-cell ABCB10 activity on glucose-stimulated insulin secretion (GSIS) was determined in isolated islets. RESULTS Carrying the T2Drisk allele G of ABCB10 rs348330 variant was associated with increased ABCB10 expression in human beta-cells. Constitutive deletion of Abcb10 in beta-cells protected mice from hyperinsulinemia and insulin resistance by limiting HFD-induced beta-cell expansion. An early limitation in GSIS and H2O2-mediated signaling caused by elevated ABCB10 activity can initiate an over-compensatory expansion of beta-cell mass in response to HFD. Accordingly, increasing ABCB10 expression was sufficient to limit GSIS capacity. In health, ABCB10 protein was decreased during islet maturation, with maturation restricting beta-cell proliferation and elevating GSIS. Finally, ex-vivo and short-term deletion of ABCB10 in islets isolated from HFD-fed mice increased H2O2 and GSIS, which was reversed by bilirubin treatments. CONCLUSIONS Beta-cell ABCB10 is required for HFD to induce insulin resistance in mice by amplifying beta-cell mass expansion to maladaptive levels that cause fasting hyperinsulinemia.
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Affiliation(s)
- Michael Shum
- Department of Medicine, Division of Endocrinology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Dr., Los Angeles, CA 90095, USA; Department of Molecular Medicine, Faculty of Medicine, Universite Laval, Quebec City G1V 0A6, Canada.
| | - Mayuko Segawa
- Department of Medicine, Division of Endocrinology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Dr., Los Angeles, CA 90095, USA
| | - Raffi Gharakhanian
- Department of Medicine, Division of Endocrinology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Dr., Los Angeles, CA 90095, USA
| | - Ana Viñuela
- Bioscience Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom
| | - Matthew Wortham
- Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
| | - Siyouneh Baghdasarian
- Department of Medicine, Division of Endocrinology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Dr., Los Angeles, CA 90095, USA
| | - Dane M Wolf
- Department of Medicine, Division of Endocrinology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Dr., Los Angeles, CA 90095, USA; Evans Biomedical Research Center, Boston University School of Medicine, 650 Albany St., Boston, MA, 02118, USA
| | - Samuel B Sereda
- Evans Biomedical Research Center, Boston University School of Medicine, 650 Albany St., Boston, MA, 02118, USA
| | - Laura Nocito
- Evans Biomedical Research Center, Boston University School of Medicine, 650 Albany St., Boston, MA, 02118, USA
| | - Linsey Stiles
- Department of Medicine, Division of Endocrinology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Dr., Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Dr., Los Angeles, CA 90095, USA
| | - Zhiqiang Zhou
- Department of Medicine, Division of Endocrinology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Dr., Los Angeles, CA 90095, USA
| | - Vincent Gutierrez
- Department of Medicine, Division of Endocrinology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Dr., Los Angeles, CA 90095, USA; Molecular and Cellular Integrative Physiology, UCLA, 612 Charles E. Young Dr., Los Angeles, CA 90095, USA
| | - Maike Sander
- Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
| | - Orian S Shirihai
- Department of Medicine, Division of Endocrinology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Dr., Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Dr., Los Angeles, CA 90095, USA; Molecular and Cellular Integrative Physiology, UCLA, 612 Charles E. Young Dr., Los Angeles, CA 90095, USA
| | - Marc Liesa
- Department of Medicine, Division of Endocrinology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Dr., Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Dr., Los Angeles, CA 90095, USA; Molecular and Cellular Integrative Physiology, UCLA, 612 Charles E. Young Dr., Los Angeles, CA 90095, USA; Molecular Biology Institute at UCLA, 611 Charles E. Young Dr., Los Angeles, CA 90095, USA.
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19
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DNA Methylation and Type 2 Diabetes: Novel Biomarkers for Risk Assessment? Int J Mol Sci 2021; 22:ijms222111652. [PMID: 34769081 PMCID: PMC8584054 DOI: 10.3390/ijms222111652] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/25/2021] [Accepted: 10/25/2021] [Indexed: 12/15/2022] Open
Abstract
Diabetes is a severe threat to global health. Almost 500 million people live with diabetes worldwide. Most of them have type 2 diabetes (T2D). T2D patients are at risk of developing severe and life-threatening complications, leading to an increased need for medical care and reduced quality of life. Improved care for people with T2D is essential. Actions aiming at identifying undiagnosed diabetes and at preventing diabetes in those at high risk are needed as well. To this end, biomarker discovery and validation of risk assessment for T2D are critical. Alterations of DNA methylation have recently helped to better understand T2D pathophysiology by explaining differences among endophenotypes of diabetic patients in tissues. Recent evidence further suggests that variations of DNA methylation might contribute to the risk of T2D even more significantly than genetic variability and might represent a valuable tool to predict T2D risk. In this review, we focus on recent information on the contribution of DNA methylation to the risk and the pathogenesis of T2D. We discuss the limitations of these studies and provide evidence supporting the potential for clinical application of DNA methylation marks to predict the risk and progression of T2D.
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20
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Olaniyi KS, Sabinari IW, Olatunji LA. Oral ethinylestradiol–levonorgestrel therapy counteracts fructose-induced renal metabolic impairment in female rats. ENDOCRINE AND METABOLIC SCIENCE 2021. [DOI: 10.1016/j.endmts.2021.100099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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21
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Muhammad SA, Qousain Naqvi ST, Nguyen T, Wu X, Munir F, Jamshed MB, Zhang Q. Cisplatin's potential for type 2 diabetes repositioning by inhibiting CDKN1A, FAS, and SESN1. Comput Biol Med 2021; 135:104640. [PMID: 34261004 DOI: 10.1016/j.compbiomed.2021.104640] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 07/06/2021] [Accepted: 07/06/2021] [Indexed: 12/16/2022]
Abstract
Cisplatin is a DNA-damaging chemotherapeutic agent used for treating cancer. Based on cDNA dataset analysis, we investigated how cisplatin modified gene expression and observed cisplatin-induced dysregulation and system-level variations relating to insulin resistance and type 2 diabetes mellitus (T2DM). T2DM is a multifactorial disease affecting 462 million people in the world, and drug-induced T2DM is a serious issue. To understand this etiology, we designed an integrative, system-level study to identify associations between cisplatin-induced differentially expressed genes (DEGs) and T2DM. From a list of differential expressed genes, cisplatin downregulated the cyclin-dependent kinase inhibitor 1 (CDKN1A), tumor necrosis factor (FAS), and sestrin-1 (SESN1) genes responsible for modifying signaling pathways, including the p53, JAK-STAT, FOXO, MAPK, mTOR, P13-AKT, Toll-like receptor (TLR), adipocytokine, and insulin signaling pathways. These enriched pathways were expressively associated with the disease. We observed significant gene signatures, including SMAD3, IRS, PDK1, PRKAA1, AKT, SOS, RAS, GRB2, MEK1/2, and ERK, interacting with source genes. This study revealed the value of system genetics for identifying the cisplatin-induced genetic variants responsible for the progression of T2DM. Also, by cross-validating gene expression data for T2DM islets, we found that downregulating IRS and PRK families is critical in insulin and T2DM signaling pathways. Cisplatin, by inhibiting CDKN1A, FAS, and SESN1, promotes IRS and PRK activity in a similar way to rosiglitazone (a popular drug used for T2DM treatment). Our integrative, network-based approach can help in understanding the drug-induced pathophysiological mechanisms of diabetes.
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Affiliation(s)
- Syed Aun Muhammad
- Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Pakistan.
| | | | - Thanh Nguyen
- Informatics Institute, School of Medicine, The University of Alabama, Birmingham, AL, USA
| | - Xiaogang Wu
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Fahad Munir
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Muhammad Babar Jamshed
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - QiYu Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
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22
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Heller S, Melzer MK, Azoitei N, Julier C, Kleger A. Human Pluripotent Stem Cells Go Diabetic: A Glimpse on Monogenic Variants. Front Endocrinol (Lausanne) 2021; 12:648284. [PMID: 34079523 PMCID: PMC8166226 DOI: 10.3389/fendo.2021.648284] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 04/13/2021] [Indexed: 12/17/2022] Open
Abstract
Diabetes, as one of the major diseases in industrial countries, affects over 350 million people worldwide. Type 1 (T1D) and type 2 diabetes (T2D) are the most common forms with both types having invariable genetic influence. It is accepted that a subset of all diabetes patients, generally estimated to account for 1-2% of all diabetic cases, is attributed to mutations in single genes. As only a subset of these genes has been identified and fully characterized, there is a dramatic need to understand the pathophysiological impact of genetic determinants on β-cell function and pancreatic development but also on cell replacement therapies. Pluripotent stem cells differentiated along the pancreatic lineage provide a valuable research platform to study such genes. This review summarizes current perspectives in applying this platform to study monogenic diabetes variants.
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Affiliation(s)
- Sandra Heller
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - Michael Karl Melzer
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
- Department of Urology, Ulm University Hospital, Ulm, Germany
| | - Ninel Azoitei
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - Cécile Julier
- Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR-8104, Paris, France
| | - Alexander Kleger
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
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23
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Chen Y, Hu W, Li Q, Zhao S, Zhao D, Zhang S, Wei Z, Yang X, Chen Y, Li X, Liao C, Han J, Miao QR, Duan Y. NGBR is required to ameliorate type 2 diabetes in mice by enhancing insulin sensitivity. J Biol Chem 2021; 296:100624. [PMID: 33812996 PMCID: PMC8111265 DOI: 10.1016/j.jbc.2021.100624] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 03/11/2021] [Accepted: 03/31/2021] [Indexed: 02/07/2023] Open
Abstract
The reduction of insulin resistance or improvement of insulin sensitivity is the most effective treatment for type 2 diabetes (T2D). We previously reported that Nogo-B receptor (NGBR), encoded by the NUS1 gene, is required for attenuating hepatic lipogenesis by blocking nuclear translocation of liver X receptor alpha, suggesting its important role in regulating hepatic lipid metabolism. Herein, we demonstrate that NGBR expression was decreased in the liver of obesity-associated T2D patients and db/db mice. NGBR knockout in mouse hepatocytes resulted in increased blood glucose, insulin resistance, and beta-cell loss. High-fat diet (HFD)/streptozotocin (STZ)-treated mice presented the T2D phenotype by showing increased nonesterified fatty acid (NEFA) and triglyceride (TG) in the liver and plasma and increased insulin resistance and beta-cell loss. AAV-mediated NGBR overexpression in the liver reduced NEFA and TG in the liver and circulation and improved liver functions. Consequently, HFD/STZ-treated mice with hepatic NGBR overexpression had increased insulin sensitivity and reduced beta-cell loss. Mechanistically, NGBR overexpression restored insulin signaling of AMPKα1-dependent phosphorylation of AKT and GSK3β. NGBR overexpression also reduced expression of endoplasmic reticulum stress-associated genes in the liver and skeletal muscle to improve insulin sensitivity. Together, our results reveal that NGBR is required to ameliorate T2D in mice, providing new insight into the role of hepatic NGBR in insulin sensitivity and T2D treatment.
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Affiliation(s)
- Yi Chen
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China; Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Wenquan Hu
- Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; Diabetes and Obesity Research Center, New York University Long Island School of Medicine, Mineola, New York, USA
| | - Qi Li
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Shiwei Zhao
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Dan Zhao
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Shuang Zhang
- Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Zhuo Wei
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Xiaoxiao Yang
- Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Yuanli Chen
- Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Xiaoju Li
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Chenzhong Liao
- Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Jihong Han
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China; Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Qing Robert Miao
- Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; Diabetes and Obesity Research Center, New York University Long Island School of Medicine, Mineola, New York, USA.
| | - Yajun Duan
- Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
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24
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Fields AM, Welle K, Ho ES, Mesaros C, Susiarjo M. Vitamin B6 deficiency disrupts serotonin signaling in pancreatic islets and induces gestational diabetes in mice. Commun Biol 2021; 4:421. [PMID: 33772108 PMCID: PMC7998034 DOI: 10.1038/s42003-021-01900-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 02/17/2021] [Indexed: 12/11/2022] Open
Abstract
In pancreatic islets, catabolism of tryptophan into serotonin and serotonin receptor 2B (HTR2B) activation is crucial for β-cell proliferation and maternal glucose regulation during pregnancy. Factors that reduce serotonin synthesis and perturb HTR2B signaling are associated with decreased β-cell number, impaired insulin secretion, and gestational glucose intolerance in mice. Albeit the tryptophan-serotonin pathway is dependent on vitamin B6 bioavailability, how vitamin B6 deficiency impacts β-cell proliferation during pregnancy has not been investigated. In this study, we created a vitamin B6 deficient mouse model and investigated how gestational deficiency influences maternal glucose tolerance. Our studies show that gestational vitamin B6 deficiency decreases serotonin levels in maternal pancreatic islets and reduces β-cell proliferation in an HTR2B-dependent manner. These changes were associated with glucose intolerance and insulin resistance, however insulin secretion remained intact. Our findings suggest that vitamin B6 deficiency-induced gestational glucose intolerance involves additional mechanisms that are complex and insulin independent. Fields et al. investigate the impact of vitamin B6 deficiency on islet β-cell proliferation during pregnancy, using vitamin B6-deficient mice. They find that gestational vitamin B6 deficiency decreases serotonin levels in pancreatic islets and reduces β-cell proliferation, showing that vitamin B6 deficiency regulates maternal glucose tolerance in a serotonin-dependent manner.
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Affiliation(s)
- Ashley M Fields
- Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Kevin Welle
- Mass Spectrometry Resource Laboratory, University of Rochester, Rochester, NY, USA
| | - Elaine S Ho
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Clementina Mesaros
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Martha Susiarjo
- Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
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25
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Mirra P, Desiderio A, Spinelli R, Nigro C, Longo M, Parrillo L, D'Esposito V, Carissimo A, Hedjazifar S, Smith U, Formisano P, Miele C, Raciti GA, Beguinot F. Adipocyte precursor cells from first degree relatives of type 2 diabetic patients feature changes in hsa-mir-23a-5p, -193a-5p, and -193b-5p and insulin-like growth factor 2 expression. FASEB J 2021; 35:e21357. [PMID: 33710685 DOI: 10.1096/fj.202002156rrr] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 12/23/2020] [Accepted: 12/24/2020] [Indexed: 12/13/2022]
Abstract
First-degree relatives (FDRs) of type 2 diabetics (T2D) feature dysfunction of subcutaneous adipose tissue (SAT) long before T2D onset. miRNAs have a role in adipocyte precursor cells (APC) differentiation and in adipocyte identity. Thus, impaired miRNA expression may contribute to SAT dysfunction in FDRs. In the present work, we have explored changes in miRNA expression associated with T2D family history which may affect gene expression in SAT APCs from FDRs. Small RNA-seq was performed in APCs from healthy FDRs and matched controls and omics data were validated by qPCR. Integrative analyses of APC miRNome and transcriptome from FDRs revealed down-regulated hsa-miR-23a-5p, -193a-5p and -193b-5p accompanied by up-regulated Insulin-like Growth Factor 2 (IGF2) gene which proved to be their direct target. The expression changes in these marks were associated with SAT adipocyte hypertrophy in FDRs. APCs from FDRs further demonstrated reduced capability to differentiate into adipocytes. Treatment with IGF2 protein decreased APC adipogenesis, while over-expression of hsa-miR-23a-5p, -193a-5p and -193b-5p enhanced adipogenesis by IGF2 targeting. Indeed, IGF2 increased the Wnt Family Member 10B gene expression in APCs. Down-regulation of the three miRNAs and IGF2 up-regulation was also observed in Peripheral Blood Leukocytes (PBLs) from FDRs. In conclusion, APCs from FDRs feature a specific miRNA/gene profile, which associates with SAT adipocyte hypertrophy and appears to contribute to impaired adipogenesis. PBL detection of this profile may help in identifying adipocyte hypertrophy in individuals at high risk of T2D.
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Affiliation(s)
- Paola Mirra
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy.,Department of Translational Medicine, Federico II University of Naples, Naples, Italy
| | - Antonella Desiderio
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy.,Department of Translational Medicine, Federico II University of Naples, Naples, Italy
| | - Rosa Spinelli
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy.,Department of Translational Medicine, Federico II University of Naples, Naples, Italy
| | - Cecilia Nigro
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy.,Department of Translational Medicine, Federico II University of Naples, Naples, Italy
| | - Michele Longo
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy.,Department of Translational Medicine, Federico II University of Naples, Naples, Italy
| | - Luca Parrillo
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy.,Department of Translational Medicine, Federico II University of Naples, Naples, Italy
| | - Vittoria D'Esposito
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy.,Department of Translational Medicine, Federico II University of Naples, Naples, Italy
| | | | - Shahram Hedjazifar
- Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ulf Smith
- Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Pietro Formisano
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy.,Department of Translational Medicine, Federico II University of Naples, Naples, Italy
| | - Claudia Miele
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy.,Department of Translational Medicine, Federico II University of Naples, Naples, Italy
| | - Gregory A Raciti
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy.,Department of Translational Medicine, Federico II University of Naples, Naples, Italy
| | - Francesco Beguinot
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy.,Department of Translational Medicine, Federico II University of Naples, Naples, Italy
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Gajeton J, Krukovets I, Yendamuri R, Verbovetskiy D, Vasanji A, Sul L, Stenina‐Adognravi O. miR-467 regulates inflammation and blood insulin and glucose. J Cell Mol Med 2021; 25:2549-2562. [PMID: 33566451 PMCID: PMC7933977 DOI: 10.1111/jcmm.16224] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 09/24/2020] [Accepted: 10/18/2020] [Indexed: 12/12/2022] Open
Abstract
Obesity is associated with inflammation and insulin resistance (IR), but the regulation of insulin sensitivity (IS) and connections between IS and inflammation remain unclear. We investigated the role of miR-467a-5p, a miRNA induced by hyperglycaemia, in regulating inflammation and blood glucose handling. We previously demonstrated that miR-467a-5p is induced by hyperglycaemia and inhibits the production of thrombospondin-1 (TSP-1), a protein implicated in regulating inflammation. To investigate the role of miR-467 in blood glucose handling and tissue inflammation, WT C57BL/6 mice were fed chow or Western diet from 5 to 32 weeks of age and injected weekly with miR-467a-5p antagonist. Inhibiting miR-467a-5p resulted in 47% increase in macrophage infiltration and increased Il6 levels in adipose tissue, higher plasma insulin levels (98 ng/mL vs 63 ng/mL), and 17% decrease in glucose clearance without increase in weight or HDL/LDL. The antagonist effect was lost in mice on Western diet. Mice lacking TSP-1 lost some but not all of the miR-467 effects, suggesting Thbs1 (and other unknown transcripts) are targeted by miR-467 to regulate inflammation. miR-467a-5p provides a physiological feedback when blood glucose is elevated to avoid inflammation and increased blood glucose and insulin levels, which may prevent IR.
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Affiliation(s)
- Jasmine Gajeton
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
- Department of Molecular MedicineCase Western Reserve UniversityClevelandOHUSA
| | - Irene Krukovets
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
| | - Revanth Yendamuri
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
- Present address:
Northeast Ohio Medical UniversityRootstownOHUSA
| | - Dmitriy Verbovetskiy
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
| | | | - Lidiya Sul
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
- Present address:
Ohio University Heritage College of Osteopathic MedicineAthensOHUSA
| | - Olga Stenina‐Adognravi
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
- Department of Molecular MedicineCase Western Reserve UniversityClevelandOHUSA
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Cha SH, Zhang C, Heo SJ, Jun HS. 5-Bromoprotocatechualdehyde Combats against Palmitate Toxicity by Inhibiting Parkin Degradation and Reducing ROS-Induced Mitochondrial Damage in Pancreatic β-Cells. Antioxidants (Basel) 2021; 10:antiox10020264. [PMID: 33572166 PMCID: PMC7914851 DOI: 10.3390/antiox10020264] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 02/05/2021] [Accepted: 02/05/2021] [Indexed: 01/09/2023] Open
Abstract
Pancreatic β-cell loss is critical in diabetes pathogenesis. Up to now, no effective treatment has become available for β-cell loss. A polyphenol recently isolated from Polysiphonia japonica, 5-Bromoprotocatechualdehyde (BPCA), is considered as a potential compound for the protection of β-cells. In this study, we examined palmitate (PA)-induced lipotoxicity in Ins-1 cells to test the protective effects of BPCA on insulin-secreting β-cells. Our results demonstrated that BPCA can protect β-cells from PA-induced lipotoxicity by reducing cellular damage, preventing reactive oxygen species (ROS) overproduction, and enhancing glucose-stimulated insulin secretion (GSIS). BPCA also improved mitochondrial morphology by preserving parkin protein expression. Moreover, BPCA exhibited a protective effect against PA-induced β-cell dysfunction in vivo in a zebrafish model. Our results provide strong evidence that BPCA could be a potential therapeutic agent for the management of diabetes.
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Affiliation(s)
- Seon-Heui Cha
- Department of Marine Bio and Medical Sciences, Hanseo University, Chungcheongman-do 31962, Korea
- Department of Integrated of Bioindustry, Hanseo University, Chungcheongman-do 31962, Korea;
- Correspondence: (S.-H.C.); (S.-J.H.); (H.-S.J.); Tel./Fax: +82-41-660-1550 (S.-H.C.); Tel.: +82-64-798-6101 (S.-J.H.); +82-32-899-6056 (H.-S.J.); Fax: +82-32-899-6057 (H.-S.J.)
| | - Chunying Zhang
- Department of Integrated of Bioindustry, Hanseo University, Chungcheongman-do 31962, Korea;
| | - Soo-Jin Heo
- Department of Biology, University of Science and Technology (UST), Daejeon 34113, Korea
- Marine Research Center, Institute of Ocean Science and Technology (KIOST), Jeju 63349, Korea
- Correspondence: (S.-H.C.); (S.-J.H.); (H.-S.J.); Tel./Fax: +82-41-660-1550 (S.-H.C.); Tel.: +82-64-798-6101 (S.-J.H.); +82-32-899-6056 (H.-S.J.); Fax: +82-32-899-6057 (H.-S.J.)
| | - Hee-Sook Jun
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea
- Gachon Medical and Convergence Institute, Gachon Gil Medical Center, Incheon 21565, Korea
- Department of Pharmacology, Gachon University, Incheon 21936, Korea
- Correspondence: (S.-H.C.); (S.-J.H.); (H.-S.J.); Tel./Fax: +82-41-660-1550 (S.-H.C.); Tel.: +82-64-798-6101 (S.-J.H.); +82-32-899-6056 (H.-S.J.); Fax: +82-32-899-6057 (H.-S.J.)
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Raza W, Guo J, Qadir MI, Bai B, Muhammad SA. qPCR Analysis Reveals Association of Differential Expression of SRR, NFKB1, and PDE4B Genes With Type 2 Diabetes Mellitus. Front Endocrinol (Lausanne) 2021; 12:774696. [PMID: 35046895 PMCID: PMC8761634 DOI: 10.3389/fendo.2021.774696] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 11/08/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is a heterogeneous, metabolic, and chronic condition affecting vast numbers of the world's population. The related variables and T2DM associations have not been fully understood due to their diverse nature. However, functional genomics can facilitate understanding of the disease. This information will be useful in drug design, advanced diagnostic, and prognostic markers. AIM To understand the genetic causes of T2DM, this study was designed to identify the differentially expressed genes (DEGs) of the disease. METHODS We investigated 20 publicly available disease-specific cDNA datasets from Gene Expression Omnibus (GEO) containing several attributes including gene symbols and clone identifiers, GenBank accession numbers, and phenotypic feature coordinates. We analyzed an integrated system-level framework involving Gene Ontology (GO), protein motifs and co-expression analysis, pathway enrichment, and transcriptional factors to reveal the biological information of genes. A co-expression network was studied to highlight the genes that showed a coordinated expression pattern across a group of samples. The DEGs were validated by quantitative PCR (qPCR) to analyze the expression levels of case and control samples (50 each) using glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as the reference gene. RESULTS From the list of 50 DEGs, we ranked three T2DM-related genes (p < 0.05): SRR, NFKB1, and PDE4B. The enriched terms revealed a significant functional role in amino acid metabolism, signal transduction, transmembrane and intracellular transport, and other vital biological functions. DMBX1, TAL1, ZFP161, NFIC (66.7%), and NR1H4 (33.3%) are transcriptional factors associated with the regulatory mechanism. We found substantial enrichment of insulin signaling and other T2DM-related pathways, such as valine, leucine and isoleucine biosynthesis, serine and threonine metabolism, adipocytokine signaling pathway, P13K/Akt pathway, and Hedgehog signaling pathway. The expression profiles of these DEGs verified by qPCR showed a substantial level of twofold change (FC) expression (2-ΔΔCT) in the genes SRR (FC ≤ 0.12), NFKB1 (FC ≤ 1.09), and PDE4B (FC ≤ 0.9) compared to controls (FC ≥ 1.6). The downregulated expression of these genes is associated with pathophysiological development and metabolic disorders. CONCLUSION This study would help to modulate the therapeutic strategies for T2DM and could speed up drug discovery outcomes.
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Affiliation(s)
- Waseem Raza
- Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Pakistan
| | - Jinlei Guo
- School of Medical Engineering, Sanquan College of Xinxiang Medical University, Xinxiang, China
| | - Muhammad Imran Qadir
- Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Pakistan
| | - Baogang Bai
- School of Information and Technology, Wenzhou Business College, Wenzhou, China
- Engineering Research Center of Intelligent Medicine, Wenzhou, China
- The 1st School of Medical, School of Information and Engineering, The 1st Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- *Correspondence: Syed Aun Muhammad, ; Baogang Bai,
| | - Syed Aun Muhammad
- Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Pakistan
- *Correspondence: Syed Aun Muhammad, ; Baogang Bai,
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Galderisi A, Tricò D, Pierpont B, Shabanova V, Samuels S, Dalla Man C, Galuppo B, Santoro N, Caprio S. A Reduced Incretin Effect Mediated by the rs7903146 Variant in the TCF7L2 Gene Is an Early Marker of β-Cell Dysfunction in Obese Youth. Diabetes Care 2020; 43:2553-2563. [PMID: 32788279 PMCID: PMC7510033 DOI: 10.2337/dc20-0445] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 07/10/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The risk genotype for the common variant rs7903146 of the transcription factor 7-like-2 (TCF7L2) gene has been found to affect the incretin response in healthy and obese adults; however, whether a similar functional defect is also present in obese adolescents remains unexplored. Herein, we examined the functional effect of the rs7903146 variant in the TCF7L2 gene on the incretin effect and determined its translational metabolic manifestation by performing deep phenotyping of the incretin system, β-cell function relative to insulin sensitivity, the gastrointestinal-induced glucose disposal (GIGD) in obese youth with normal and impaired glucose tolerance. RESEARCH DESIGN AND METHODS Thirty-nine obese adolescents without diabetes (median age 15 [25th, 75th percentile 14, 18] years; BMI 37 [33, 43] kg/m2) were genotyped for the rs7903146 variant of TCF7L2 and underwent a 3-h oral glucose tolerance test (OGTT) followed by an isoglycemic intravenous glucose infusion (iso-intravenous glucose tolerance test [IVGTT]) to match the plasma glucose concentrations during the OGTT and a hyperglycemic clamp with arginine stimulation. The incretin effect was measured as 100 * (AUC-SROGTT - AUC-SRiso-IVGTT) / AUC-SROGTT, where AUC-SR = area under the curve of C-peptide secretion rate. Participants were grouped into tertiles according to the percentage incretin effect (high, moderate, and low) to describe their metabolic phenotype. RESULTS The presence of T risk allele for TCF7L2 was associated with a markedly reduced incretin effect compared with the wild-type genotype (0.3% [-7.2, 14] vs. 37.8% [12.5, 52.4], P < 0.002). When the cohort was stratified by incretin effect, the high, moderate, and low incretin effect groups did not differ with respect to anthropometric features, while the low incretin effect group exhibited higher 1-h glucose (P = 0.015) and a reduced disposition index, insulin sensitivity, and insulin clearance compared with the high incretin effect group. GIGD was reduced in the low incretin effect group (P = 0.001). The three groups did not differ with respect to intravenous glucose-induced insulin secretion and arginine response during the hyperglycemic clamp. CONCLUSIONS A reduced incretin effect and its association with the TCF7L2 variant rs7903146 identify an early metabolic phenotype in obese youth without diabetes, featuring a higher plasma glucose peak at 1 h; lower insulin secretion, sensitivity, and clearance; and GIGD.
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Affiliation(s)
- Alfonso Galderisi
- Pediatrics Endocrinology and Diabetes Section, Department of Pediatrics, Yale School of Medicine, New Haven, CT.,Department of Woman and Child's Health, University of Padova, Padova, Italy
| | - Domenico Tricò
- Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy.,Institute of Life Sciences, Sant'Anna School of Advanced Studies, Pisa, Italy
| | - Bridget Pierpont
- Pediatrics Endocrinology and Diabetes Section, Department of Pediatrics, Yale School of Medicine, New Haven, CT
| | - Veronika Shabanova
- Pediatrics Endocrinology and Diabetes Section, Department of Pediatrics, Yale School of Medicine, New Haven, CT.,Yale School of Public Health, New Haven, CT
| | - Stephanie Samuels
- Pediatrics Endocrinology and Diabetes Section, Department of Pediatrics, Yale School of Medicine, New Haven, CT
| | - Chiara Dalla Man
- Department of Information Engineering, University of Padova, Padova, Italy
| | - Brittany Galuppo
- Pediatrics Endocrinology and Diabetes Section, Department of Pediatrics, Yale School of Medicine, New Haven, CT
| | - Nicola Santoro
- Pediatrics Endocrinology and Diabetes Section, Department of Pediatrics, Yale School of Medicine, New Haven, CT
| | - Sonia Caprio
- Pediatrics Endocrinology and Diabetes Section, Department of Pediatrics, Yale School of Medicine, New Haven, CT
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31
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Functional Interactomes of Genes Showing Association with Type-2 Diabetes and Its Intermediate Phenotypic Traits Point towards Adipo-Centric Mechanisms in Its Pathophysiology. Biomolecules 2020; 10:biom10040601. [PMID: 32294959 PMCID: PMC7226597 DOI: 10.3390/biom10040601] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 03/20/2020] [Accepted: 03/23/2020] [Indexed: 11/23/2022] Open
Abstract
The pathogenic mechanisms causing type 2 diabetes (T2D) are still poorly understood; a greater awareness of its causation can lead to the development of newer and better antidiabetic drugs. In this study, we used a network-based approach to assess the cellular processes associated with protein–protein interaction subnetworks of glycemic traits—HOMA-β and HOMA-IR. Their subnetworks were further analyzed in terms of their overlap with the differentially expressed genes (DEGs) in pancreatic, muscle, and adipose tissue in diabetics. We found several DEGs in these tissues showing an overlap with the HOMA-β subnetwork, suggesting a role of these tissues in β-cell failure. Many genes in the HOMA-IR subnetwork too showed an overlap with the HOMA-β subnetwork. For understanding the functional theme of these subnetworks, a pathway-to-pathway complementary network analysis was done, which identified various adipose biology-related pathways, containing genes involved in both insulin secretion and action. In conclusion, network analysis of genes showing an association between T2D and its intermediate phenotypic traits suggests their potential role in beta cell failure. These genes enriched the adipo-centric pathways and were expressed in both pancreatic and adipose tissue and, therefore, might be one of the potential targets for future antidiabetic treatment.
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32
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Michlin M, Argaev-Frenkel L, Weinstein-Fudim L, Ornoy A, Rosenzweig T. Maternal N-Acetyl Cysteine Intake Improved Glucose Tolerance in Obese Mice Offspring. Int J Mol Sci 2020; 21:E1981. [PMID: 32183232 PMCID: PMC7139991 DOI: 10.3390/ijms21061981] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 02/20/2020] [Accepted: 03/09/2020] [Indexed: 12/17/2022] Open
Abstract
Exposure to certain environmental factors during the early stages of development was found to affect health in adulthood. Among other environmental factors, oxidative stress has been suggested to be involved in fetal programming, leading to elevated risk for metabolic disorders, including type 2 diabetes; however, the possibility that antioxidant consumption during early life may affect the development of diabetes has scarcely been studied. The aim of this study was to investigate the effects of N-acetyl-l-cysteine (NAC) given during pregnancy and lactation on the susceptibility of offspring to develop glucose intolerance at adulthood. C57bl6/J mice were given NAC during pregnancy and lactation. High fat diet (HFD) was given to offspring at an age of 6 weeks for an additional 9 weeks, till the end of the study. Isolated islets of NAC-treated offspring (6 weeks old, before HFD feeding) had an increased efficacy of glucose-stimulated insulin secretion and a higher resistance to oxidative damage. Following HFD feeding, glucose tolerance and insulin sensitivity of NAC-treated offspring were improved. In addition, islet diameter was lower in male offspring of NAC-treated mice compared to their HFD-fed littermates. NAC consumption during early life improves glucose tolerance in adulthood in mice.
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Affiliation(s)
- Michal Michlin
- Departments of Molecular Biology and Nutrition Sciences, Ariel University, Ariel 40700, Israel; (M.M.); (L.A.-F.)
| | - Lital Argaev-Frenkel
- Departments of Molecular Biology and Nutrition Sciences, Ariel University, Ariel 40700, Israel; (M.M.); (L.A.-F.)
| | - Liza Weinstein-Fudim
- Laboratory of Teratology, Department of Medical Neurobiology, Hebrew University Hadassah Medical School, Jerusalem 91120, Israel; (L.W.-F.); (A.O.)
| | - Asher Ornoy
- Laboratory of Teratology, Department of Medical Neurobiology, Hebrew University Hadassah Medical School, Jerusalem 91120, Israel; (L.W.-F.); (A.O.)
- Adelson School of Medicine, Ariel University, Ariel 40700, Israel
| | - Tovit Rosenzweig
- Departments of Molecular Biology and Nutrition Sciences, Ariel University, Ariel 40700, Israel; (M.M.); (L.A.-F.)
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Protection from β-cell apoptosis by inhibition of TGF-β/Smad3 signaling. Cell Death Dis 2020; 11:184. [PMID: 32170115 PMCID: PMC7070087 DOI: 10.1038/s41419-020-2365-8] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 02/11/2020] [Accepted: 02/14/2020] [Indexed: 12/18/2022]
Abstract
Prevailing insulin resistance and the resultant hyperglycemia elicits a compensatory response from pancreatic islet beta cells (β-cells) that involves increases in β-cell function and β-cell mass. However, the sustained metabolic stress eventually leads to β-cell failure characterized by severe β-cell dysfunction and progressive loss of β-cell mass. Whereas, β-cell dysfunction is relatively well understood at the mechanistic level, the avenues leading to loss of β-cell mass are less clear with reduced proliferation, dedifferentiation, and apoptosis all potential mechanisms. Butler and colleagues documented increased β-cell apoptosis in pancreas from lean and obese human Type 2 diabetes (T2D) subjects, with no changes in rates of β-cell replication or neogenesis, strongly suggesting a role for apoptosis in β-cell failure. Here, we describe a permissive role for TGF-β/Smad3 in β-cell apoptosis. Human islets undergoing β-cell apoptosis release increased levels of TGF-β1 ligand and phosphorylation levels of TGF-β's chief transcription factor, Smad3, are increased in human T2D islets suggestive of an autocrine role for TGF-β/Smad3 signaling in β-cell apoptosis. Smad3 phosphorylation is similarly increased in diabetic mouse islets undergoing β-cell apoptosis. In mice, β-cell-specific activation of Smad3 promotes apoptosis and loss of β-cell mass in association with β-cell dysfunction, glucose intolerance, and diabetes. In contrast, inactive Smad3 protects from apoptosis and preserves β-cell mass while improving β-cell function and glucose tolerance. At the molecular level, Smad3 associates with Foxo1 to propagate TGF-β-dependent β-cell apoptosis. Indeed, genetic or pharmacologic inhibition of TGF-β/Smad3 signals or knocking down Foxo1 protects from β-cell apoptosis. These findings reveal the importance of TGF-β/Smad3 in promoting β-cell apoptosis and demonstrate the therapeutic potential of TGF-β/Smad3 antagonism to restore β-cell mass lost in diabetes.
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Zaiou M. circRNAs Signature as Potential Diagnostic and Prognostic Biomarker for Diabetes Mellitus and Related Cardiovascular Complications. Cells 2020; 9:659. [PMID: 32182790 PMCID: PMC7140626 DOI: 10.3390/cells9030659] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 02/28/2020] [Accepted: 03/05/2020] [Indexed: 12/15/2022] Open
Abstract
Circular RNAs (circRNAs) belong to the ever-growing class of naturally occurring noncoding RNAs (ncRNAs) molecules. Unlike linear RNA, circRNAs are covalently closed transcripts mostly generated from precursor-mRNA by a non-canonical event called back-splicing. They are highly stable, evolutionarily conserved, and widely distributed in eukaryotes. Some circRNAs are believed to fulfill a variety of functions inside the cell mainly by acting as microRNAs (miRNAs) or RNA-binding proteins (RBPs) sponges. Furthermore, mounting evidence suggests that the misregulation of circRNAs is among the first alterations in various metabolic disorders including obesity, hypertension, and cardiovascular diseases. More recent research has revealed that circRNAs also play a substantial role in the pathogenesis of diabetes mellitus (DM) and related vascular complications. These findings have added a new layer of complexity to our understanding of DM and underscored the need to reexamine the molecular pathways that lead to this disorder in the context of epigenetics and circRNA regulatory mechanisms. Here, I review current knowledge about circRNAs dysregulation in diabetes and describe their potential role as innovative biomarkers to predict diabetes-related cardiovascular (CV) events. Finally, I discuss some of the actual limitations to the promise of these RNA transcripts as emerging therapeutics and provide recommendations for future research on circRNA-based medicine.
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Affiliation(s)
- Mohamed Zaiou
- School of Pharmacy, Institut Jean-Lamour, The University of Lorraine, 7 Avenue de la Foret de Haye, CEDEX BP 90170, 54500 Vandoeuvre les Nancy, France
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Mattis KK, Gloyn AL. From Genetic Association to Molecular Mechanisms for Islet-cell Dysfunction in Type 2 Diabetes. J Mol Biol 2020; 432:1551-1578. [PMID: 31945378 DOI: 10.1016/j.jmb.2019.12.045] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 12/15/2019] [Accepted: 12/17/2019] [Indexed: 12/30/2022]
Abstract
Genome-wide association studies (GWAS) have identified over 400 signals robustly associated with risk for type 2 diabetes (T2D). At the vast majority of these loci, the lead single nucleotide polymorphisms (SNPs) reside in noncoding regions of the genome, which hampers biological inference and translation of genetic discoveries into disease mechanisms. The study of these T2D risk variants in normoglycemic individuals has revealed that a significant proportion are exerting their disease risk through islet-cell dysfunction. The central role of the islet is also demonstrated by numerous studies, which have shown an enrichment of these signals in islet-specific epigenomic annotations. In recent years the emergence of authentic human beta-cell lines, and advances in genome-editing technologies coupled with improved protocols differentiating human pluripotent stem cells into beta-like cells has opened up new opportunities for T2D disease modeling. Here we review the current understanding on the genetic basis of T2D focusing on approaches, which have facilitated the identification of causal variants and their effector transcripts in human islets. We will present examples of functional studies based on animal and conventional cellular systems and highlight the potential of novel stem cell-based T2D disease models.
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Affiliation(s)
- Katia K Mattis
- Oxford Centre for Diabetes Endocrinology & Metabolism, University of Oxford, UK
| | - Anna L Gloyn
- Oxford Centre for Diabetes Endocrinology & Metabolism, University of Oxford, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, UK; National Institute of Health Research, Biomedical Research Centre, Churchill Hospital, Headington, Oxford, UK.
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Gómez-Peralta F, Abreu C, Cos X, Gómez-Huelgas R. When does diabetes start? Early detection and intervention in type2 diabetes mellitus. Rev Clin Esp 2020; 220:305-314. [PMID: 32107016 DOI: 10.1016/j.rce.2019.12.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 12/12/2019] [Accepted: 12/14/2019] [Indexed: 01/09/2023]
Abstract
Type 2 diabetes mellitus (DM2) is a progressive disease whose pathophysiological changes occur several years before its detection. An approach based on the pathophysiological development of DM2 and its complications emphasises the importance of early and intensive intervention, not only to prevent beta-cell dysfunction but also to act on the potential associated cardiovascular risk factors before reaching the blood glucose thresholds currently set for diagnosing DM2. In the field of recently diagnosed DM2, the VERIFY study has shown that early treatment combined with metformin-vildagliptin provides relevant improvements in long-term glycaemic control and can positively affect the disease's progression.
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Affiliation(s)
- F Gómez-Peralta
- Unidad de Endocrinología y Nutrición, Hospital General de Segovia, Segovia, España.
| | - C Abreu
- Unidad de Endocrinología y Nutrición, Hospital General de Segovia, Segovia, España
| | - X Cos
- Innovation and Health in Primary Care Barcelona City, Gerència Barcelona Ciutat, Institut Català de la Salut, Barcelona, España; Fundació Institut Universitari d'Investigació en Atenció Primària Jordi Gol i Gurina (IDIAPJGol), Barcelona, España
| | - R Gómez-Huelgas
- Departamento de Medicina Interna, Hospital Regional Universitario, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga (UMA), Málaga, España
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Human Physiology of Genetic Defects Causing Beta-cell Dysfunction. J Mol Biol 2020; 432:1579-1598. [PMID: 31953147 DOI: 10.1016/j.jmb.2019.12.038] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 12/17/2019] [Accepted: 12/18/2019] [Indexed: 02/07/2023]
Abstract
The last decade has revealed hundreds of genetic variants associated with type 2 diabetes, many especially with insulin secretion. However, the evidence for their single or combined effect on beta-cell function relies mostly on genetic association of the variants or genetic risk scores with simple traits, and few have been functionally fully characterized even in cell or animal models. Translating the measured traits into human physiology is not straightforward: none of the various indices for beta-cell function or insulin sensitivity recapitulates the dynamic interplay between glucose sensing, endogenous glucose production, insulin production and secretion, insulin clearance, insulin resistance-to name just a few factors. Because insulin sensitivity is a major determinant of physiological need of insulin, insulin secretion should be evaluated in parallel with insulin sensitivity. On the other hand, multiple physiological or pathogenic processes can either mask or unmask subtle defects in beta-cell function. Even in monogenic diabetes, a clearly pathogenic genetic variant can result in different phenotypic characteristics-or no phenotype at all. In this review, we evaluate the methods available for studying beta-cell function in humans, critically examine the evidence linking some identified variants to a specific beta-cell phenotype, and highlight areas requiring further study.
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Beta-cell dysfunction and abnormal glucose metabolism among non-diabetic women with recurrent miscarriages. Arch Gynecol Obstet 2019; 301:559-564. [PMID: 31823038 DOI: 10.1007/s00404-019-05407-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Accepted: 12/02/2019] [Indexed: 10/25/2022]
Abstract
BACKGROUND Subclinical beta-cell (β-cell) dysfunction is an endocrine abnormality and its association with recurrent miscarriages (RM) has not been extensively studied. OBJECTIVE This study aimed to determine the prevalence of β-cell dysfunction and abnormal glucose metabolism [fasting blood glucose (FBG) ≥ 5.1 mmol/L] among non-diabetic women with recurrent miscarriages and to establish if there was an association between RM and β-cell dysfunction and FBG ≥ 5.1 mmol/L. METHODOLOGY This was a cross-sectional study involving 80 women with miscarriages at ≤ 13 weeks gestation and 80 women with normal pregnancies at ≤ 13 weeks of gestation with at least one successful live-birth and no history of miscarriage (comparison group). Interviewer-administered questionnaire was used to obtain relevant information. From each participant, FBG and fasting insulin were assayed. β-Cell function was computed. The data obtained was analysed using IBM-SPSS version 22.0. RESULTS A significantly higher prevalence of β-cell dysfunction and abnormal glucose metabolism were observed among non-diabetic women with RM compared to age-matched controls (38.8% vs 10.0%, P < 0.001) and (27.5% vs 6.3%, P = 0.005) respectively. The mean β-cell function of the cases was 59.0% of the controls (264.41 ± 105.13 vs 447.82 ± 181.24, P < 0.001). Mean FBG was significantly higher in the case-group compared to the controls (4.77 ± 1.14 mmol/L vs 3.58 ± 0.78 mmol/L, P < 0.001). There was a significant association between RM and FBG ≥ 5.1 mmol/L and low β-cell function (P < 0.001). CONCLUSION This study suggests that women with recurrent miscarriages are more likely to have impaired β-cell function and abnormal glucose metabolism (FBG ≥ 5.1 mmol/L).
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Serotonin is elevated in risk-genotype carriers of TCF7L2 - rs7903146. Sci Rep 2019; 9:12863. [PMID: 31492908 PMCID: PMC6731216 DOI: 10.1038/s41598-019-49347-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 08/12/2019] [Indexed: 01/21/2023] Open
Abstract
The transcription factor 7-like 2 (TCF7L2) polymorphism rs7903146 is known to be tightly associated with an elevated risk for type 2 diabetes, whereas the molecular mechanisms remain elusive. We evaluated the metabolic profile of a total of 394 patients' serum samples with respect to their rs7903146 genotype using targeted metabolomics in a discovery (n = 154) and a validation (n = 240) study. We have identified serotonin as the top metabolite being increased in carriers of the risk allele. Serotonin was significantly associated with the rs7903146 genotype after full adjustment including type 2 diabetes and further top ranked metabolites. Given the role of peripheral serotonin in metabolic homeostasis and type 2 diabetes, this finding provides a first hint that the well-known impact of the TCF7L2 polymorphism on type 2 diabetes risk may involve a serotonin-dependent pathway.
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Ferreira MC, da Silva MER, Fukui RT, do Carmo Arruda-Marques M, Azhar S, dos Santos RF. Effect of TCF7L2 polymorphism on pancreatic hormones after exenatide in type 2 diabetes. Diabetol Metab Syndr 2019; 11:10. [PMID: 30700996 PMCID: PMC6347826 DOI: 10.1186/s13098-019-0401-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Accepted: 01/17/2019] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and reduces blood glucose in type 2 diabetes mellitus (T2DM). TCF7L2 rs7903146 polymorphism has been associated with decreased insulin secretion, reduced GLP-1 action, and possible impaired peripheral insulin sensitivity. OBJECTIVES To evaluate the postprandial pancreatic hormone response in patients with T2DM carriers of the TCF7L2 variant rs7903146 (CT/TT) compared with noncarriers of this variant (CC) after treatment with the GLP-1 agonist exenatide. METHODS Intervention study. Patients with T2DM (n = 162) were genotyped for the TCF7L2 rs7903146 single nucleotide polymorphism (SNP). Individuals with CT/TT and CC genotypes were compared regarding basal serum levels of glucose, glycosylated hemoglobin A1C (HbA1c), HDL, uric acid, insulin, and C-peptide. A subset of 56 individuals was evaluated during a 500-calorie mixed-meal test with measurements of glucose, insulin, proinsulin, C-peptide and glucagon before and after treatment with exenatide for 8 weeks. RESULTS Patients with genotypes CC and CT/TT presented similar glucose area under the curve (AUC) 0-180 min before treatment and a similar decrease after treatment (p < 0.001). Before exenatide, insulin levels at 30-120 min were higher in CT/TT versus CC subjects (p < 0.05). After treatment with exenatide, only CT/TT individuals demonstrated insulin reduction at 30-180 min during the meal test (p < 0.05). Patients with the CC genotype presented no differences in insulin concentrations before and after treatment. The areas under the glucagon curve between 0 and 180 min were similar before treatment and reduced after treatment in both groups (p < 0.001). CONCLUSIONS The presence of the TCF7L2 rs7903146 T allele in patients with T2DM was associated with increased secretion of insulin response to a mixed-meal test. Furthermore, after treatment with exenatide, only the carriers of the T allele showed significantly decreased postprandial plasma insulin peak levels comparing with non carriers.
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Affiliation(s)
- Mari Cassol Ferreira
- School of Medicine, Unochapeco University, Chapeco, Santa Catarina Brazil
- School of Medicine, University of Sao Paulo, São Paulo, Brazil
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Xin Y, Wang Y, Chi J, Zhu X, Zhao H, Zhao S, Wang Y. Elevated free fatty acid level is associated with insulin-resistant state in nondiabetic Chinese people. Diabetes Metab Syndr Obes 2019; 12:139-147. [PMID: 30705599 PMCID: PMC6342222 DOI: 10.2147/dmso.s186505] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Free fatty acids (FFAs) are associated with insulin secretion and insulin resistance. However, the associations among FFAs, obesity, and progression from a normal to a prediabetic state are unclear. METHODS Nondiabetic subjects (5,952) were divided in two groups according to their body mass index (BMI): obese subjects (BMI ≥24 kg/m2) and nonobese subjects (BMI <24 kg/m2). Clinical and multiple glucolipid metabolism data were collected. The homeostasis model assessment for insulin resistance (HOMA-IR) and β-cell function (HOMA-β) was used. HbA1c level between 5.7% and 6.4% was considered prediabetic. Nonparametric tests, one-way ANOVA, and linear correlation analysis were performed. R and SPSS 23.0 software programs were used to analyze the results. RESULTS A U-shaped relationship between FFAs and HOMA-IR was observed. After adjusting for potential confounders, the turning points of FFA levels in the curves were 0.54 mmol/L in the nonobese group and 0.61 mmol/L in the obese group. HOMA-IR levels decreased with increasing FFA concentrations before the turning points (regression coefficient [β]= - 0.9, P=0.0111, for the nonobese group; β=0.2, P=0.5094, for the obese group) and then increased (β=0.9, P=0.0069, for the nonobese group; β=1.5, P=0.0263 for the obese group) after the points. Additionally, our study also identified that FFAs were associated with the prediabetes status in obese individuals. CONCLUSION FFA levels were associated with insulin resistance in nondiabetic subjects, and HOMA-IR in nonobese individuals was more sensitive to FFA changes. Monitoring and controlling plasma FFA levels in obese subjects is significant in decreasing insulin resistance and preventing diabetes.
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Affiliation(s)
- Yanlu Xin
- Department of Endocrinology and Metabolism, Affiliated Hospital of Qingdao University, Qingdao, China, ;
| | - Yunyang Wang
- Department of Endocrinology and Metabolism, Affiliated Hospital of Qingdao University, Qingdao, China, ;
| | - Jingwei Chi
- Laboratory of Thyroid Disease, Affiliated Hospital of Qingdao University, Qingdao, China,
| | - Xvhua Zhu
- Department of Endocrinology and Metabolism, Second People's Hospital of Qingdao West Coast, Qingdao, China
| | - Hui Zhao
- Department of Endocrinology and Metabolism, Hiser Medical Center of Qingdao, Qingdao, China
| | - Shihua Zhao
- Department of Endocrinology and Metabolism, Affiliated Hospital of Qingdao University, Qingdao, China, ;
- Laboratory of Thyroid Disease, Affiliated Hospital of Qingdao University, Qingdao, China,
| | - Yangang Wang
- Department of Endocrinology and Metabolism, Affiliated Hospital of Qingdao University, Qingdao, China, ;
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Evans-Molina C, Sims EK, DiMeglio LA, Ismail HM, Steck AK, Palmer JP, Krischer JP, Geyer S, Xu P, Sosenko JM. β Cell dysfunction exists more than 5 years before type 1 diabetes diagnosis. JCI Insight 2018; 3:120877. [PMID: 30089716 DOI: 10.1172/jci.insight.120877] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 06/21/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The duration and patterns of β cell dysfunction during type 1 diabetes (T1D) development have not been fully defined. METHODS Metabolic measures derived from oral glucose tolerance tests (OGTTs) were compared between autoantibody-positive (aAb+) individuals followed in the TrialNet Pathway to Prevention study who developed diabetes after 5 or more years or less than 5 years of longitudinal follow-up (Progressors≥5, n = 75; Progressors<5, n = 474) and 144 aAb-negative (aAb-) relatives. RESULTS Mean age at study entry was 15.0 ± 12.6 years for Progressors≥5; 12.0 ± 9.1 for Progressors<5; and 16.3 ± 10.4 for aAb- relatives. At baseline, Progressors≥5 already exhibited significantly lower fasting C-peptide (P < 0.01), C-peptide AUC (P < 0.001), and early C-peptide responses (30- to 0-minute C-peptide; P < 0.001) compared with aAb- relatives, while 2-hour glucose (P = 0.03), glucose AUC (<0.001), and Index60 (<0.001) were all higher. Despite significant baseline impairment, metabolic measures in Progressors≥5 were relatively stable until 2 years prior to T1D diagnosis, when there was accelerated C-peptide decline and rising glycemia from 2 years until diabetes diagnosis. Remarkably, patterns of progression within 3 years of diagnosis were nearly identical between Progressors≥5 and Progressors<5. CONCLUSION These data provide insight into the chronicity of β cell dysfunction in T1D and indicate that β cell dysfunction may precede diabetes diagnosis by more than 5 years in a subset of aAb+ individuals. Even among individuals with varying lengths of aAb positivity, our findings indicate that patterns of metabolic decline are uniform within the last 3 years of progression to T1D. TRIAL REGISTRATION Clinicaltrials.gov NCT00097292. FUNDING The Type 1 Diabetes TrialNet Study Group is a clinical trials network currently funded by the NIH through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Juvenile Diabetes Research Foundation.
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Affiliation(s)
- Carmella Evans-Molina
- Departments of Medicine.,Cellular and Integrative Physiology.,Biochemistry and Molecular Biology.,Pediatrics, and the.,Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Roudebush VA Medical Center, Indianapolis, Indiana, USA
| | - Emily K Sims
- Pediatrics, and the.,Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Linda A DiMeglio
- Pediatrics, and the.,Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Heba M Ismail
- Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Andrea K Steck
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Denver, Colorado, USA
| | - Jerry P Palmer
- VA Puget Sound Health Care System and the University of Washington, Seattle, Washington, USA
| | - Jeffrey P Krischer
- Health Informatics Institute, University of South Florida, Tampa, Florida, USA
| | - Susan Geyer
- Health Informatics Institute, University of South Florida, Tampa, Florida, USA
| | - Ping Xu
- Health Informatics Institute, University of South Florida, Tampa, Florida, USA
| | - Jay M Sosenko
- Department of Medicine and the Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, Florida, USA
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Abstract
Metabolic disease risk is driven by defects in the function of cells that regulate energy homeostasis, as well as altered communication between the different tissues or organs that these cells occupy. Thus, it is desirable to use model organisms to understand the contribution of different cells, tissues and organs to metabolism. Mice are widely used for metabolic research, since well-characterised mouse strains (in terms of their genotype and phenotype) allow comparative studies and human disease modelling. Such research involves strains containing spontaneous mutations that lead to obesity and diabetes, surgically- and chemically-induced models, those that are secondary to caloric excess, genetic mutants created by transgenesis and gene knockout technologies, and peripheral models generated by Cre-Lox or CRISPR/Cas9 approaches. Focussing on obesity and type 2 diabetes as relevant metabolic diseases, we systematically review each of these models, discussing their use, limitations, and future potential.
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Affiliation(s)
- Gabriela da Silva Xavier
- Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London W12 0NN, UK; Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Edgbaston, B15 2TT, UK.
| | - David J Hodson
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Edgbaston, B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, UK; COMPARE University of Birmingham and University of Nottingham Midlands, UK.
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Xu M, Hu H, Deng D, Chen M, Xu Z, Wang Y. Prediabetes is associated with genetic variations in the gene encoding the Kir6.2 subunit of the pancreatic ATP-sensitive potassium channel (KCNJ11): A case-control study in a Han Chinese youth population. J Diabetes 2018; 10:121-129. [PMID: 28449408 DOI: 10.1111/1753-0407.12565] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Revised: 04/06/2017] [Accepted: 04/24/2017] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND The E23K variant of the potassium voltage-gated channel subfamily J member 11 (KCNJ11) gene has been reported to be associated with type 2 diabetes (T2D) in many populations. However, little is known about the role of E23K in the development of prediabetes in Chinese youth. METHODS To investigate the role of E23K in the development of prediabetes, 279 subjects with prediabetes and 240 normal controls (mean [± SD] age 18.1 ± 3.2 and 17.8 ± 4.3 years, respectively) were recruited to the study. Height, weight, and hip and waist circumferences were measured by trained physicians. Genotyping of KCNJ11 polymorphisms and clinical laboratory tests to determine cholesterol, triglyceride (TG), blood glucose, and insulin levels were performed. RESULTS The carrier rate of K23 allele-containing genotypes was higher for prediabetic than control subjects (P = 0.005). Logistic regression analyses revealed that higher body mass index percentiles (P = 0.013), lower insulin levels at 30 min during an oral glucose tolerance test (P = 0.001), a higher ratio of total cholesterol: high-density lipoprotein cholesterol (P = 0.001), and a K allele-containing genotype (P = 0.019) are independent risk factors for prediabetes in Chinese Han youth. Furthermore, K23 allele-containing genotypes were associated with impaired indices of insulin secretion and β-cell function in female youth with prediabetes. These effects were not seen in male youth with prediabetes. CONCLUSIONS The results confirm that the common E23K polymorphism of KCNJ11 carries a higher susceptibility to the development of prediabetes in the Chinese Han population. The results suggest that E23K may have a greater effect on the development of T2D in female Chinese youth.
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Affiliation(s)
- Min Xu
- Department of Endocrinology, The First Hospital of An Hui Medical University, Hefei, China
| | - Honglin Hu
- Department of Endocrinology, The First Hospital of An Hui Medical University, Hefei, China
| | - Datong Deng
- Department of Endocrinology, The First Hospital of An Hui Medical University, Hefei, China
| | - Mingwei Chen
- Department of Endocrinology, The First Hospital of An Hui Medical University, Hefei, China
| | - Zhenshan Xu
- AnHui AnKe Biotechnology Group, Hefei, China
| | - Youmin Wang
- Department of Endocrinology, The First Hospital of An Hui Medical University, Hefei, China
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Hong KW, Kim SH, Zhang X, Park S. Interactions among the variants of insulin-related genes and nutrients increase the risk of type 2 diabetes. Nutr Res 2018; 51:82-92. [PMID: 29673546 DOI: 10.1016/j.nutres.2017.12.012] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Revised: 12/27/2017] [Accepted: 12/29/2017] [Indexed: 01/14/2023]
Abstract
Asians easily develops type 2 diabetes (T2DM) since they have insufficient glucose-stimulated insulin secretion (GSIS) in insulin resistant states. Since this may be associated with genetic background, the hypothesis of this study was that inter-genetic and gene-nutrient interactions may explain the low insulin secretory capacity of Asians. Accordingly, we identified the best gene-gene and gene-nutrient interactions using generalized multifactor dimensionality reduction (GMDR) in a large Korean cohort (n=8,842). Initially, we used 105 genetic variants associated with GSIS to identify the best gene-gene interaction model using the GMDR method. The best model included six SNPs, FNBP1L-rs4847428, FNBP1L-rs23766, GLIS3-rs2027393, GLIS3-rs3892354, GLIS3-rs486163 and DLC1-rs17093957. For each individual, we obtained the genetic risk scores based on the best model (GRSBM) to predict the GSIS levels. The GRSBM were divided into low, medium and high groups, and the association between T2DM and the GRSBM was measured using logistic regression. We analyzed the interaction between the GRSBM and the nutrition intakes. The adjusted odds ratios for T2DM risk increased by 1.701 fold in the high-score group compared to the low-score group. HOMA-B, an index of insulin secretion capacity, but not insulin resistance index was much lower in the high-score group than the low-score group. The association between the GRSBM and T2DM risk was greater in subjects with high energy intakes and low Ca intake, than those with low energy intake and high Ca intake. The high-score group was susceptible to T2DM incidence due to lower GSIS than the low-score group especially in subjects with high energy intake. In conclusion, the hypothesis of the study was accepted. These findings suggested that individuals with high GRSBM of the 6 genes in the model should avoid diets in high energy and low in calcium (<500 mg/day) to protect against T2DM.
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Affiliation(s)
- Kyung-Won Hong
- Division of Personal Genome Service, Theragen Etex Bio Institute Co., Ltd., Suwon, Gyeonggi, South Korea
| | - Sung Hoon Kim
- Division of Endocrinology & Metabolism, Cheil General Hospital & Women's Healthcare Center, Dankook University College of Medicine, Seoul, South Korea
| | - Xin Zhang
- Dept. of Food and Nutrition, Obesity/Diabetes Research Center, Hoseo University, Asan, South Korea
| | - Sunmin Park
- Dept. of Food and Nutrition, Obesity/Diabetes Research Center, Hoseo University, Asan, South Korea.
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Abstract
This chapter reviews both statistical and physiologic issues related to the pathophysiologic effects of genetic variation in the context of type 2 diabetes. The goal is to review current methodologies used to analyze disease-related quantitative traits for those who do not have extensive quantitative and physiologic background, as an attempt to bridge that gap. We leverage mathematical modeling to illustrate the strengths and weaknesses of different approaches and attempt to reinforce with real data analysis. Topics reviewed include phenotype selection, phenotype specificity, multiple variant analysis via the genetic risk score, and consideration of multiple disease-related phenotypes. Type 2 diabetes is used as the example, not only because of the extensive existing knowledge at the genetic, physiologic, clinical, and epidemiologic levels, but also because type 2 diabetes has been at the forefront of complex disease genetics, with many examples to draw from.
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Affiliation(s)
- Richard M Watanabe
- Departments of Preventive Medicine and Physiology & Biophysics, Keck School of Medicine of USC, 2250 Alcazar Street, CSC-204, Los Angeles, CA, 90089-9073, USA.
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Hall MA, Moore JH, Ritchie MD. Embracing Complex Associations in Common Traits: Critical Considerations for Precision Medicine. Trends Genet 2017; 32:470-484. [PMID: 27392675 DOI: 10.1016/j.tig.2016.06.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 06/01/2016] [Accepted: 06/02/2016] [Indexed: 10/21/2022]
Abstract
Genome-wide association studies (GWAS) have identified numerous loci associated with human phenotypes. This approach, however, does not consider the richly diverse and complex environment with which humans interact throughout the life course, nor does it allow for interrelationships between genetic loci and across traits. As we move toward making precision medicine a reality, whereby we make predictions about disease risk based on genomic profiles, we need to identify improved predictive models of the relationship between genome and phenome. Methods that embrace pleiotropy (the effect of one locus on more than one trait), and gene-environment (G×E) and gene-gene (G×G) interactions, will further unveil the impact of alterations in biological pathways and identify genes that are only involved with disease in the context of the environment. This valuable information can be used to assess personal risk and choose the most appropriate medical interventions based on the genotype and environment of an individual, the whole premise of precision medicine.
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Affiliation(s)
- Molly A Hall
- Institute for Biomedical Informatics, Departments of Genetics and Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, 3535 Market Street, Philadelphia, PA 19104, USA
| | - Jason H Moore
- Institute for Biomedical Informatics, Departments of Genetics and Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, 3535 Market Street, Philadelphia, PA 19104, USA
| | - Marylyn D Ritchie
- Biomedical and Translational Informatics, Geisinger Health System, Danville, PA, USA; Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Eberly College of Science, The Pennsylvania State University, University Park, PA, USA.
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Sharma A, Vella A. Obstacles to Translating Genotype-Phenotype Correlates in Metabolic Disease. Physiology (Bethesda) 2017; 32:42-50. [PMID: 27927804 DOI: 10.1152/physiol.00009.2016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Type 2 diabetes mellitus is a polygenic disease with a variable phenotype. Many genetic associations have been described; however, understanding their underlying pathophysiological role in Type 2 diabetes mellitus is important for development of future therapeutic targets. Here, we review the physiological mechanisms of diabetes-associated variants that affect glycemia.
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Affiliation(s)
- Anu Sharma
- Department of Endocrinology, Diabetes and Nutrition, Mayo Clinic, Rochester, Minnesota
| | - Adrian Vella
- Department of Endocrinology, Diabetes and Nutrition, Mayo Clinic, Rochester, Minnesota
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Zhu L, Xie Z, Lu J, Hao Q, Kang M, Chen S, Tang W, Ding H, Chen Y, Liu C, Wu H. TCF7L2 rs290481 T>C polymorphism is associated with an increased risk of type 2 diabetes mellitus and fasting plasma glucose level. Oncotarget 2017; 8:77000-77008. [PMID: 29100364 PMCID: PMC5652758 DOI: 10.18632/oncotarget.20300] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 06/20/2017] [Indexed: 01/19/2023] Open
Abstract
Genetic polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene may be key agents in the etiology of type 2 diabetes mellitus (T2DM). In the present case-control study, we aimed to assess the possible relationship of TCF7L2 polymorphisms with T2DM and determine the effect of TCF7L2 polymorphisms on the level of fasting plasma glucose (FPG) in Eastern Chinese Han subjects. The TCF7L2 rs7903146C>T and rs290481 T>C polymorphisms were genotyped by SNPscan genotyping assays in 502 subjects with T2DM and 782 non-diabetic controls. After adjusting for age, gender, drinking, smoking and body mass index (BMI), the association of TCF7L2 rs7903146C>T and rs290481 T>C polymorphisms with T2DM was determined. We found that TCF7L2 rs290481 T>C polymorphism increased the susceptibility of T2DM in the overall comparison. In subgroup analyses by age, sex, BMI, alcohol use and smoking status, a significantly increased risk of T2DM was also found in female, older subject and never drinking and BMI < 24 kg/m2 subgroups. The relationship of TCF7L2 rs290481 T>C polymorphism with the biochemistry characteristics in controls was also assessed. We found that TCF7L2 rs290481 T>C polymorphism significantly increased the level of FPG in controls. Our findings suggest that TCF7L2 rs290481 T>C polymorphism is associated with T2DM in Eastern Chinese Han population and links to variations in FPG level. In addition, these relationships are more pronounced in female, older subject and never drinking and BMI < 24 kg/m2 subgroups. A comprehensive fine-mapping study with functional investigation is needed to confirm or refute these potential correlations.
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Affiliation(s)
- Li Zhu
- Department of Nephrology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, China
| | - Zhiqiang Xie
- Department of Clinical Laboratory, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Jianping Lu
- Department of Pathology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian Province, China
| | - Qiu Hao
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China
| | - Mingqiang Kang
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Shuchen Chen
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Weifeng Tang
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Hao Ding
- Department of Respiratory Disease, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, China
| | - Yu Chen
- Department of Medical Oncology, Fujian Provincial Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian Province, China
| | - Chao Liu
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, China
| | - Haojie Wu
- Department of Endocrinology, Zhongshan Hospital Xiamen University, Xiamen, Fujian Province, China
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Cropano C, Santoro N, Groop L, Dalla Man C, Cobelli C, Galderisi A, Kursawe R, Pierpont B, Goffredo M, Caprio S. The rs7903146 Variant in the TCF7L2 Gene Increases the Risk of Prediabetes/Type 2 Diabetes in Obese Adolescents by Impairing β-Cell Function and Hepatic Insulin Sensitivity. Diabetes Care 2017; 40:1082-1089. [PMID: 28611053 PMCID: PMC5521977 DOI: 10.2337/dc17-0290] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 05/06/2017] [Indexed: 02/03/2023]
Abstract
OBJECTIVE In this study, we aimed to explore the mechanism by which TCF7L2 rs7903146 risk allele confers susceptibility to impaired glucose tolerance (IGT) or type 2 diabetes (T2D) in obese adolescents. RESEARCH DESIGN AND METHODS The rs7903146 variant in the TCF7L2 gene was genotyped in a multiethnic cohort of 955 youths. All subjects underwent an oral glucose tolerance test with the use of the Oral Minimal Model to assess insulin secretion, and 33 subjects underwent a hyperinsulinemic-euglycemic clamp. In 307 subjects, a follow-up oral glucose tolerance test was repeated after 3.11 ± 2.36 years. RESULTS The TCF7L2 rs7903146 risk allele was associated with higher 2-h glucose levels in Caucasians (P = 0.006) and African Americans (P = 0.009), and a trend was seen also in Hispanics (P = 0.072). Also, the T allele was associated with decreased β-cell responsivity and IGT (P < 0.05). Suppression of endogenous hepatic glucose production was lower in subjects with the risk variant (P = 0.006). Finally, the odds of showing IGT/T2D at follow-up were higher in subjects carrying the minor allele (odds ratio 2.224; 95% CI 1.370-3.612; P = 0.0012). CONCLUSIONS The rs7903146 variant in the TCF7L2 gene increases the risk of IGT/T2D in obese adolescents by impairing β-cell function, and hepatic insulin sensitivity predicts the development of IGT/T2D over time.
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Affiliation(s)
- Catrina Cropano
- Division of Pediatric Endocrinology, Department of Pediatrics, Yale University School of Medicine, New Haven, CT
| | - Nicola Santoro
- Division of Pediatric Endocrinology, Department of Pediatrics, Yale University School of Medicine, New Haven, CT
| | - Leif Groop
- Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Malmo, Sweden.,Lund University Diabetes Center, Lund University, Malmo, Sweden
| | - Chiara Dalla Man
- Department of Information Engineering, University of Padua, Padua, Italy
| | - Claudio Cobelli
- Department of Information Engineering, University of Padua, Padua, Italy
| | - Alfonso Galderisi
- Division of Pediatric Endocrinology, Department of Pediatrics, Yale University School of Medicine, New Haven, CT
| | | | - Bridget Pierpont
- Division of Pediatric Endocrinology, Department of Pediatrics, Yale University School of Medicine, New Haven, CT
| | - Martina Goffredo
- Division of Pediatric Endocrinology, Department of Pediatrics, Yale University School of Medicine, New Haven, CT
| | - Sonia Caprio
- Division of Pediatric Endocrinology, Department of Pediatrics, Yale University School of Medicine, New Haven, CT
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