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Attaye I, Bird JK, Nieuwdorp M, Gül S, Seegers JFML, Morrison S, Hofkens S, Herrema H, Bui N, Puhlmann ML, de Vos WM. Anaerobutyricum soehngenii improves glycemic control and other markers of cardio-metabolic health in adults at risk of type 2 diabetes. Gut Microbes 2025; 17:2504115. [PMID: 40371708 PMCID: PMC12087665 DOI: 10.1080/19490976.2025.2504115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 03/11/2025] [Accepted: 04/25/2025] [Indexed: 05/16/2025] Open
Abstract
Anaerobutyricum soehngenii (previously Eubacterium hallii) is a butyrate-producing next-generation beneficial microbe generally recognized as safe. Several short-term intervention trials by A. soehngenii L2-7 have shown improvement of insulin sensitivity in prediabetic subjects and type 2 diabetes patients. To determine the long-term cardiometabolic benefits and safety, we performed a 3-month double-blind, randomized placebo-controlled intervention in 98 prediabetic insulin-resistant adults in Europe and U.S. with daily administration of encapsulated cells of A. soehngenii CH-106, a tetracycline-sensitive isogenic derivative of strain L2-7. Compared to placebo, A. soehngenii-treated subjects showed significantly reduced glycemic variability (1% reduction in the coefficient of variation; p = 0.01) and improved glycemic control (6% reduction in the overall net glycemic action-1; p < 0.05), including reduced serum glycated hemoglobin (HbA1c) levels when including the 4-week washout period (1 mmol/mol reduction; p < 0.05). Moreover, diastolic blood pressure was significantly reduced in all A. soehngenii-treated subjects (3 mm Hg; p < 0.05). The study product was well-tolerated and had no effect on the global intestinal microbiota composition, including alpha and beta-diversity, besides an increased abundance of A. soehngenii in the treatment group, indicative of compliance. The U.S. participants, compared to those in Europe, responded best, notably in the oral glucose tolerance tests (15% improvement in the area-under-the curve of plasma glucose levels; p = 0.039) or coefficient of variation (reduction of 3.1%; p < 0.05). This potentially relates to a more severe prediabetic state in U.S. subjects, associated with significantly reduced (1.5-3.5-fold) relative abundance of Bifidobacterium, Coprococcus, Ruminococcus spp. and two-fold increased relative abundance of Lachnoclostridium spp. In conclusion, daily oral supplementation with A. soehngenii was safe and improved various markers of glycemic control, reduced HbA1c levels and diastolic blood pressure, indicating a novel microbiome-based approach to improve cardio-metabolic health in adults at risk for developing type 2 diabetes.Clinical trial reg. no. NCT04529473, clinicaltrials.govSocial media summary 120 characters: Anaerobutyricum soehngenii supplementation improves #cardio-metabolic health in subjects at risk for type 2 #diabetes.
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Affiliation(s)
- Ilias Attaye
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, The Netherlands
- Amsterdam Cardiovascular Sciences, Diabetes & Metabolism, Amsterdam, The Netherlands
| | | | - Max Nieuwdorp
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, The Netherlands
- Amsterdam Cardiovascular Sciences, Diabetes & Metabolism, Amsterdam, The Netherlands
- Department of Experimental Vascular Medicine, Amsterdam University Medical Centers, The Netherlands
| | - Sahin Gül
- Caelus Health, Zegveld, The Netherlands
| | | | | | | | - Hilde Herrema
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, The Netherlands
- Amsterdam Cardiovascular Sciences, Diabetes & Metabolism, Amsterdam, The Netherlands
| | - Nam Bui
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, The Netherlands
- Amsterdam Cardiovascular Sciences, Diabetes & Metabolism, Amsterdam, The Netherlands
| | | | - Willem M. de Vos
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, The Netherlands
- Caelus Health, Zegveld, The Netherlands
- Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Finland
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Adeva-Andany MM, Adeva-Contreras L, Carneiro-Freire N, Ameneiros-Rodríguez E, Vila-Altesor M, Calvo-Castro I. The impact of high altitude (hypobaric hypoxia) on insulin resistance in humans. J Physiol Biochem 2025; 81:35-55. [PMID: 40019670 DOI: 10.1007/s13105-025-01069-8] [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: 06/22/2024] [Accepted: 01/30/2025] [Indexed: 03/01/2025]
Abstract
Exposure to hypobaric hypoxia (high altitude) diminishes systemic tissue oxygenation. Tissue hypoxia induces insulin resistance and a metabolic switch that reduces oxidative phosphorylation and glucose storage while enhancing glycolysis. Similarly to hypobaric hypoxia, insulin resistance develops in normal humans undergoing normobaric hypoxia and in patients with obstructive sleep apnea. Following acute exposure to high altitude, insulin resistance returns to baseline values upon returning to sea level or when compensatory mechanisms restore tissue oxygenation. However, insulin resistance persists in subjects unable to achieve sufficient oxygen delivery to tissues. Likewise, long-term residents at high altitude develop persistent insulin resistance when compensatory mechanisms do not attain adequate tissue oxygenation. Among these subjects, insulin resistance may cause clinical complications, such as hypertriglyceridemia, reduced HDL-c, visceral obesity, metabolic dysfunction-associated steatotic liver disease, essential hypertension, type 2 diabetes, subclinical vascular injury, cardiovascular disease, and kidney disease. Impaired tissue oxygenation allows the stabilization of hypoxia-inducible factor-1 (HIF-1), a transcription factor that modulates the transcriptional activity of a number of genes to coordinate the physiological responses to tissue hypoxia. Among them, HIF-1 downregulates PPARG, that codes peroxisome proliferator-activated receptor-gamma (PPAR-γ) and PPARGCA, that codes PPAR-γ coactivator-1α, in order to enable insulin resistance and the metabolic switch from oxidative phosphorylation toward glycolysis.
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Affiliation(s)
- María M Adeva-Andany
- Internal Medicine Department, Hospital General Juan Cardona, c/ Pardo Bazán s/n, Ferrol, 15406, Spain.
| | - Lucia Adeva-Contreras
- School of Medicine, Santiago de Compostela University, Santiago de Compostela, Galicia, Spain
| | - Natalia Carneiro-Freire
- Internal Medicine Department, Hospital General Juan Cardona, c/ Pardo Bazán s/n, Ferrol, 15406, Spain
| | - Eva Ameneiros-Rodríguez
- Internal Medicine Department, Hospital General Juan Cardona, c/ Pardo Bazán s/n, Ferrol, 15406, Spain
| | - Matilde Vila-Altesor
- Internal Medicine Department, Hospital General Juan Cardona, c/ Pardo Bazán s/n, Ferrol, 15406, Spain
| | - Isabel Calvo-Castro
- Internal Medicine Department, Hospital General Juan Cardona, c/ Pardo Bazán s/n, Ferrol, 15406, Spain
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Fulghum K, Salathe SF, Davis X, Thyfault JP, Puchalska P, Crawford PA. Ketone body metabolism and cardiometabolic implications for cognitive health. NPJ METABOLIC HEALTH AND DISEASE 2024; 2:29. [PMID: 40093558 PMCID: PMC11908690 DOI: 10.1038/s44324-024-00029-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 08/05/2024] [Indexed: 03/19/2025]
Abstract
Cardiometabolic complications of obesity present a growing public health concern and are associated with poor outcomes, mediated in part by an increased risk for cardiovascular disease, metabolic dysfunction-associated fatty liver disease, and systemic insulin resistance. Recent studies support that both insulin resistance and obesity are also associated with aberrant brain metabolism and cognitive impairment similar to what is observed in neurodegenerative diseases. Central to these pathological outcomes are adverse changes in tissue glucose and ketone body metabolism, suggesting that regulation of substrate utilization could be a mechanistic link between the cardiometabolic outcomes of obesity and the progression of cognitive decline. Here, we review ketone body metabolism in physiological and pathological conditions with an emphasis on the therapeutic potential of ketone bodies in treating cardiometabolic diseases and neurodegenerative diseases that lead to cognitive decline. We highlight recent findings in the associations among cardiometabolic disease, ketone body metabolism, and cognitive health while providing a theoretical framework by which ketone bodies may promote positive health outcomes and preserve cognitive function.
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Affiliation(s)
- Kyle Fulghum
- Division of Molecular Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Sebastian F. Salathe
- Departments of Cell Biology and Physiology and Internal Medicine – Division of Endocrinology and Metabolism, Kansas University Medical Center, Kansas City, KS, USA
| | - Xin Davis
- Departments of Cell Biology and Physiology and Internal Medicine – Division of Endocrinology and Metabolism, Kansas University Medical Center, Kansas City, KS, USA
| | - John P. Thyfault
- Departments of Cell Biology and Physiology and Internal Medicine – Division of Endocrinology and Metabolism, Kansas University Medical Center, Kansas City, KS, USA
| | - Patrycja Puchalska
- Division of Molecular Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Peter A. Crawford
- Division of Molecular Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
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Arevalo JA, Leija RG, Osmond AD, Curl CC, Duong JJ, Huie MJ, Masharani U, Brooks GA. Delayed and diminished postprandial lactate shuttling in healthy older men and women. Am J Physiol Endocrinol Metab 2024; 327:E430-E440. [PMID: 39110417 PMCID: PMC11482286 DOI: 10.1152/ajpendo.00183.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 07/22/2024] [Accepted: 07/30/2024] [Indexed: 09/19/2024]
Abstract
Lactate, a product of glycolysis, is formed under aerobic conditions. Extensive work has shown lactate flux in young and exercising humans; however, the effect of age is not known. We tested the hypothesis that postprandial lactate shuttling (PLS) would be diminished in older adults. We used [3-13C]lactate and [6,6-2H]glucose tracers, an oral glucose tolerance test (OGTT), and arterialized blood sampling to determine postprandial lactate rates of appearance (Ra), disappearance (Rd), and oxidation (Rox) in 15 young (28.1 ± 1.4 yr) and 13 older (70.6 ± 2.4 yr) healthy men and women. In young participants, fasting blood [lactate] (≈0.5 mM) rose after the glucose challenge, peaked at 15 min, dipped to a nadir at 30 min, and rose again peaking at 60 min (≈1.0 mM). Initial responses in lactate Ra of older participants were delayed and diminished until 90 min rising by 0.83 mg·kg-1·min-1. Lactate Rox was higher throughout the entire trial in young participants by a difference of ∼0.5 mg·kg-1·min-1. Initial peaks in lactate Ra and concentration in all volunteers demonstrated the presence of an enteric PLS following an OGTT. Notably, in the systemic, but not enteric, PLS phase, lactate Ra correlated highly with glucose Rd (r2 = 0.92). Correspondence of second peaks in lactate Ra and concentration and glucose Rd shows dependence of lactate Ra on glucose Rd. Although results show both enteric and systemic PLS phases in young and older study cohorts, metabolic responses were delayed and diminished in healthy older individuals.NEW & NOTEWORTHY We used isotope tracers, an oral glucose tolerance test, and arterialized blood sampling to determine postprandial lactate flux rates in healthy young and older men and women. Lactate rates of appearance and oxidation and the lactate-pyruvate exchange were delayed and diminished in both enteric and systemic postprandial lactate shuttle phases in older participants.
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Affiliation(s)
- Jose A. Arevalo
- Exercise Physiology Laboratory, Department of Integrative Biology, University of California, Berkeley, United States
| | - Robert G. Leija
- Exercise Physiology Laboratory, Department of Integrative Biology, University of California, Berkeley, United States
| | - Adam D. Osmond
- Exercise Physiology Laboratory, Department of Integrative Biology, University of California, Berkeley, United States
| | - Casey C. Curl
- Exercise Physiology Laboratory, Department of Integrative Biology, University of California, Berkeley, United States
| | - Justin J. Duong
- Exercise Physiology Laboratory, Department of Integrative Biology, University of California, Berkeley, United States
| | - Melvin J. Huie
- Exercise Physiology Laboratory, Department of Integrative Biology, University of California, Berkeley, United States
| | - Umesh Masharani
- Department of Medicine, University of California, San Francisco, United States
| | - George A. Brooks
- Exercise Physiology Laboratory, Department of Integrative Biology, University of California, Berkeley, United States
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Bonet J, Barbieri E, Santoro N, Dalla Man C. Modeling Glucose, Insulin, C-Peptide, and Lactate Interplay in Adolescents During an Oral Glucose Tolerance Test. J Diabetes Sci Technol 2024:19322968241266825. [PMID: 39076151 PMCID: PMC11572107 DOI: 10.1177/19322968241266825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/31/2024]
Abstract
BACKGROUND Lactate is not considered just a "waste product" of anaerobic glycolysis anymore. It has been proved to play a key role in several metabolic diseases, such as in the metabolic dysfunction-associated steatotic liver disease, obesity, and diabetes. The capability of simulating glucose-insulin-lactate interaction would be useful to design and test drugs targeting lactate metabolism in such pathological conditions. Minimal models are available, which describe and quantify glucose-lactate interaction but models to simulate postprandial glucose-insulin-C-peptide-lactate time courses are missing. The aim of this study is to fill this gap. METHODS Starting from the Padova Type 2 Diabetes Simulator (T2DS), we first added a description of glucose-lactate kinetics and then created a population of 100 in silico subjects to match glucose-insulin-C-peptide-lactate data of 44 adolescents with/without obesity who underwent a standard oral glucose tolerance test (OGTT) of 75 g. RESULTS The developed model accurately predicts all molecules time courses, guaranteeing precise model parameter estimates (percent coefficient of variation [CV%] median [25th-75th percentile] = 19 [9-29]%). The generated in silico population shows good agreement with the clinical data in terms of area under the curve (AUC) (P = .6, .6, .9, .6 for glucose, insulin, C-peptide, and lactate, respectively) and parameter distributions (P > .1). CONCLUSIONS We have developed a simulator to describe glucose, insulin, C-peptide, and lactate kinetics during an OGTT, which captures the behavior of a real population of adolescents with/without obesity both in terms of average and intersubject variability. Such simulator can be used to investigate the pharmacodynamics of drugs targeting lactate metabolic pathway in various pathological conditions.
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Affiliation(s)
- Jacopo Bonet
- Department of Information Engineering, University of Padua, Padova, Italy
| | - Emiliano Barbieri
- Section of Pediatrics, Department of Translational Sciences, University of Naples Federico II, Napoli, Italy
| | - Nicola Santoro
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
- Department of Medicine and Health Sciences, “V. Tiberio” University of Molise, Campobasso, Italy
| | - Chiara Dalla Man
- Department of Information Engineering, University of Padua, Padova, Italy
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Goerdeler C, Engelmann B, Aldehoff AS, Schaffert A, Blüher M, Heiker JT, Wabitsch M, Schubert K, Rolle-Kampczyk U, von Bergen M. Metabolomics in human SGBS cells as new approach method for studying adipogenic effects: Analysis of the effects of DINCH and MINCH on central carbon metabolism. ENVIRONMENTAL RESEARCH 2024; 252:118847. [PMID: 38582427 DOI: 10.1016/j.envres.2024.118847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 03/20/2024] [Accepted: 03/31/2024] [Indexed: 04/08/2024]
Abstract
Growing evidence suggests that exposure to certain metabolism-disrupting chemicals (MDCs), such as the phthalate plasticizer DEHP, might promote obesity in humans, contributing to the spread of this global health problem. Due to the restriction on the use of phthalates, there has been a shift to safer declared substitutes, including the plasticizer diisononyl-cyclohexane-1,2-dicarboxylate (DINCH). Notwithstanding, recent studies suggest that the primary metabolite monoisononyl-cyclohexane-1,2-dicarboxylic acid ester (MINCH), induces differentiation of human adipocytes and affects enzyme levels of key metabolic pathways. Given the lack of methods for assessing metabolism-disrupting effects of chemicals on adipose tissue, we used metabolomics to analyze human SGSB cells exposed to DINCH or MINCH. Concentration analysis of DINCH and MINCH revealed that uptake of MINCH in preadipocytes was associated with increased lipid accumulation during adipogenesis. Although we also observed intracellular uptake for DINCH, the solubility of DINCH in cell culture medium was limited, hampering the analysis of possible effects in the μM concentration range. Metabolomics revealed that MINCH induces lipid accumulation similar to peroxisome proliferator-activated receptor gamma (PPARG)-agonist rosiglitazone through upregulation of the pyruvate cycle, which was recently identified as a key driver of de novo lipogenesis. Analysis of the metabolome in the presence of the PPARG-inhibitor GW9662 indicated that the effect of MINCH on metabolism was mediated at least partly by a PPARG-independent mechanism. However, all effects of MINCH were only observed at high concentrations of 10 μM, which are three orders of magnitudes higher than the current concentrations of plasticizers in human serum. Overall, the assessment of the effects of DINCH and MINCH on SGBS cells by metabolomics revealed no adipogenic potential at physiologically relevant concentrations. This finding aligns with previous in vivo studies and supports the potential of our method as a New Approach Method (NAM) for the assessment of adipogenic effects of environmental chemicals.
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Affiliation(s)
- Cornelius Goerdeler
- Department of Molecular Toxicology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany.
| | - Beatrice Engelmann
- Department of Molecular Toxicology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany.
| | - Alix Sarah Aldehoff
- Department of Molecular Toxicology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany.
| | - Alexandra Schaffert
- Department of Molecular Toxicology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany.
| | - Matthias Blüher
- Department of Endocrinology, Nephrology and Rheumatology, Faculty of Medicine, University of Leipzig, Leipzig, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany.
| | - John T Heiker
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany.
| | - Martin Wabitsch
- Division of Pediatric Endocrinology and Diabetes, Ulm University Medical Center, Ulm, Germany.
| | - Kristin Schubert
- Department of Molecular Toxicology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany.
| | - Ulrike Rolle-Kampczyk
- Department of Molecular Toxicology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany.
| | - Martin von Bergen
- Department of Molecular Toxicology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany; Institute of Biochemistry, Leipzig University, Leipzig, Germany; German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany.
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García-Gavilán JF, Atzeni A, Babio N, Liang L, Belzer C, Vioque J, Corella D, Fitó M, Vidal J, Moreno-Indias I, Torres-Collado L, Coltell O, Toledo E, Clish C, Hernando J, Yun H, Hernández-Cacho A, Jeanfavre S, Dennis C, Gómez-Pérez AM, Martínez MA, Ruiz-Canela M, Tinahones FJ, Hu FB, Salas-Salvadó J. Effect of 1-year lifestyle intervention with energy-reduced Mediterranean diet and physical activity promotion on the gut metabolome and microbiota: a randomized clinical trial. Am J Clin Nutr 2024; 119:1143-1154. [PMID: 38428742 DOI: 10.1016/j.ajcnut.2024.02.021] [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: 11/30/2023] [Revised: 02/23/2024] [Accepted: 02/26/2024] [Indexed: 03/03/2024] Open
Abstract
BACKGROUND The health benefits of the Mediterranean diet (MedDiet) have been linked to the presence of beneficial gut microbes and related metabolites. However, its impact on the fecal metabolome remains poorly understood. OBJECTIVES Our goal was to investigate the weight-loss effects of a 1-y lifestyle intervention based on an energy-reduced MedDiet coupled with physical activity (intervention group), compared with an ad libitum MedDiet (control group), on fecal metabolites, fecal microbiota, and their potential association with cardiovascular disease risk factors. METHODS A total of 400 participants (200 from each study group), aged 55-75 y, and at high cardiovascular disease risk, were included. Dietary and lifestyle information, anthropometric measurements, blood biochemical parameters, and stool samples were collected at baseline and after 1 y of follow-up. Liquid chromatography-tandem mass spectrometry was used to profile endogenous fecal metabolites, and 16S amplicon sequencing was employed to profile the fecal microbiota. RESULTS Compared with the control group, the intervention group exhibited greater weight loss and improvement in various cardiovascular disease risk factors. We identified intervention effects on 4 stool metabolites and subnetworks primarily composed of bile acids, ceramides, and sphingosines, fatty acids, carnitines, nucleotides, and metabolites of purine and the Krebs cycle. Some of these were associated with changes in several cardiovascular disease risk factors. In addition, we observed a reduction in the abundance of the genera Eubacterium hallii group and Dorea, and an increase in alpha diversity in the intervention group after 1 y of follow-up. Changes in the intervention-related microbiota profiles were also associated with alterations in different fecal metabolite subnetworks and some cardiovascular disease risk factors. CONCLUSIONS An intervention based on an energy-reduced MedDiet and physical activity promotion, compared with an ad libitum MedDiet, was associated with improvements in cardiometabolic risk factors, potentially through modulation of the fecal microbiota and metabolome. This trial was registered at https://www.isrctn.com/ as ISRCTN89898870 (https://doi.org/10.1186/ISRCTN89898870).
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Affiliation(s)
- Jesús F García-Gavilán
- CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain; Departament de Bioquímica i Biotecnologia, Alimentaciò, Nutrició, Desenvolupament i Salut Mental (ANUT-DSM), Universitat Rovira i Virgili, Reus, Spain; Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain
| | - Alessandro Atzeni
- CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain; Departament de Bioquímica i Biotecnologia, Alimentaciò, Nutrició, Desenvolupament i Salut Mental (ANUT-DSM), Universitat Rovira i Virgili, Reus, Spain; Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain.
| | - Nancy Babio
- CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain; Departament de Bioquímica i Biotecnologia, Alimentaciò, Nutrició, Desenvolupament i Salut Mental (ANUT-DSM), Universitat Rovira i Virgili, Reus, Spain; Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain
| | - Liming Liang
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, United States
| | - Clara Belzer
- Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands
| | - Jesús Vioque
- CIBER de Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigación Sanitaria y Biomédica de Alicante, Universidad Miguel Hernández (ISABIAL-UMH), Alicante, Spain
| | - Dolores Corella
- CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain; Department of Preventive Medicine, University of Valencia, Valencia, Spain
| | - Montserrat Fitó
- CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain; Unit of Cardiovascular Risk and Nutrition, Institut Hospital del Mar de Investigaciones Médicas Municipal d'Investigació Médica (IMIM), Barcelona, Spain
| | - Josep Vidal
- CIBER Diabetes y Enfermedades Metabólicas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Endocrinology, Institut d'Investigacions Biomédiques August Pi Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Isabel Moreno-Indias
- CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain; Department of Endocrinology and Nutrition, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Málaga, Spain
| | - Laura Torres-Collado
- CIBER de Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigación Sanitaria y Biomédica de Alicante, Universidad Miguel Hernández (ISABIAL-UMH), Alicante, Spain
| | - Oscar Coltell
- CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain; Department of Computer Languages and Systems, Jaume I University, Castellón, Spain
| | - Estefanía Toledo
- CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain; Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain; Epidemiología y Salud Pública, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Clary Clish
- Metabolomics Platform, The Broad Institute of MIT and Harvard, Boston, MA, United States
| | - Javier Hernando
- CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain; Unit of Cardiovascular Risk and Nutrition, Institut Hospital del Mar de Investigaciones Médicas Municipal d'Investigació Médica (IMIM), Barcelona, Spain
| | - Huan Yun
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, United States
| | - Adrián Hernández-Cacho
- Departament de Bioquímica i Biotecnologia, Alimentaciò, Nutrició, Desenvolupament i Salut Mental (ANUT-DSM), Universitat Rovira i Virgili, Reus, Spain; Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain
| | - Sarah Jeanfavre
- Metabolomics Platform, The Broad Institute of MIT and Harvard, Boston, MA, United States
| | - Courtney Dennis
- Metabolomics Platform, The Broad Institute of MIT and Harvard, Boston, MA, United States
| | - Ana M Gómez-Pérez
- CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain; Department of Endocrinology and Nutrition, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Málaga, Spain
| | - Maria Angeles Martínez
- CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain; Departament de Bioquímica i Biotecnologia, Alimentaciò, Nutrició, Desenvolupament i Salut Mental (ANUT-DSM), Universitat Rovira i Virgili, Reus, Spain; Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain
| | - Miguel Ruiz-Canela
- CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain; Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain; Epidemiología y Salud Pública, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Francisco J Tinahones
- CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain; Department of Endocrinology and Nutrition, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Málaga, Spain
| | - Frank B Hu
- Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA, United States; Channing Division for Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
| | - Jordi Salas-Salvadó
- CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain; Departament de Bioquímica i Biotecnologia, Alimentaciò, Nutrició, Desenvolupament i Salut Mental (ANUT-DSM), Universitat Rovira i Virgili, Reus, Spain; Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain.
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8
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Li X, Cai P, Tang X, Wu Y, Zhang Y, Rong X. Lactylation Modification in Cardiometabolic Disorders: Function and Mechanism. Metabolites 2024; 14:217. [PMID: 38668345 PMCID: PMC11052226 DOI: 10.3390/metabo14040217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 04/01/2024] [Accepted: 04/04/2024] [Indexed: 04/28/2024] Open
Abstract
Cardiovascular disease (CVD) is recognized as the primary cause of mortality and morbidity on a global scale, and developing a clear treatment is an important tool for improving it. Cardiometabolic disorder (CMD) is a syndrome resulting from the combination of cardiovascular, endocrine, pro-thrombotic, and inflammatory health hazards. Due to their complex pathological mechanisms, there is a lack of effective diagnostic and treatment methods for cardiac metabolic disorders. Lactylation is a type of post-translational modification (PTM) that plays a regulatory role in various cellular physiological processes by inducing changes in the spatial conformation of proteins. Numerous studies have reported that lactylation modification plays a crucial role in post-translational modifications and is closely related to cardiac metabolic diseases. This article discusses the molecular biology of lactylation modifications and outlines the roles and mechanisms of lactylation modifications in cardiometabolic disorders, offering valuable insights for the diagnosis and treatment of such conditions.
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Affiliation(s)
- Xu Li
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China; (X.L.); (P.C.); (X.T.); (Y.W.)
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, Guangzhou 510006, China
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM, State Administration of Traditional Chinese Medicine, Guangzhou 510006, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Pingdong Cai
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China; (X.L.); (P.C.); (X.T.); (Y.W.)
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, Guangzhou 510006, China
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM, State Administration of Traditional Chinese Medicine, Guangzhou 510006, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Xinyuan Tang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China; (X.L.); (P.C.); (X.T.); (Y.W.)
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, Guangzhou 510006, China
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM, State Administration of Traditional Chinese Medicine, Guangzhou 510006, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yingzi Wu
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China; (X.L.); (P.C.); (X.T.); (Y.W.)
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, Guangzhou 510006, China
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM, State Administration of Traditional Chinese Medicine, Guangzhou 510006, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yue Zhang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China; (X.L.); (P.C.); (X.T.); (Y.W.)
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, Guangzhou 510006, China
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM, State Administration of Traditional Chinese Medicine, Guangzhou 510006, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Xianglu Rong
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China; (X.L.); (P.C.); (X.T.); (Y.W.)
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, Guangzhou 510006, China
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM, State Administration of Traditional Chinese Medicine, Guangzhou 510006, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
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9
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Min K, Yenilmez B, Kelly M, Echeverria D, Elleby M, Lifshitz LM, Raymond N, Tsagkaraki E, Harney SM, DiMarzio C, Wang H, McHugh N, Bramato B, Morrison B, Rothstein JD, Khvorova A, Czech MP. Lactate transporter MCT1 in hepatic stellate cells promotes fibrotic collagen expression in nonalcoholic steatohepatitis. eLife 2024; 12:RP89136. [PMID: 38564479 PMCID: PMC10987092 DOI: 10.7554/elife.89136] [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] [Indexed: 04/04/2024] Open
Abstract
Circulating lactate is a fuel source for liver metabolism but may exacerbate metabolic diseases such as nonalcoholic steatohepatitis (NASH). Indeed, haploinsufficiency of lactate transporter monocarboxylate transporter 1 (MCT1) in mice reportedly promotes resistance to hepatic steatosis and inflammation. Here, we used adeno-associated virus (AAV) vectors to deliver thyroxin binding globulin (TBG)-Cre or lecithin-retinol acyltransferase (Lrat)-Cre to MCT1fl/fl mice on a choline-deficient, high-fat NASH diet to deplete hepatocyte or stellate cell MCT1, respectively. Stellate cell MCT1KO (AAV-Lrat-Cre) attenuated liver type 1 collagen protein expression and caused a downward trend in trichrome staining. MCT1 depletion in cultured human LX2 stellate cells also diminished collagen 1 protein expression. Tetra-ethylenglycol-cholesterol (Chol)-conjugated siRNAs, which enter all hepatic cell types, and hepatocyte-selective tri-N-acetyl galactosamine (GN)-conjugated siRNAs were then used to evaluate MCT1 function in a genetically obese NASH mouse model. MCT1 silencing by Chol-siRNA decreased liver collagen 1 levels, while hepatocyte-selective MCT1 depletion by AAV-TBG-Cre or by GN-siRNA unexpectedly increased collagen 1 and total fibrosis without effect on triglyceride accumulation. These findings demonstrate that stellate cell lactate transporter MCT1 significantly contributes to liver fibrosis through increased collagen 1 protein expression in vitro and in vivo, while hepatocyte MCT1 appears not to be an attractive therapeutic target for NASH.
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Affiliation(s)
- Kyounghee Min
- Program in Molecular Medicine, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Batuhan Yenilmez
- Program in Molecular Medicine, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Mark Kelly
- Program in Molecular Medicine, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Dimas Echeverria
- RNA Therapeutics Institute, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Michael Elleby
- Program in Molecular Medicine, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Lawrence M Lifshitz
- Program in Molecular Medicine, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Naideline Raymond
- Program in Molecular Medicine, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Emmanouela Tsagkaraki
- Program in Molecular Medicine, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Shauna M Harney
- Program in Molecular Medicine, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Chloe DiMarzio
- Program in Molecular Medicine, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Hui Wang
- Program in Molecular Medicine, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Nicholas McHugh
- RNA Therapeutics Institute, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Brianna Bramato
- RNA Therapeutics Institute, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Brett Morrison
- Department of Neurology, Johns Hopkins School of MedicineBaltimoreUnited States
| | - Jeffery D Rothstein
- Department of Neurology, Johns Hopkins School of MedicineBaltimoreUnited States
| | - Anastasia Khvorova
- RNA Therapeutics Institute, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Michael P Czech
- Program in Molecular Medicine, University of Massachusetts Chan Medical SchoolWorcesterUnited States
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10
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Nan Tie E, Nanayakkara S, Vizi D, Mariani J, Kaye DM. The Impact of Diabetes on Haemodynamic and Cardiometabolic Responses in Heart Failure With Preserved Ejection Fraction. Heart Lung Circ 2024; 33:376-383. [PMID: 38336542 DOI: 10.1016/j.hlc.2023.12.008] [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: 07/10/2023] [Revised: 11/26/2023] [Accepted: 12/07/2023] [Indexed: 02/12/2024]
Abstract
AIMS Heart failure with preserved ejection (HFpEF) and diabetes mellitus (DM) commonly co-exist. However, it is unclear if DM modifies the haemodynamic and cardiometabolic phenotype in patients with HFpEF. We aimed to interrogate the haemodynamic and cardiometabolic effects of DM in HFpEF. METHODS We compared the haemodynamic and metabolic profiles of non-DM patients and patients with DM-HFpEF at rest and during exercise using right heart catheterisation and mixed venous blood gas analysis. RESULTS Of 181 patients with HFpEF, 37 (20%) had DM. Patients with DM displayed a more adverse exercise haemodynamic response vs HFpEF alone (mean pulmonary arterial pressure: 47 mmHg [interquartile range {IQR} 42-55] vs 42 [38-47], p<0.001; workload indexed pulmonary capillary wedge pressure indexed: 0.80 mmHg/W [0.44-1.23] vs 0.57 [0.43-1.01], p=0.047). HFpEF-DM patients had a lower mixed venous oxygen saturation at rest (70% [IQR 66-73] vs 72 [69-75], p=0.003) and were unable to enhance O2 extraction to the same extent (Δ-28% [-33 to -15] vs -29 [-36 to -21], p=0.029), this occurred at a 22% lower median workload. Resting mixed venous lactate levels were higher in those with DM (1.5 mmol/L [IQR 1.1-1.9] vs 1 [0.9-1.3], p<0.001), and during exercise indexed to workload (0.09 mmol/L/W [0.06-0.13] vs 0.08 [0.05-0.11], p=0.018). CONCLUSION Concurrent diabetes and HFpEF was associated with greater metabolic responses at rest, with enhanced wedge driven pulmonary hypertension and relative lactataemia during exercise without appropriate augmentation of oxygen consumption.
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Affiliation(s)
- Emilia Nan Tie
- Department of Cardiology, Alfred Hospital, Melbourne, Vic, Australia. http://www.twitter.com/EmiliaNanTie
| | - Shane Nanayakkara
- Department of Cardiology, Alfred Hospital, Melbourne, Vic, Australia; Heart Failure Research Group, Baker Heart & Diabetes Institute, Melbourne, Vic, Australia
| | - Donna Vizi
- Department of Cardiology, Alfred Hospital, Melbourne, Vic, Australia
| | - Justin Mariani
- Department of Cardiology, Alfred Hospital, Melbourne, Vic, Australia; Heart Failure Research Group, Baker Heart & Diabetes Institute, Melbourne, Vic, Australia; Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Vic, Australia
| | - David M Kaye
- Department of Cardiology, Alfred Hospital, Melbourne, Vic, Australia; Heart Failure Research Group, Baker Heart & Diabetes Institute, Melbourne, Vic, Australia; Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Vic, Australia.
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11
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Bahadoran Z, Mirmiran P, Ghasemi A. Adipose organ dysfunction and type 2 diabetes: Role of nitric oxide. Biochem Pharmacol 2024; 221:116043. [PMID: 38325496 DOI: 10.1016/j.bcp.2024.116043] [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: 10/30/2023] [Revised: 01/07/2024] [Accepted: 02/01/2024] [Indexed: 02/09/2024]
Abstract
Adipose organ, historically known as specialized lipid-handling tissue serving as the long-term fat depot, is now appreciated as the largest endocrine organ composed of two main compartments, i.e., subcutaneous and visceral adipose tissue (AT), madding up white and beige/brown adipocytes. Adipose organ dysfunction manifested as maldistribution of the compartments, hypertrophic, hypoxic, inflamed, and insulin-resistant AT, contributes to the development of type 2 diabetes (T2D). Here, we highlight the role of nitric oxide (NO·) in AT (dys)function in relation to developing T2D. The key aspects determining lipid and glucose homeostasis in AT depend on the physiological levels of the NO· produced via endothelial NO· synthases (eNOS). In addition to decreased NO· bioavailability (via decreased expression/activity of eNOS or scavenging NO·), excessive NO· produced by inducible NOS (iNOS) in response to hypoxia and AT inflammation may be a critical interfering factor diverting NO· signaling to the formation of reactive oxygen and nitrogen species, resulting in AT and whole-body metabolic dysfunction. Pharmacological approaches boosting AT-NO· availability at physiological levels (by increasing NO· production and its stability), as well as suppression of iNOS-NO· synthesis, are potential candidates for developing NO·-based therapeutics in T2D.
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Affiliation(s)
- Zahra Bahadoran
- Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parvin Mirmiran
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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12
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Cai M, Li S, Cai K, Du X, Han J, Hu J. Empowering mitochondrial metabolism: Exploring L-lactate supplementation as a promising therapeutic approach for metabolic syndrome. Metabolism 2024; 152:155787. [PMID: 38215964 DOI: 10.1016/j.metabol.2024.155787] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 12/08/2023] [Accepted: 01/05/2024] [Indexed: 01/14/2024]
Abstract
Mitochondrial dysfunction plays a critical role in the pathogenesis of metabolic syndrome (MetS), affecting various cell types and organs. In MetS animal models, mitochondria exhibit decreased quality control, characterized by abnormal morphological structure, impaired metabolic activity, reduced energy production, disrupted signaling cascades, and oxidative stress. The aberrant changes in mitochondrial function exacerbate the progression of metabolic syndrome, setting in motion a pernicious cycle. From this perspective, reversing mitochondrial dysfunction is likely to become a novel and powerful approach for treating MetS. Unfortunately, there are currently no effective drugs available in clinical practice to improve mitochondrial function. Recently, L-lactate has garnered significant attention as a valuable metabolite due to its ability to regulate mitochondrial metabolic processes and function. It is highly likely that treating MetS and its related complications can be achieved by correcting mitochondrial homeostasis disorders. In this review, we comprehensively discuss the complex relationship between mitochondrial function and MetS and the involvement of L-lactate in regulating mitochondrial metabolism and associated signaling pathways. Furthermore, it highlights recent findings on the involvement of L-lactate in common pathologies of MetS and explores its potential clinical application and further prospects, thus providing new insights into treatment possibilities for MetS.
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Affiliation(s)
- Ming Cai
- College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai 201318, PR China; Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Shuyao Li
- College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai 201318, PR China
| | - Keren Cai
- College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai 201318, PR China
| | - Xinlin Du
- College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai 201318, PR China
| | - Jia Han
- College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai 201318, PR China.
| | - Jingyun Hu
- Central Lab, Shanghai Key Laboratory of Pathogenic Fungi Medical Testing, Shanghai Pudong New Area People's Hospital, Shanghai 201299, PR China.
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13
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Broskey NT, Pories WJ, DeMaria EJ, Jones TE, Tanner CJ, Zheng D, Krassovskaia PM, Mitchell LA, Matarese LE, O'Brien KF, Cortright RN, Dohm GL, Houmard JA. Fasting plasma lactate as a possible early clinical marker for metabolic disease risk. Diabetes Metab Syndr 2024; 18:102955. [PMID: 38310736 PMCID: PMC10997452 DOI: 10.1016/j.dsx.2024.102955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 01/17/2024] [Accepted: 01/28/2024] [Indexed: 02/06/2024]
Abstract
BACKGROUND AND AIM Elevated fasting plasma lactate concentrations are evident in individuals with metabolic diseases. However, it has yet to be determined if these associations exist in a young, healthy population as a possible early marker for metabolic disease risk. The purpose of this study was to determine if indices of the metabolic syndrome are related to plasma lactate concentrations in this population. METHODS Fifty (29 ± 7 yr) men (n = 19) and women (n = 31) classified as overweight (26.4 ± 1.8 kg/m2) participated in this observational study. Blood pressure and blood metabolites were measured after an overnight fast. Lactate was also measured before and after a three-day eucaloric high-fat (70 %) diet. The homeostatic model assessment for insulin resistance (HOMA-IR) was calculated as a measure of insulin resistance. Visceral adipose tissue mass was determined via dual X-ray absorptiometry. RESULTS Triglycerides (r = 0.55, p=<0.0001), HOMA-IR (r = 0.53, p=<0.0001), and systolic and diastolic (both, r = 0.36, p = 0.01) blood pressures associated with fasting plasma lactate. No differences in visceral adipose tissue existed between the sexes (p = 0.41); however, the relationship between visceral adipose tissue and lactate existed only in females (r = 0.59, p = 0.02) but not in males (p = 0.53). Fasting lactate and HOMA-IR increased in males (p = 0.01 and p = 0.02, respectively), but not females, following a three-day high-fat diet. CONCLUSION Indices of the metabolic syndrome associated with fasting plasma lactates in young relatively healthy individuals. Fasting lactate also increased in a sex-specific manner after a three-day high fat diet. Thus, lactate could become a clinical marker for metabolic disease risk.
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Affiliation(s)
- Nicholas T Broskey
- Departments of Kinesiology, East Carolina University, Greenville, NC, USA; Surgery, East Carolina University, Greenville, NC, USA; Human Performance Laboratory, East Carolina University, Greenville, NC, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA.
| | - Walter J Pories
- Surgery, East Carolina University, Greenville, NC, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA
| | | | - Terry E Jones
- Physical Therapy, East Carolina University, Greenville, NC, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA
| | - Charles J Tanner
- Departments of Kinesiology, East Carolina University, Greenville, NC, USA; Human Performance Laboratory, East Carolina University, Greenville, NC, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA
| | - Donghai Zheng
- Departments of Kinesiology, East Carolina University, Greenville, NC, USA; Human Performance Laboratory, East Carolina University, Greenville, NC, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA
| | - Polina M Krassovskaia
- Departments of Kinesiology, East Carolina University, Greenville, NC, USA; Human Performance Laboratory, East Carolina University, Greenville, NC, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA
| | | | - Laura E Matarese
- Surgery, East Carolina University, Greenville, NC, USA; Internal Medicine, East Carolina University, Greenville, NC, USA
| | - Kevin F O'Brien
- Public Health, East Carolina University, Greenville, NC, USA
| | - Ronald N Cortright
- Departments of Kinesiology, East Carolina University, Greenville, NC, USA; Human Performance Laboratory, East Carolina University, Greenville, NC, USA; Physiology, East Carolina University, Greenville, NC, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA
| | - G Lynis Dohm
- Physiology, East Carolina University, Greenville, NC, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA
| | - Joseph A Houmard
- Departments of Kinesiology, East Carolina University, Greenville, NC, USA; Surgery, East Carolina University, Greenville, NC, USA; Human Performance Laboratory, East Carolina University, Greenville, NC, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA
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14
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Monshizadeh M, Ye Y. Incorporating metabolic activity, taxonomy and community structure to improve microbiome-based predictive models for host phenotype prediction. Gut Microbes 2024; 16:2302076. [PMID: 38214657 PMCID: PMC10793686 DOI: 10.1080/19490976.2024.2302076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 01/02/2024] [Indexed: 01/13/2024] Open
Abstract
We developed MicroKPNN, a prior-knowledge guided interpretable neural network for microbiome-based human host phenotype prediction. The prior knowledge used in MicroKPNN includes the metabolic activities of different bacterial species, phylogenetic relationships, and bacterial community structure, all in a shallow neural network. Application of MicroKPNN to seven gut microbiome datasets (involving five different human diseases including inflammatory bowel disease, type 2 diabetes, liver cirrhosis, colorectal cancer, and obesity) shows that incorporation of the prior knowledge helped improve the microbiome-based host phenotype prediction. MicroKPNN outperformed fully connected neural network-based approaches in all seven cases, with the most improvement of accuracy in the prediction of type 2 diabetes. MicroKPNN outperformed a recently developed deep-learning based approach DeepMicro, which selects the best combination of autoencoder and machine learning approach to make predictions, in all of the seven cases. Importantly, we showed that MicroKPNN provides a way for interpretation of the predictive models. Using importance scores estimated for the hidden nodes, MicroKPNN could provide explanations for prior research findings by highlighting the roles of specific microbiome components in phenotype predictions. In addition, it may suggest potential future research directions for studying the impacts of microbiome on host health and diseases. MicroKPNN is publicly available at https://github.com/mgtools/MicroKPNN.
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Affiliation(s)
- Mahsa Monshizadeh
- Computer Science Department, Luddy School of Informatics, Computing and Engineering, Indiana University, Bloomington, IN, USA
| | - Yuzhen Ye
- Computer Science Department, Luddy School of Informatics, Computing and Engineering, Indiana University, Bloomington, IN, USA
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15
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Min K, Yenilmez B, Kelly M, Echeverria D, Elleby M, Lifshitz LM, Raymond N, Tsagkaraki E, Harney SM, DiMarzio C, Wang H, McHugh N, Bramato B, Morrision B, Rothstein JD, Khvorova A, Czech MP. Lactate transporter MCT1 in hepatic stellate cells promotes fibrotic collagen expression in nonalcoholic steatohepatitis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.03.539244. [PMID: 37205462 PMCID: PMC10187148 DOI: 10.1101/2023.05.03.539244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Circulating lactate is a fuel source for liver metabolism but may exacerbate metabolic diseases such as nonalcoholic steatohepatitis (NASH). Indeed, haploinsufficiency of lactate transporter monocarboxylate transporter 1 (MCT1) in mice reportedly promotes resistance to hepatic steatosis and inflammation. Here, we used adeno-associated virus (AAV) vectors to deliver thyroxin binding globulin (TBG)-Cre or lecithin-retinol acyltransferase (Lrat)-Cre to MCT1fl/fl mice on a choline deficient, high fat NASH diet to deplete hepatocyte or stellate cell MCT1, respectively. Stellate cell MCT1KO (AAV-Lrat-Cre) attenuated liver type 1 collagen protein expression and caused a downward trend in trichrome staining. MCT1 depletion in cultured human LX2 stellate cells also diminished collagen 1 protein expression. Tetra-ethylenglycol-cholesterol (Chol)-conjugated siRNAs, which enter all hepatic cell types, and hepatocyte-selective tri-N-acetyl galactosamine (GN)-conjugated siRNAs were then used to evaluate MCT1 function in a genetically obese NASH mouse model. MCT1 silencing by Chol-siRNA decreased liver collagen 1 levels, while hepatocyte-selective MCT1 depletion by AAV-TBG-Cre or by GN-siRNA unexpectedly increased collagen 1 and total fibrosis without effect on triglyceride accumulation. These findings demonstrate that stellate cell lactate transporter MCT1 significantly contributes to liver fibrosis through increased collagen 1 protein expression in vitro and in vivo, while hepatocyte MCT1 appears not to be an attractive therapeutic target for NASH.
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Affiliation(s)
- Kyounghee Min
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, USA
| | - Batuhan Yenilmez
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, USA
| | - Mark Kelly
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, USA
| | - Dimas Echeverria
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, USA
| | - Michael Elleby
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, USA
| | - Lawrence M Lifshitz
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, USA
| | - Naideline Raymond
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, USA
| | | | - Shauna M Harney
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, USA
| | - Chloe DiMarzio
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, USA
| | - Hui Wang
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, USA
| | - Nicholas McHugh
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, USA
| | - Brianna Bramato
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, USA
| | - Brett Morrision
- Department of Neurology, Johns Hopkins School of Medicine, USA
| | | | - Anastasia Khvorova
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, USA
| | - Michael P Czech
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, USA
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16
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Moody M, Schmidt TA, Trivedi R, Deymier A. Administration of alendronate exacerbates ammonium chloride-induced acidosis in mice. PLoS One 2023; 18:e0291649. [PMID: 37713420 PMCID: PMC10503749 DOI: 10.1371/journal.pone.0291649] [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: 04/27/2023] [Accepted: 09/04/2023] [Indexed: 09/17/2023] Open
Abstract
Bone disease is highly prevalent in patients with chronic kidney disease (CKD), leading to an increased risk of bone fractures. This is due in part to metabolic acid-induced bone dissolution. Bisphosphonates (BPPs) are a potential treatment for inhibiting bone dissolution; however, there are limited studies observing the use of BPPs on acidotic patients. We aimed to determine efficacy of BPPs on maintaining bone health and pH regulation in acid-exposed mice. Using a diet-induced murine model of metabolic acidosis, we examined bone structure, composition, and mechanics as well as blood gases for three groups: control, acidosis, and acidosis + bisphosphonates (acidosis+BPP). Acidosis was induced for 14 days and alendronate was administered every 3 days for the acidosis+BPP group. The administration of BPP had little to no effect on bone structure, mechanics, and composition of the acidosis bones. However, administration of BPP did cause the mice to develop more severe acidosis than the acidosis only group. Overall, we discovered that BPPs may exacerbate acidosis symptoms by inhibiting the release of buffering ions from bone. Therefore, we propose that BPP administration should be carefully considered for those with CKD and that alkali supplementation could help minimize acidifying effects.
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Affiliation(s)
- Mikayla Moody
- Department of Biomedical Engineering, School of Dental Medicine, University of Connecticut Health Center, Farmington, CT, United States of America
| | - Tannin A. Schmidt
- Department of Biomedical Engineering, School of Dental Medicine, University of Connecticut Health Center, Farmington, CT, United States of America
| | - Ruchir Trivedi
- Department of Nephrology, School of Medicine, University of Connecticut Health Center, Farmington, CT, United States of America
| | - Alix Deymier
- Department of Biomedical Engineering, School of Dental Medicine, University of Connecticut Health Center, Farmington, CT, United States of America
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17
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Abstract
Gluconeogenesis is a critical biosynthetic process that helps maintain whole-body glucose homeostasis and becomes altered in certain medical diseases. We review gluconeogenic flux in various medical diseases, including common metabolic disorders, hormonal imbalances, specific inborn genetic errors, and cancer. We discuss how the altered gluconeogenic activity contributes to disease pathogenesis using data from experiments using isotopic tracer and spectroscopy methodologies. These in vitro, animal, and human studies provide insights into the changes in circulating levels of available gluconeogenesis substrates and the efficiency of converting those substrates to glucose by gluconeogenic organs. We highlight ongoing knowledge gaps, discuss emerging research areas, and suggest future investigations. A better understanding of altered gluconeogenesis flux may ultimately identify novel and targeted treatment strategies for such diseases.
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Affiliation(s)
- Ankit Shah
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA; ,
| | - Fredric E Wondisford
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA; ,
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18
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Mouton AJ, do Carmo JM, da Silva AA, Omoto ACM, Hall JE. Targeting immunometabolism during cardiorenal injury: roles of conventional and alternative macrophage metabolic fuels. Front Physiol 2023; 14:1139296. [PMID: 37234412 PMCID: PMC10208225 DOI: 10.3389/fphys.2023.1139296] [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: 01/06/2023] [Accepted: 04/14/2023] [Indexed: 05/28/2023] Open
Abstract
Macrophages play critical roles in mediating and resolving tissue injury as well as tissue remodeling during cardiorenal disease. Altered immunometabolism, particularly macrophage metabolism, is a critical underlying mechanism of immune dysfunction and inflammation, particularly in individuals with underlying metabolic abnormalities. In this review, we discuss the critical roles of macrophages in cardiac and renal injury and disease. We also highlight the roles of macrophage metabolism and discuss metabolic abnormalities, such as obesity and diabetes, which may impair normal macrophage metabolism and thus predispose individuals to cardiorenal inflammation and injury. As the roles of macrophage glucose and fatty acid metabolism have been extensively discussed elsewhere, we focus on the roles of alternative fuels, such as lactate and ketones, which play underappreciated roles during cardiac and renal injury and heavily influence macrophage phenotypes.
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Affiliation(s)
- Alan J. Mouton
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, United States
- Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, MS, United States
| | - Jussara M. do Carmo
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, United States
- Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, MS, United States
| | - Alexandre A. da Silva
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, United States
- Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, MS, United States
| | - Ana C. M. Omoto
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, United States
- Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, MS, United States
| | - John E. Hall
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, United States
- Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, MS, United States
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19
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Keijer J, Escoté X, Galmés S, Palou-March A, Serra F, Aldubayan MA, Pigsborg K, Magkos F, Baker EJ, Calder PC, Góralska J, Razny U, Malczewska-Malec M, Suñol D, Galofré M, Rodríguez MA, Canela N, Malcic RG, Bosch M, Favari C, Mena P, Del Rio D, Caimari A, Gutierrez B, Del Bas JM. Omics biomarkers and an approach for their practical implementation to delineate health status for personalized nutrition strategies. Crit Rev Food Sci Nutr 2023; 64:8279-8307. [PMID: 37077157 DOI: 10.1080/10408398.2023.2198605] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/21/2023]
Abstract
Personalized nutrition (PN) has gained much attention as a tool for empowerment of consumers to promote changes in dietary behavior, optimizing health status and preventing diet related diseases. Generalized implementation of PN faces different obstacles, one of the most relevant being metabolic characterization of the individual. Although omics technologies allow for assessment the dynamics of metabolism with unprecedented detail, its translatability as affordable and simple PN protocols is still difficult due to the complexity of metabolic regulation and to different technical and economical constrains. In this work, we propose a conceptual framework that considers the dysregulation of a few overarching processes, namely Carbohydrate metabolism, lipid metabolism, inflammation, oxidative stress and microbiota-derived metabolites, as the basis of the onset of several non-communicable diseases. These processes can be assessed and characterized by specific sets of proteomic, metabolomic and genetic markers that minimize operational constrains and maximize the information obtained at the individual level. Current machine learning and data analysis methodologies allow the development of algorithms to integrate omics and genetic markers. Reduction of dimensionality of variables facilitates the implementation of omics and genetic information in digital tools. This framework is exemplified by presenting the EU-Funded project PREVENTOMICS as a use case.
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Affiliation(s)
- Jaap Keijer
- Human and Animal Physiology, Wageningen University, Wageningen, the Netherlands
| | - Xavier Escoté
- EURECAT, Centre Tecnològic de Catalunya, Nutrition and Health, Reus, Spain
| | - Sebastià Galmés
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Group of Nutrigenomics, Biomarkers and Risk Evaluation - NuBE), University of the Balearic Islands, Palma, Spain
- Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
- Spin-off n.1 of the University of the Balearic Islands, Alimentómica S.L, Palma, Spain
| | - Andreu Palou-March
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Group of Nutrigenomics, Biomarkers and Risk Evaluation - NuBE), University of the Balearic Islands, Palma, Spain
- Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
- Spin-off n.1 of the University of the Balearic Islands, Alimentómica S.L, Palma, Spain
| | - Francisca Serra
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Group of Nutrigenomics, Biomarkers and Risk Evaluation - NuBE), University of the Balearic Islands, Palma, Spain
- Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
- Spin-off n.1 of the University of the Balearic Islands, Alimentómica S.L, Palma, Spain
| | - Mona Adnan Aldubayan
- Department of Nutrition, Exercise, and Sports, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Nutrition, College of Applied Medical Sciences, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Kristina Pigsborg
- Department of Nutrition, Exercise, and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Faidon Magkos
- Department of Nutrition, Exercise, and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Ella J Baker
- School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Philip C Calder
- School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
| | - Joanna Góralska
- Department of Clinical Biochemistry, Jagiellonian University Medical College, Krakow, Poland
| | - Urszula Razny
- Department of Clinical Biochemistry, Jagiellonian University Medical College, Krakow, Poland
| | | | - David Suñol
- Digital Health, Eurecat, Centre Tecnològic de Catalunya, Barcelona, Spain
| | - Mar Galofré
- Digital Health, Eurecat, Centre Tecnològic de Catalunya, Barcelona, Spain
| | - Miguel A Rodríguez
- Centre for Omic Sciences (COS), Joint Unit URV-EURECAT, Unique Scientific and Technical Infrastructures (ICTS), Eurecat, Centre Tecnològic de Catalunya, Reus, Spain
| | - Núria Canela
- Centre for Omic Sciences (COS), Joint Unit URV-EURECAT, Unique Scientific and Technical Infrastructures (ICTS), Eurecat, Centre Tecnològic de Catalunya, Reus, Spain
| | - Radu G Malcic
- Health and Biomedicine, LEITAT Technological Centre, Barcelona, Spain
| | - Montserrat Bosch
- Applied Microbiology and Biotechnologies, LEITAT Technological Centre, Terrassa, Spain
| | - Claudia Favari
- Human Nutrition Unit, Department of Food & Drug, University of Parma, Parma, Italy
| | - Pedro Mena
- Human Nutrition Unit, Department of Food & Drug, University of Parma, Parma, Italy
| | - Daniele Del Rio
- Human Nutrition Unit, Department of Food & Drug, University of Parma, Parma, Italy
| | - Antoni Caimari
- Eurecat, Centre Tecnològic de Catalunya, Biotechnology area, Reus, Spain
| | | | - Josep M Del Bas
- Eurecat, Centre Tecnològic de Catalunya, Biotechnology area, Reus, Spain
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20
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Blokhin ME, Kuranov SO, Khvostov MV, Fomenko VV, Luzina OA, Zhukova NA, Elhajjar C, Tolstikova TG, Salakhutdinov NF. Terpene-Containing Analogues of Glitazars as Potential Therapeutic Agents for Metabolic Syndrome. Curr Issues Mol Biol 2023; 45:2230-2247. [PMID: 36975514 PMCID: PMC10047834 DOI: 10.3390/cimb45030144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/02/2023] [Accepted: 03/03/2023] [Indexed: 03/29/2023] Open
Abstract
Metabolic syndrome is a complex of abnormalities involving impaired glucose and lipid metabolism, which needs effective pharmacotherapy. One way to reduce lipid and glucose levels associated with this pathology is the simultaneous activation of nuclear PPAR-alpha and gamma. For this purpose, we synthesized a number of potential agonists based on the pharmacophore fragment of glitazars with the inclusion of mono- or diterpenic moiety in the molecular structure. The study of their pharmacological activity in mice with obesity and type 2 diabetes mellitus (C57Bl/6Ay) revealed one substance that was capable of reducing the triglyceride levels in the liver and adipose tissue of mice by enhancing their catabolism and expressing a hypoglycemic effect connected with the sensitization of mice tissue to insulin. It has also been shown to have no toxic effects on the liver.
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Affiliation(s)
- Mikhail E Blokhin
- N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 630090 Novosibirsk, Russia
| | - Sergey O Kuranov
- N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 630090 Novosibirsk, Russia
| | - Mikhail V Khvostov
- N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 630090 Novosibirsk, Russia
| | - Vladislav V Fomenko
- N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 630090 Novosibirsk, Russia
| | - Olga A Luzina
- N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 630090 Novosibirsk, Russia
| | - Natalia A Zhukova
- N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 630090 Novosibirsk, Russia
| | - Cham Elhajjar
- N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 630090 Novosibirsk, Russia
| | - Tatiana G Tolstikova
- N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 630090 Novosibirsk, Russia
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21
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Abstract
Brown adipose tissue (BAT) displays the unique capacity to generate heat through uncoupled oxidative phosphorylation that makes it a very attractive therapeutic target for cardiometabolic diseases. Here, we review BAT cellular metabolism, its regulation by the central nervous and endocrine systems and circulating metabolites, the plausible roles of this tissue in human thermoregulation, energy balance, and cardiometabolic disorders, and the current knowledge on its pharmacological stimulation in humans. The current definition and measurement of BAT in human studies relies almost exclusively on BAT glucose uptake from positron emission tomography with 18F-fluorodeoxiglucose, which can be dissociated from BAT thermogenic activity, as for example in insulin-resistant states. The most important energy substrate for BAT thermogenesis is its intracellular fatty acid content mobilized from sympathetic stimulation of intracellular triglyceride lipolysis. This lipolytic BAT response is intertwined with that of white adipose (WAT) and other metabolic tissues, and cannot be independently stimulated with the drugs tested thus far. BAT is an interesting and biologically plausible target that has yet to be fully and selectively activated to increase the body's thermogenic response and shift energy balance. The field of human BAT research is in need of methods able to directly, specifically, and reliably measure BAT thermogenic capacity while also tracking the related thermogenic responses in WAT and other tissues. Until this is achieved, uncertainty will remain about the role played by this fascinating tissue in human cardiometabolic diseases.
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Affiliation(s)
- André C Carpentier
- Division of Endocrinology, Department of Medicine, Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Quebec, J1H 5N4, Canada
| | - Denis P Blondin
- Division of Neurology, Department of Medicine, Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Quebec, J1H 5N4, Canada
| | | | - Denis Richard
- Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec City, Quebec, G1V 4G5, Canada
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22
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Stacpoole PW, McCall CE. The pyruvate dehydrogenase complex: Life's essential, vulnerable and druggable energy homeostat. Mitochondrion 2023; 70:59-102. [PMID: 36863425 DOI: 10.1016/j.mito.2023.02.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 01/30/2023] [Accepted: 02/13/2023] [Indexed: 03/04/2023]
Abstract
Found in all organisms, pyruvate dehydrogenase complexes (PDC) are the keystones of prokaryotic and eukaryotic energy metabolism. In eukaryotic organisms these multi-component megacomplexes provide a crucial mechanistic link between cytoplasmic glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle. As a consequence, PDCs also influence the metabolism of branched chain amino acids, lipids and, ultimately, oxidative phosphorylation (OXPHOS). PDC activity is an essential determinant of the metabolic and bioenergetic flexibility of metazoan organisms in adapting to changes in development, nutrient availability and various stresses that challenge maintenance of homeostasis. This canonical role of the PDC has been extensively probed over the past decades by multidisciplinary investigations into its causal association with diverse physiological and pathological conditions, the latter making the PDC an increasingly viable therapeutic target. Here we review the biology of the remarkable PDC and its emerging importance in the pathobiology and treatment of diverse congenital and acquired disorders of metabolic integration.
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Affiliation(s)
- Peter W Stacpoole
- Department of Medicine (Division of Endocrinology, Metabolism and Diabetes), and Department of Biochemistry and Molecular Biology, University of Florida, College of Medicine, Gainesville, FL, United States.
| | - Charles E McCall
- Department of Internal Medicine and Translational Sciences, and Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
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23
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Guo X, Yu Z, Yin D. Sex-dependent obesogenic effect of tetracycline on Drosophila melanogaster deteriorated by dysrhythmia. J Environ Sci (China) 2023; 124:472-480. [PMID: 36182155 DOI: 10.1016/j.jes.2021.11.029] [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: 08/12/2021] [Revised: 11/19/2021] [Accepted: 11/23/2021] [Indexed: 06/16/2023]
Abstract
Antibiotics have been identified as obesogens contributing to the prevalence of obesity. Moreover, their environmental toxicity shows sex dependence, which might also explain the sex-dependent obesity observed. Yet, the direct evidence for such a connection and the underlying mechanisms remain to be explored. In this study, the effects of tetracycline, which is a representative antibiotic found in both environmental and food samples, on Drosophila melanogaster were studied with consideration of both sex and circadian rhythms (represented by the eclosion rhythm). Results showed that in morning-eclosed adults, tetracycline significantly stimulated the body weight of females (AM females) at 0.1, 1.0, 10.0 and 100.0 µg/L, while tetracycline only stimulated the body weight of males (AM males) at 1.0 µg/L. In the afternoon-eclosed adults, tetracycline significantly stimulated the body weight of females (PM females) at 0.1, 1.0 and 100.0 µg/L, while it showed more significant stimulation in males (PM males) at all concentrations. Notably, the stimulation levels were the greatest in PM males among all the adults. The results showed the clear sex dependence of the obesogenic effects, which was diminished by dysrhythmia. Further biochemical assays and clustering analysis suggested that the sex- and rhythm-dependent obesogenic effects resulted from the bias toward lipogenesis against lipolysis. Moreover, they were closely related to the preference for the energy storage forms of lactate and glucose and also to the presence of excessive insulin, with the involvement of glucolipid metabolism. Such relationships indicated potential bridges between the obesogenic effects of pollutants and other diseases, e.g., cancer and diabetes.
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Affiliation(s)
- Xueping Guo
- State Key Laboratory of Pollution Control and Resource Reuse, Key Laboratory of Yangtze River Water Environment, Ministry of Education, College of Environmental Science and Engineering, Tongji University, Shanghai 200092, China; Jiaxing Tongji Institute for Environment, Jiaxing 3014051, China; Shanghai Institute of Pollution Control and Ecological Security, Shanghai 200092, China
| | - Zhenyang Yu
- State Key Laboratory of Pollution Control and Resource Reuse, Key Laboratory of Yangtze River Water Environment, Ministry of Education, College of Environmental Science and Engineering, Tongji University, Shanghai 200092, China; Jiaxing Tongji Institute for Environment, Jiaxing 3014051, China; Shanghai Institute of Pollution Control and Ecological Security, Shanghai 200092, China.
| | - Daqiang Yin
- State Key Laboratory of Pollution Control and Resource Reuse, Key Laboratory of Yangtze River Water Environment, Ministry of Education, College of Environmental Science and Engineering, Tongji University, Shanghai 200092, China; Shanghai Institute of Pollution Control and Ecological Security, Shanghai 200092, China
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24
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Sanches JM, Zhao LN, Salehi A, Wollheim CB, Kaldis P. Pathophysiology of type 2 diabetes and the impact of altered metabolic interorgan crosstalk. FEBS J 2023; 290:620-648. [PMID: 34847289 DOI: 10.1111/febs.16306] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 10/14/2021] [Accepted: 11/29/2021] [Indexed: 02/06/2023]
Abstract
Diabetes is a complex and multifactorial disease that affects millions of people worldwide, reducing the quality of life significantly, and results in grave consequences for our health care system. In type 2 diabetes (T2D), the lack of β-cell compensatory mechanisms overcoming peripherally developed insulin resistance is a paramount factor leading to disturbed blood glucose levels and lipid metabolism. Impaired β-cell functions and insulin resistance have been studied extensively resulting in a good understanding of these pathways but much less is known about interorgan crosstalk, which we define as signaling between tissues by secreted factors. Besides hormones and organokines, dysregulated blood glucose and long-lasting hyperglycemia in T2D is associated with changes in metabolism with metabolites from different tissues contributing to the development of this disease. Recent data suggest that metabolites, such as lipids including free fatty acids and amino acids, play important roles in the interorgan crosstalk during the development of T2D. In general, metabolic remodeling affects physiological homeostasis and impacts the development of T2D. Hence, we highlight the importance of metabolic interorgan crosstalk in this review to gain enhanced knowledge of the pathophysiology of T2D, which may lead to new therapeutic approaches to treat this disease.
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Affiliation(s)
| | - Li Na Zhao
- Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Albert Salehi
- Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Claes B Wollheim
- Department of Clinical Sciences, Lund University, Malmö, Sweden.,Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Philipp Kaldis
- Department of Clinical Sciences, Lund University, Malmö, Sweden
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25
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9-N-n-alkyl Berberine Derivatives: Hypoglycemic Activity Evaluation. Pharmaceutics 2022; 15:pharmaceutics15010044. [PMID: 36678673 PMCID: PMC9865096 DOI: 10.3390/pharmaceutics15010044] [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: 12/05/2022] [Revised: 12/13/2022] [Accepted: 12/21/2022] [Indexed: 12/25/2022] Open
Abstract
Several novel 9-N-n-alkyl derivatives of berberine (C5, C7, C10, C12) were synthesized. They were analyzed in vitro and in vivo for their hypoglycemic activity. In vitro studies showed that the derivatives with shorter alkyl substitutes at concentrations ranging from 2.5 to 10 μM were able to stimulate glucose consumption by HepG2 cells more prominently than the derivatives with longer substitutes (C10 and C12). All compounds demonstrated a better effect compared to berberine. Their impact on cells' viability also depended on the alkyl substitutes length, but in this case, C10 and C12 derivatives demonstrated the best results. A similar correlation was also found in the OGTT, where the C5 derivative demonstrated a pronounced hypoglycemic effect at a dose of 15 mg/kg and C12 was less effective. This compound was further investigated in C57BL/6Ay mice for four weeks and was administered at a dose of 15 mg/kg. Pronounced effect of C12 on carbohydrate metabolism in mice was discovered: there was a decrease in fasting glucose levels and an increase in glucose tolerance in OGTT on the 14th and 28th days of the experiment. However, at the end of the experiment, signs of hepatosis exacerbation and an increase in the content of hepatic aminotransferases in blood were found.
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26
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Study of Hypoglycemic Activity of Novel 9-N-alkyltetrahydroberberine Derivatives. Int J Mol Sci 2022; 23:ijms232214186. [PMID: 36430664 PMCID: PMC9698964 DOI: 10.3390/ijms232214186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/11/2022] [Accepted: 11/14/2022] [Indexed: 11/18/2022] Open
Abstract
Novel 9-N-alkyltetrahydroberberine derivatives were synthesized, among which, based on the results of OGTT, one compound containing the longest aliphatic substituent was selected for study in mice C57BL/6Ay, which demonstrate obesity, impaired glucose tolerance, and concomitant liver non-alcoholic fatty disease. Administration of this substance at a dose of 15 mg/kg for four weeks improved the insulin sensitivity of mice, which resulted in a decrease in fasting glucose levels and improved the tolerance of mice to OGTT glucose loading. A decrease in the level of lactate in the blood and a decrease in the amount of glucokinase in the liver were also found. The introduction of compound 3c did not have a toxic effect on animals based on biochemical data, histological analysis, and measurements of general parameters such as body weight and feed intake. Thus, the 9-N-heptyltetrahydroberberine derivative showed prominent hypoglycemic effects, which makes it promising to obtain and study other derivatives with longer substituents.
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27
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Maschari D, Saxena G, Law TD, Walsh E, Campbell MC, Consitt LA. Lactate-induced lactylation in skeletal muscle is associated with insulin resistance in humans. Front Physiol 2022; 13:951390. [PMID: 36111162 PMCID: PMC9468271 DOI: 10.3389/fphys.2022.951390] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 07/25/2022] [Indexed: 11/17/2022] Open
Abstract
Elevated circulating lactate has been associated with obesity and insulin resistance. The aim of the current study was to determine if lactate-induced lysine lactylation (kla), a post-translational modification, was present in human skeletal muscle and related to insulin resistance. Fifteen lean (Body Mass Index: 22.1 ± 0.5 kg/m2) and fourteen obese (40.6 ± 1.4 kg/m2) adults underwent a muscle biopsy and 2-h oral glucose tolerance test. Skeletal muscle lactylation was increased in obese compared to lean females (19%, p < 0.05) and associated with insulin resistance (r = 0.37, p < 0.05) in the whole group. Skeletal muscle lactylation levels were significantly associated with markers of anaerobic metabolism (plasma lactate and skeletal muscle lactate dehydrogenase [LDH], p < 0.05) and negatively associated with markers of oxidative metabolism (skeletal muscle cytochrome c oxidase subunit 4 and Complex I [pyruvate] OXPHOS capacity, p < 0.05). Treatment of primary human skeletal muscle cells (HSkMC) with sodium lactate for 24 h increased protein lactylation and IRS-1 serine 636 phosphorylation in a similar dose-dependent manner (p < 0.05). Inhibition of glycolysis (with 2-deoxy-d-glucose) or LDH-A (with sodium oxamate or LDH-A siRNA) for 24 h reduced HSkMC lactylation which paralleled reductions in culture media lactate accumulation. This study identified the existence of a lactate-derived post-translational modification in human skeletal muscle and suggests skeletal muscle lactylation could provide additional insight into the regulation of skeletal muscle metabolism, including insulin resistance.
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Affiliation(s)
- Dominic Maschari
- College of Health Sciences and Professions, Ohio University, Athens, OH, United States
| | - Gunjan Saxena
- Department of Biomedical Sciences, Ohio University, Athens, OH, United States
| | - Timothy D. Law
- Ohio Musculoskeletal and Neurological Institute, Ohio University, Athens, OH, United States
| | - Erin Walsh
- Biological Sciences Department, Ohio University, Athens, OH, United States
| | - Mason C. Campbell
- Biological Sciences Department, Ohio University, Athens, OH, United States
| | - Leslie A Consitt
- Department of Biomedical Sciences, Ohio University, Athens, OH, United States
- Ohio Musculoskeletal and Neurological Institute, Ohio University, Athens, OH, United States
- Diabetes Institute, Ohio University, Athens, OH, United States
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28
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Khvostov MV, Gladkova ED, Borisov SA, Zhukova NA, Marenina MK, Meshkova YV, Luzina OA, Tolstikova TG, Salakhutdinov NF. Discovery of the First in Class 9-N-Berberine Derivative as Hypoglycemic Agent with Extra-Strong Action. Pharmaceutics 2021; 13:pharmaceutics13122138. [PMID: 34959419 PMCID: PMC8708145 DOI: 10.3390/pharmaceutics13122138] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/06/2021] [Accepted: 12/10/2021] [Indexed: 12/13/2022] Open
Abstract
Berberine is well known for its ability to reduce the blood glucose level, but its high effective dose and poor bioavailability limits its use. In this work we synthesized a new derivative of berberine, 9-(hexylamino)-2,3-methylenedioxy-10-methoxyprotoberberine chloride (SHE-196), and analyzed the profile of its hypoglycemic effects. Biological tests have shown that the substance has a very pronounced hypoglycemic activity due to increased insulin sensitivity after single and multiple dosing. In obese type 2 diabetes mellitus (T2DM) mice, it was characterized by improved glucose tolerance, decreased fasting insulin levels and sensitivity, decreased total body weight and interscapular fat mass, and increased interscapular brown fat activity. All these effects were also confirmed histologically, where a decrease in fatty degeneration of the liver, an improvement in the condition of the islets of Langerhans and a decrease in the size of fat droplets in brown adipose tissue were found. Our results indicate that 9-(hexylamino)-2,3-methylenedioxy-10-methoxyprotoberberine chloride could be the first in a new series of therapeutic agents for the treatment of diabetes mellitus.
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Lagarde D, Jeanson Y, Portais JC, Galinier A, Ader I, Casteilla L, Carrière A. Lactate Fluxes and Plasticity of Adipose Tissues: A Redox Perspective. Front Physiol 2021; 12:689747. [PMID: 34276410 PMCID: PMC8278056 DOI: 10.3389/fphys.2021.689747] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 06/09/2021] [Indexed: 12/18/2022] Open
Abstract
Lactate, a metabolite produced when the glycolytic flux exceeds mitochondrial oxidative capacities, is now viewed as a critical regulator of metabolism by acting as both a carbon and electron carrier and a signaling molecule between cells and tissues. In recent years, increasing evidence report its key role in white, beige, and brown adipose tissue biology, and highlights new mechanisms by which lactate participates in the maintenance of whole-body energy homeostasis. Lactate displays a wide range of biological effects in adipose cells not only through its binding to the membrane receptor but also through its transport and the subsequent effect on intracellular metabolism notably on redox balance. This study explores how lactate regulates adipocyte metabolism and plasticity by balancing intracellular redox state and by regulating specific signaling pathways. We also emphasized the contribution of adipose tissues to the regulation of systemic lactate metabolism, their roles in redox homeostasis, and related putative physiopathological repercussions associated with their decline in metabolic diseases and aging.
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Affiliation(s)
- Damien Lagarde
- Goodman Cancer Research Center, McGill University, Montreal, QC, Canada.,Department of Biochemistry, McGill University, Montreal, QC, Canada.,Institut RESTORE, UMR 1301 INSERM, 5070 CNRS, Université Paul Sabatier, Toulouse, France
| | - Yannick Jeanson
- Institut RESTORE, UMR 1301 INSERM, 5070 CNRS, Université Paul Sabatier, Toulouse, France
| | - Jean-Charles Portais
- Institut RESTORE, UMR 1301 INSERM, 5070 CNRS, Université Paul Sabatier, Toulouse, France.,MetaboHUB-MetaToul, National Infrastructure of Metabolomics and Fluxomics, Toulouse, France
| | - Anne Galinier
- Institut RESTORE, UMR 1301 INSERM, 5070 CNRS, Université Paul Sabatier, Toulouse, France.,Institut Fédératif de Biologie, CHU Purpan, Toulouse, France
| | - Isabelle Ader
- Institut RESTORE, UMR 1301 INSERM, 5070 CNRS, Université Paul Sabatier, Toulouse, France
| | - Louis Casteilla
- Institut RESTORE, UMR 1301 INSERM, 5070 CNRS, Université Paul Sabatier, Toulouse, France
| | - Audrey Carrière
- Institut RESTORE, UMR 1301 INSERM, 5070 CNRS, Université Paul Sabatier, Toulouse, France
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30
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El-Sikaily A, Helal M. Environmental pollution and diabetes mellitus. World J Meta-Anal 2021; 9:234-256. [DOI: 10.13105/wjma.v9.i3.234] [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: 01/28/2021] [Revised: 03/17/2021] [Accepted: 06/03/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus (DM) is a chromic metabolic disease that affects a large segment of the population worldwide. Physical inactivity, poor nutrition, and genetic predisposition are main risk factors for disease development. In the last decade, it was clear to the scientific community that DM development is linked to a novel disease inducer that was later defined as diabetogenic factors of pollution and endocrine disrupting agents. Environmental pollution is exponentially increasing in uncontrolled manner in several countries. Environmental pollutants are of diverse nature and toxicities, including polyaromatic hydrocarbons (PAHs), pesticides, and heavy metals. In the current review, we shed light on the impact of each class of these pollutants and the underlined molecular mechanism of diabetes induction and biological toxicities. Finally, a brief overview about the connection between coronavirus disease 2019 and diabetes pandemics is presented.
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Affiliation(s)
- Amany El-Sikaily
- National Institute of Oceanography and Fisheries (NIOF), Cairo 21513, Egypt
| | - Mohamed Helal
- National Institute of Oceanography and Fisheries (NIOF), Cairo 21513, Egypt
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Abstract
OBJECTIVES Multiple studies have demonstrated an obesity paradox such that obese ICU patients have lower mortality and better outcomes. We conducted this study to determine if the mortality benefit conferred by obesity is affected by baseline serum lactate and mean arterial pressure. DESIGN Retrospective analysis of prospectively collected clinical data. SETTING Five community-based and one academic medical center in the Omaha, NE. PATIENTS 7,967 adults hospitalized with sepsis. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Patients were categorized by body mass index as underweight, normal weight, overweight, or obese. Multivariable logistic regression models were used to estimate the odds of in-hospital death by body mass index category; two-way interactions between body mass index and each covariate were also evaluated. Subgroup and sensitivity analyses were conducted using an ICU cohort and Acute Physiology and Chronic Health Evaluation III scores, respectively. The overall unadjusted mortality rate was 12.1% and was consistently lower in higher body mass index categories (all comparisons, p < 0.007). The adjusted mortality benefit observed in patients with higher body mass index was smaller in patients with higher lactate levels with no mortality benefit in higher body mass index categories observed at lactate greater than 5 mmol/L. By contrast, the association between lower MAP and higher mortality was constant across body mass index categories. Similar results were observed in the ICU cohort. Finally, the obesity paradox was not observed after including Acute Physiology and Chronic Health Evaluation III scores as a covariate. CONCLUSIONS Our retrospective analysis suggests that although patient size (i.e., body mass index) is a predictor of in-hospital death among all-comers with sepsis-providing further evidence to the obesity paradox-it adds that illness severity is critically important whether quantified as higher lactate or by Acute Physiology and Chronic Health Evaluation III score. Our results highlight that the obesity paradox is more than a simple association between body mass index and mortality and reinforces the importance of illness severity.
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32
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Bui TPN, de Vos WM. Next-generation therapeutic bacteria for treatment of obesity, diabetes, and other endocrine diseases. Best Pract Res Clin Endocrinol Metab 2021; 35:101504. [PMID: 33785319 DOI: 10.1016/j.beem.2021.101504] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The human gut microbiota has appeared as an important factor affecting host health and intestinal bacteria have recently emerged as potential therapeutics to treat diabetes and other endocrine diseases. These mainly anaerobic bacteria have been identified either via comparative "omics" analysis of the intestinal microbiota in healthy and diseased subjects or of data collected by fecal microbiota transplantation studies. Both approaches require advanced and in-depth sequencing technologies to perform massive genomic screening to select bacteria with potential benefits. It has been shown that these potentially therapeutic bacteria can either produce bioactive products that directly influence the host patho-physiology and endocrine systems or produce specific signaling molecules that may do so. These bioactive compounds can be formed via degradation of dietary or host-derived components or the conversion of intermediate compounds produced by fermentation of intestinal bacteria. Several of these bacteria have shown causality in preclinical models and entered clinical phase studies, while their mode of action is being analyzed. In this review, we summarize the research on the most promising bacterial candidates with therapeutic properties with a specific focus on diabetes.
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Affiliation(s)
- Thi Phuong Nam Bui
- Laboratory of Microbiology, Wageningen University, Stippeneng 4, 6708, WE, Wageningen, the Netherlands; Caelus Pharmaceuticals BV, 3474, KG, Zegveld, the Netherlands
| | - Willem M de Vos
- Laboratory of Microbiology, Wageningen University, Stippeneng 4, 6708, WE, Wageningen, the Netherlands; Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
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Moriggi M, Belloli S, Barbacini P, Murtaj V, Torretta E, Chaabane L, Canu T, Penati S, Malosio ML, Esposito A, Gelfi C, Moresco RM, Capitanio D. Skeletal Muscle Proteomic Profile Revealed Gender-Related Metabolic Responses in a Diet-Induced Obesity Animal Model. Int J Mol Sci 2021; 22:ijms22094680. [PMID: 33925229 PMCID: PMC8125379 DOI: 10.3390/ijms22094680] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 04/15/2021] [Accepted: 04/27/2021] [Indexed: 02/08/2023] Open
Abstract
Obesity is a chronic, complex pathology associated with a risk of developing secondary pathologies, including cardiovascular diseases, cancer, type 2 diabetes (T2DM) and musculoskeletal disorders. Since skeletal muscle accounts for more than 70% of total glucose disposal, metabolic alterations are strictly associated with the onset of insulin resistance and T2DM. The present study relies on the proteomic analysis of gastrocnemius muscle from 15 male and 15 female C56BL/J mice fed for 14 weeks with standard, 45% or 60% high-fat diets (HFD) adopting a label-free LC–MS/MS approach followed by bioinformatic pathway analysis. Results indicate changes in males due to HFD, with increased muscular stiffness (Col1a1, Col1a2, Actb), fiber-type switch from slow/oxidative to fast/glycolytic (decreased Myh7, Myl2, Myl3 and increased Myh2, Mylpf, Mybpc2, Myl1), increased oxidative stress and mitochondrial dysfunction (decreased respiratory chain complex I and V and increased complex III subunits). At variance, females show few alterations and activation of compensatory mechanisms to counteract the increase of fatty acids. Bioinformatics analysis allows identifying upstream molecules involved in regulating pathways identified at variance in our analysis (Ppargc1a, Pparg, Cpt1b, Clpp, Tp53, Kdm5a, Hif1a). These findings underline the presence of a gender-specific response to be considered when approaching obesity and related comorbidities.
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Affiliation(s)
- Manuela Moriggi
- Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, 20097 San Donato Milanese, Italy;
| | - Sara Belloli
- Institute of Molecular Bioimaging and Physiology, CNR, 20090 Segrate, Italy; (S.B.); (R.M.M.)
- Department of Nuclear Medicine, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy;
| | - Pietro Barbacini
- Department of Biomedical Sciences for Health, University of Milan, 20090 Segrate, Italy; (P.B.); (C.G.)
| | - Valentina Murtaj
- Department of Nuclear Medicine, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy;
- PhD Program in Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
| | | | - Linda Chaabane
- Experimental Imaging Center, Preclinical Imaging Facility, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; (L.C.); (T.C.); (A.E.)
| | - Tamara Canu
- Experimental Imaging Center, Preclinical Imaging Facility, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; (L.C.); (T.C.); (A.E.)
| | - Silvia Penati
- Laboratory of Pharmacology and Brain Pathology, Neuro Center, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (S.P.); (M.L.M.)
- Institute of Neuroscience, Humanitas Mirasole S.p.A, 20089 Rozzano, Italy
| | - Maria Luisa Malosio
- Laboratory of Pharmacology and Brain Pathology, Neuro Center, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (S.P.); (M.L.M.)
- Institute of Neuroscience, Humanitas Mirasole S.p.A, 20089 Rozzano, Italy
| | - Antonio Esposito
- Experimental Imaging Center, Preclinical Imaging Facility, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; (L.C.); (T.C.); (A.E.)
- Experimental Imaging Center, Radiology Department, IRCCS San Raffaele Scientific Institute, School of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Cecilia Gelfi
- Department of Biomedical Sciences for Health, University of Milan, 20090 Segrate, Italy; (P.B.); (C.G.)
- IRCCS Istituto Ortopedico Galeazzi, 20161 Milan, Italy;
| | - Rosa Maria Moresco
- Institute of Molecular Bioimaging and Physiology, CNR, 20090 Segrate, Italy; (S.B.); (R.M.M.)
- Department of Nuclear Medicine, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy;
- Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
| | - Daniele Capitanio
- Department of Biomedical Sciences for Health, University of Milan, 20090 Segrate, Italy; (P.B.); (C.G.)
- Correspondence: ; Tel.: +39-0250330411
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34
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Rodríguez-López JM, Lachica M, González-Valero L, Fernández-Fígares I. Determining insulin sensitivity from glucose tolerance tests in Iberian and landrace pigs. PeerJ 2021; 9:e11014. [PMID: 33854837 PMCID: PMC7955676 DOI: 10.7717/peerj.11014] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 02/05/2021] [Indexed: 11/20/2022] Open
Abstract
As insulin sensitivity may help to explain divergences in growth and body composition between native and modern breeds, metabolic responses to glucose infusion were measured using an intra-arterial glucose tolerance test (IAGTT). Iberian (n = 4) and Landrace (n = 5) barrows (47.0 ± 1.2 kg body weight (BW)), fitted with a permanent carotid artery catheter were injected with glucose (500 mg/kg BW) and blood samples collected at -10, 0, 5, 10, 15, 20, 25, 30, 45, 60, 90, 120 and 180 min following glucose infusion. Plasma samples were analysed for insulin, glucose, lactate, triglycerides, cholesterol, creatinine, albumin and urea. Insulin sensitivity indices were calculated and analysed. Mean plasma glucose, creatinine and cholesterol concentrations were lower (P < 0.01) in Iberian (14, 68 and 22%, respectively) than in Landrace pigs during the IAGTT. However, mean plasma insulin, lactate, triglycerides and urea concentrations were greater (P < 0.001) in Iberian (50, 35, 18 and 23%, respectively) than in Landrace pigs. Iberian pigs had larger area under the curve (AUC) of insulin (P < 0.05) or tended to a greater AUC of lactate (P < 0.10), and a smaller (P < 0.05) AUC for glucose 0-60 min compared with Landrace pigs. Indices for estimating insulin sensitivity in fasting conditions indicated improved β-cell function in Iberian compared with Landrace pigs, but no difference (P > 0.10) in calculated insulin sensitivity index was found after IAGTT between breeds. A time response (P < 0.05) was obtained for insulin, glucose and lactate so that maximum concentration was achieved at 10 and 15 min post-infusion for insulin (Iberian and Landrace pigs, respectively), immediately post-infusion for glucose, and 20 min post-infusion for lactate, decreasing thereafter until basal levels. There was no time effect for the rest of metabolites evaluated. In conclusion, growing Iberian pigs challenged with an IAGTT showed changes in biochemical parameters and insulin response that may indicate an early stage of insulin resistance.
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Affiliation(s)
| | - Manuel Lachica
- Department of Physiology and Biochemistry of Animal Nutrition, Estación Experimental del Zaidín, Consejo Superior de Investigaciones Científicas, Granada, Spain
| | - Lucrecia González-Valero
- Department of Physiology and Biochemistry of Animal Nutrition, Estación Experimental del Zaidín, Consejo Superior de Investigaciones Científicas, Granada, Spain
| | - Ignacio Fernández-Fígares
- Department of Physiology and Biochemistry of Animal Nutrition, Estación Experimental del Zaidín, Consejo Superior de Investigaciones Científicas, Granada, Spain
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35
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Broskey NT, Pories WJ, Jones TE, Tanner CJ, Zheng D, Cortright RN, Yang ZW, Khang N, Yang J, Houmard JA, Lynis Dohm G. The association between lactate and muscle aerobic substrate oxidation: Is lactate an early marker for metabolic disease in healthy subjects? Physiol Rep 2021; 9:e14729. [PMID: 33527749 PMCID: PMC7851428 DOI: 10.14814/phy2.14729] [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: 11/12/2020] [Revised: 12/17/2020] [Accepted: 12/20/2020] [Indexed: 11/24/2022] Open
Abstract
Fasting plasma lactate concentrations are elevated in individuals with metabolic disease. The aim of this study was to determine if the variance in fasting lactate concentrations were associated with factors linked with cardiometabolic health even in a young, lean cohort. Young (age 22 ± 0.5; N = 30) lean (BMI (22.4 ± 0.4 kg/m2) women were assessed for waist‐to‐hip ratio, aerobic capacity (VO2peak), skeletal muscle oxidative capacity (near infrared spectroscopy; fat oxidation from muscle biopsies), and fasting glucose and insulin (HOMA‐IR). Subjects had a mean fasting lactate of 0.9 ± 0.1 mmol/L. The rate of deoxygenation of hemoglobin/myoglobin (R2 = .23, p = .03) in resting muscle and skeletal muscle homogenate fatty acid oxidation (R2 = .72, p = .004) were inversely associated with fasting lactate. Likewise, cardiorespiratory fitness (time to exhaustion during the VO2peak test) was inversely associated with lactate (R2 = .20, p = .05). Lactate concentration was inversely correlated with HDL:LDL (R2 = .57, p = .02) and positively correlated with the waist to hip ratio (R2 = .52, p = .02). Plasma lactate was associated with various indices of cardiometabolic health. Thus, early determination of fasting lactate concentration could become a common biomarker used for identifying individuals at early risk for metabolic diseases.
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Affiliation(s)
- Nicholas T Broskey
- Department of Kinesiology, East Carolina University, Greenville, North Carolina, USA.,Department of Human Performance Laboratory, East Carolina University, Greenville, North Carolina, USA.,Department of Diabetes, Obesity Institute, East Carolina University, Greenville, North Carolina, USA
| | - Walter J Pories
- Department of Diabetes, Obesity Institute, East Carolina University, Greenville, North Carolina, USA.,Department of Surgery, East Carolina University, Greenville, North Carolina, USA
| | - Terry E Jones
- Department of Diabetes, Obesity Institute, East Carolina University, Greenville, North Carolina, USA.,Department of Physical Therapy, East Carolina University, Greenville, North Carolina, USA
| | - Charles J Tanner
- Department of Kinesiology, East Carolina University, Greenville, North Carolina, USA.,Department of Human Performance Laboratory, East Carolina University, Greenville, North Carolina, USA.,Department of Diabetes, Obesity Institute, East Carolina University, Greenville, North Carolina, USA
| | - Donghai Zheng
- Department of Kinesiology, East Carolina University, Greenville, North Carolina, USA.,Department of Human Performance Laboratory, East Carolina University, Greenville, North Carolina, USA.,Department of Diabetes, Obesity Institute, East Carolina University, Greenville, North Carolina, USA
| | - Ronald N Cortright
- Department of Kinesiology, East Carolina University, Greenville, North Carolina, USA.,Department of Human Performance Laboratory, East Carolina University, Greenville, North Carolina, USA.,Department of Diabetes, Obesity Institute, East Carolina University, Greenville, North Carolina, USA
| | - Zhen W Yang
- Department of Kinesiology, East Carolina University, Greenville, North Carolina, USA.,Department of Human Performance Laboratory, East Carolina University, Greenville, North Carolina, USA
| | - Nkaujyi Khang
- Department of Kinesiology, East Carolina University, Greenville, North Carolina, USA.,Department of Human Performance Laboratory, East Carolina University, Greenville, North Carolina, USA
| | - Josh Yang
- Department of Physiology, East Carolina University, Greenville, North Carolina, USA
| | - Joseph A Houmard
- Department of Kinesiology, East Carolina University, Greenville, North Carolina, USA.,Department of Human Performance Laboratory, East Carolina University, Greenville, North Carolina, USA.,Department of Diabetes, Obesity Institute, East Carolina University, Greenville, North Carolina, USA
| | - G Lynis Dohm
- Department of Diabetes, Obesity Institute, East Carolina University, Greenville, North Carolina, USA.,Department of Physiology, East Carolina University, Greenville, North Carolina, USA
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36
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Insulin/Glucose-Responsive Cells Derived from Induced Pluripotent Stem Cells: Disease Modeling and Treatment of Diabetes. Cells 2020; 9:cells9112465. [PMID: 33198288 PMCID: PMC7696367 DOI: 10.3390/cells9112465] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/03/2020] [Accepted: 11/09/2020] [Indexed: 12/21/2022] Open
Abstract
Type 2 diabetes, characterized by dysfunction of pancreatic β-cells and insulin resistance in peripheral organs, accounts for more than 90% of all diabetes. Despite current developments of new drugs and strategies to prevent/treat diabetes, there is no ideal therapy targeting all aspects of the disease. Restoration, however, of insulin-producing β-cells, as well as insulin-responsive cells, would be a logical strategy for the treatment of diabetes. In recent years, generation of transplantable cells derived from stem cells in vitro has emerged as an important research area. Pluripotent stem cells, either embryonic or induced, are alternative and feasible sources of insulin-secreting and glucose-responsive cells. This notwithstanding, consistent generation of robust glucose/insulin-responsive cells remains challenging. In this review, we describe basic concepts of the generation of induced pluripotent stem cells and subsequent differentiation of these into pancreatic β-like cells, myotubes, as well as adipocyte- and hepatocyte-like cells. Use of these for modeling of human disease is now feasible, while development of replacement therapies requires continued efforts.
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37
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Oyabambi AO, Olaniyi KS, Soladoye AO, Olatunji LA. Suppression of uric acid and lactate production by sodium acetate ameliorates hepatic triglyceride accumulation in fructose-insulin resistant pregnant rats. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2020; 80:103452. [PMID: 32610186 DOI: 10.1016/j.etap.2020.103452] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 05/30/2020] [Accepted: 06/26/2020] [Indexed: 06/11/2023]
Abstract
High fructose intake has been associated with perturbed lipid, uric acid and lactate homeostasis. However, consumption of fructose-sweetened beverages is not usually regulated during pregnancy. The effect of short-chain fatty acid (acetate) on the metabolic effects of high fructose intake during pregnancy is not known. We hypothesized that acetate prevents gestational fructose-induced hepatic triglyceride (TG) accumulation by suppressing uric acid and lactate production. Pregnant Wistar rats were randomly separated into three groups (n = 6/group) receiving drinking water (CON), 10 % (w/v) fructose drink (FRU) and 10 % (w/v) fructose with 200 mg/kg (w/w; p.o.) sodium acetate (FRU + ACE) daily for nineteen days. Fructose intake resulted in increased body weight gain, liver weight, fluid intake, visceral fat, insulin resistance, fasting blood glucose, insulin, plasma and hepatic TG, total cholesterol, free fatty acid, lipid peroxidation, adenosine deaminase, xanthine oxidase, uric acid, lactate, lactate dehydrogenase, and liver injury marker enzymes. However, gestational high fructose intake led to depressed plasma and hepatic glucose-6-phosphate dehydrogenase (G6PD)-dependent antioxidant barrier, adenosine and food intake. All these effects except water intake and food intake were abated by sodium acetate. These results demonstrate that maternal fructose-enriched drink would cause hepatic TG accumulation that is associated with perturbed glucose, uric acid, lactate homeostasis, and G6PD-dependent antioxidant barrier. These results also demonstrate that acetate protects the liver against gestational fructose-induced TG accumulation by inhibiting uric acid and lactate production. Thus, acetate may be useful in the treatment of hyperuricemia- and hyperlactatemia-related disorders.
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Affiliation(s)
- Adewumi O Oyabambi
- HOPE Cardiometabolic Research Team & Department of Physiology, Faculty of Basic Medical Sciences, University of Ilorin, Ilorin, Nigeria
| | - Kehinde S Olaniyi
- HOPE Cardiometabolic Research Team & Department of Physiology, Faculty of Basic Medical Sciences, University of Ilorin, Ilorin, Nigeria; Department of Physiology, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Nigeria
| | - Ayodele O Soladoye
- HOPE Cardiometabolic Research Team & Department of Physiology, Faculty of Basic Medical Sciences, University of Ilorin, Ilorin, Nigeria; Department of Physiology, College of Health Sciences, Bowen University, Iwo, Nigeria
| | - Lawrence A Olatunji
- HOPE Cardiometabolic Research Team & Department of Physiology, Faculty of Basic Medical Sciences, University of Ilorin, Ilorin, Nigeria.
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38
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Zou K, Turner K, Zheng D, Hinkley JM, Kugler BA, Hornby PJ, Lenhard J, Jones TE, Pories WJ, Dohm GL, Houmard JA. Impaired glucose partitioning in primary myotubes from severely obese women with type 2 diabetes. Am J Physiol Cell Physiol 2020; 319:C1011-C1019. [PMID: 32966127 DOI: 10.1152/ajpcell.00157.2020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The purpose of this study was to determine whether intramyocellular glucose partitioning was altered in primary human myotubes derived from severely obese women with type 2 diabetes. Human skeletal muscle cells were obtained from lean nondiabetic and severely obese Caucasian females with type 2 diabetes [body mass index (BMI): 23.6 ± 2.6 vs. 48.8 ± 1.9 kg/m2, fasting glucose: 86.9 ± 1.6 vs. 135.6 ± 12.0 mg/dL, n = 9/group]. 1-[14C]-Glucose metabolism (glycogen synthesis, glucose oxidation, and nonoxidized glycolysis) and 1- and 2-[14C]-pyruvate oxidation were examined in fully differentiated myotubes under basal and insulin-stimulated conditions. Tricarboxylic acid cycle intermediates were determined via targeted metabolomics. Myotubes derived from severely obese individuals with type 2 diabetes exhibited impaired insulin-mediated glucose partitioning with reduced rates of glycogen synthesis and glucose oxidation and increased rates of nonoxidized glycolytic products, when compared with myotubes derived from the nondiabetic individuals (P < 0.05). Both 1- and 2-[14C]-pyruvate oxidation rates were significantly blunted in myotubes from severely obese women with type 2 diabetes compared with myotubes from the nondiabetic controls. Lastly, concentrations of tricarboxylic acid cycle intermediates, namely, citrate (P < 0.05), cis-aconitic acid (P = 0.07), and α-ketoglutarate (P < 0.05), were lower in myotubes from severely obese women with type 2 diabetes. These data suggest that intramyocellular insulin-mediated glucose partitioning is intrinsically altered in the skeletal muscle of severely obese women with type 2 diabetes in a manner that favors the production of glycolytic end products. Defects in pyruvate dehydrogenase and tricarboxylic acid cycle may be responsible for this metabolic derangement associated with type 2 diabetes.
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Affiliation(s)
- Kai Zou
- Department of Exercise and Health Sciences, University of Massachusetts Boston, Boston, Massachusetts
| | - Kristen Turner
- Department of Kinesiology, East Carolina University, Greenville, North Carolina.,Human Performance Laboratory, East Carolina University, Greenville, North Carolina.,East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina
| | - Donghai Zheng
- Department of Kinesiology, East Carolina University, Greenville, North Carolina.,Human Performance Laboratory, East Carolina University, Greenville, North Carolina.,Department of Physiology, East Carolina University, Greenville, North Carolina
| | - J Matthew Hinkley
- Department of Kinesiology, East Carolina University, Greenville, North Carolina.,Human Performance Laboratory, East Carolina University, Greenville, North Carolina.,East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina
| | - Benjamin A Kugler
- Department of Exercise and Health Sciences, University of Massachusetts Boston, Boston, Massachusetts
| | - Pamela J Hornby
- Janssen Research & Development, LLC, Spring House, Pennsylvania
| | - James Lenhard
- Janssen Research & Development, LLC, Spring House, Pennsylvania
| | - Terry E Jones
- Department of Physical Therapy, East Carolina University, Greenville, North Carolina
| | - Walter J Pories
- Department of Surgery, East Carolina University, Greenville, North Carolina.,East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina
| | - G Lynis Dohm
- Department of Physiology, East Carolina University, Greenville, North Carolina.,East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina
| | - Joseph A Houmard
- Department of Kinesiology, East Carolina University, Greenville, North Carolina.,Human Performance Laboratory, East Carolina University, Greenville, North Carolina.,East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina
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Short-Term Effects of Early Menopause on Adiposity, Fatty Acids Profile and Insulin Sensitivity of a Swine Model of Female Obesity. BIOLOGY 2020; 9:biology9090284. [PMID: 32932852 PMCID: PMC7565410 DOI: 10.3390/biology9090284] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 08/31/2020] [Accepted: 09/03/2020] [Indexed: 02/07/2023]
Abstract
Menopause strongly increases incidence and consequences of obesity and non-communicable diseases in women, with recent research suggesting a very early onset of changes in lipid accumulation, dyslipidemia, and insulin resistance. However, there is a lack of adequate preclinical models for its study. The present trial evaluated the usefulness of an alternative method to surgical ovariectomy, the administration of two doses of a GnRH analogue-protein conjugate (Vacsincel®), for inducing ovarian inactivity in sows used as preclinical models of obesity and menopause. All the sows treated with the compound developed ovarian stoppage after the second dose and, when exposed to obesogenic diets during the following three months, showed changes in the patterns of fat deposition, in the fatty acids profiles at the different tissues and in the plasma concentrations of fructosamine, urea, β-hydroxibutirate, and haptoglobin when compared to obese fed with the same diet but maintaining ovarian activity. Altogether, these results indicate that menopause early augments the deleterious effects induced by overfeeding and obesity on metabolic traits, paving the way for future research on physiopathology of these conditions and possible therapeutic targets using the swine model.
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Chalmers E, Samocha-Bonet D. The effect of body acid-base state and manipulations on body glucose regulation in human. Eur J Clin Nutr 2020; 74:20-26. [PMID: 32873953 DOI: 10.1038/s41430-020-0692-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Long-term exposure to high dietary acid load has been associated with insulin resistance and type 2 diabetes in epidemiological studies. However, it remains unclear whether the acid load of the diet translates to mild metabolic acidosis and whether it is responsible for the impairment in glucose regulation in humans. Previously, in a cross-sectional study we have reported that dietary acid load was not different between healthy individuals with normal weight and those with overweight/obesity, irrespective of insulin sensitivity. However, 4-week high acid load diet increased plasma lactate (a small component of the anion gap) and increased insulin resistance in healthy participants. The change in plasma lactate correlated significantly with the change in insulin resistance. Because cause-and-effect could not be evaluated in these settings, we sought to directly test the effect of an alkalizing treatment preload on postprandial glucose regulation. In a randomized placebo-controlled study with a crossover design, we administered sodium bicarbonate (NaHCO3, 1.68 g) prior to high acid load meal to healthy individuals. We found that while the bicarbonate preload attenuated the post meal decrease in pH observed with placebo, no effect on postprandial glucose regulation (glucose, insulin, and C-peptide) was observed. Following 3-month treatment of nondiabetic individuals with bicarbonate, others have reported no change in insulin resistance markers, consistent with our findings. Together, studies in human suggest that insulin resistance associated with longstanding obesogenic diet may be mediated by mild metabolic acidosis. However, buffering the Western diet with bicarbonate and increasing body pH does not change glucose homeostasis in nondiabetic individuals. Further studies are required to shed light on the role of body acid-base balance and glucose homeostasis in health and disease.
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Affiliation(s)
- Eliza Chalmers
- Diabetes & Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Dorit Samocha-Bonet
- Diabetes & Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW, Australia. .,St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
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Chaplin A, Gao H, Asase C, Rengasamy P, Park B, Skander D, Bebek G, Rajagopalan S, Maiseyeu A. Systemically-delivered biodegradable PLGA alters gut microbiota and induces transcriptomic reprogramming in the liver in an obesity mouse model. Sci Rep 2020; 10:13786. [PMID: 32796856 PMCID: PMC7429827 DOI: 10.1038/s41598-020-69745-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 07/17/2020] [Indexed: 02/07/2023] Open
Abstract
Biodegradable materials, including the widely used poly (lactic-co-glycolic acid) (PLGA) nanoparticles contained in slow-release drug formulations, scaffolds and implants, are ubiquitous in modern biomedicine and are considered inert or capable of being metabolized through intermediates such as lactate. However, in the presence of metabolic stress, such as in obesity, the resulting degradation products may play a detrimental role, which is still not well understood. We evaluated the effect of intravenously-administered PLGA nanoparticles on the gut-liver axis under conditions of caloric excess in C57BL/6 mice. Our results show that PLGA nanoparticles accumulate and cause gut acidification in the cecum, accompanied by significant changes in the microbiome, with a marked decrease of Firmicutes and Bacteroidetes. This was associated with transcriptomic reprogramming in the liver, with a downregulation of mitochondrial function, and an increase in key enzymatic, inflammation and cell activation pathways. No changes were observed in systemic inflammation. Metagenome analysis coupled with publicly available microarray data suggested a mechanism of impaired PLGA degradation and intestinal acidification confirming an important enterohepatic axis of metabolite-microbiome interaction resulting in maintenance of metabolic homeostasis. Thus, our results have important implications for the investigation of PLGA use in metabolically-compromised clinical and experimental settings.
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Affiliation(s)
- Alice Chaplin
- School of Medicine, Cardiovascular Research Institute, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA
| | - Huiyun Gao
- School of Medicine, Cardiovascular Research Institute, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA
| | - Courteney Asase
- School of Medicine, Cardiovascular Research Institute, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA
| | - Palanivel Rengasamy
- School of Medicine, Cardiovascular Research Institute, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA
| | - Bongsoo Park
- Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Danielle Skander
- Department of Nutrition, Department of Electrical Engineering and Computer Science, Center for Proteomics and Bioinformatics, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA
| | - Gürkan Bebek
- Department of Nutrition, Department of Electrical Engineering and Computer Science, Center for Proteomics and Bioinformatics, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA
| | - Sanjay Rajagopalan
- School of Medicine, Cardiovascular Research Institute, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA
| | - Andrei Maiseyeu
- School of Medicine, Cardiovascular Research Institute, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA.
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Hu JR, Wu Y, Sacks FM, Appel LJ, Miller Iii ER, Young JH, Juraschek SP. Effects of carbohydrate quality and amount on plasma lactate: results from the OmniCarb trial. BMJ Open Diabetes Res Care 2020; 8:8/1/e001457. [PMID: 32868311 PMCID: PMC7462151 DOI: 10.1136/bmjdrc-2020-001457] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 07/16/2020] [Accepted: 07/21/2020] [Indexed: 11/15/2022] Open
Abstract
INTRODUCTION Plasma lactate is a marker of non-oxidative glucose metabolism associated with progression to diabetes. We examined the effect of carbohydrate quality (glycemic index (GI)) and amount (%kcal) on plasma lactate. We hypothesized that low GI (≤45 (g)) versus high (≥65 (G)) and low %kcal from carbohydrate (40% kcal (c)) versus high (58% kcal (C)) each would reduce lactate levels. RESEARCH DESIGN AND METHODS We measured lactate in OmniCarb, a randomized, cross-over trial of four diets in overweight/obese adults without diabetes or cardiovascular disease (N=163). The four diets were high carbohydrate+high GI (CG, reference), high carbohydrate+low GI (Cg), low carbohydrate+high GI (cG), and low carbohydrate+low GI (cg). Participants (N=163) consumed each of the four diets over a 5-week period, separated by 2-week washout periods. Plasma lactate levels were measured at baseline, during which the participants consumed their own diets, and after each 5-week period. RESULTS Baseline plasma lactate was 1.2 mmol/L. In the setting of high carbohydrate amount, reducing GI lowered plasma lactate non-significantly by 0.08 mmol/L (Cg vs CG: 95% CI -0.16 to 0.00; p=0.06). In the setting of high GI, reducing carbohydrate amount lowered plasma lactate by 0.10 mmol/L (cG vs CG: 95% CI -0.19 to -0.02; p=0.02). The combined effect of reducing GI and carbohydrate proportion in the diet (cg vs CG) was similar (cg vs CG: -0.08; 95% CI -0.16 to 0.00; p=0.04). All four diets reduced plasma lactate compared with baseline. CONCLUSIONS Compared with a diet with high GI and high carbohydrate amount, diets with low GI and/or low carbohydrate amount reduced plasma lactate. Whether this change in lactate leads to long-term change in glucose metabolism needs to be examined. TRIAL REGISTRATION NUMBER NCT00608049.
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Affiliation(s)
- Jiun-Ruey Hu
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Yingfei Wu
- Welch Center for Epidemiology, Prevention, and Clinical Research, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Frank M Sacks
- Department of Nutrition, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
| | - Lawrence J Appel
- Welch Center for Epidemiology, Prevention, and Clinical Research, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Edgar R Miller Iii
- Welch Center for Epidemiology, Prevention, and Clinical Research, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - J Hunter Young
- Welch Center for Epidemiology, Prevention, and Clinical Research, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Stephen P Juraschek
- Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
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Fan L, Cacicedo JM, Ido Y. Impaired nicotinamide adenine dinucleotide (NAD + ) metabolism in diabetes and diabetic tissues: Implications for nicotinamide-related compound treatment. J Diabetes Investig 2020; 11:1403-1419. [PMID: 32428995 PMCID: PMC7610120 DOI: 10.1111/jdi.13303] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 05/13/2020] [Accepted: 05/14/2020] [Indexed: 01/08/2023] Open
Abstract
One of the biochemical abnormalities found in diabetic tissues is a decrease in the cytosolic oxidized to reduced forms of the nicotinamide adenine dinucleotide ratio (NAD+/NADH also known as pseudohypoxia) caused by oxidation of excessive substrates (glucose through the polyol pathway, free fatty acids and lactate). Subsequently, a decline in NAD+ levels as a result of the activation of poly adenine nucleotide diphosphate‐ribose polymerase (mainly in type 1 diabetes) or the inhibition of adenine nucleotide monophosphate‐activated protein kinase (in type 2 diabetes). Thus, replenishment of NAD+ levels by nicotinamide‐related compounds could be beneficial. However, these compounds also increase nicotinamide catabolites that cause oxidative stress. This is particularly troublesome for patients with diabetes, because they have impaired nicotinamide salvage pathway reactions at the level of nicotinamide phosphoribosyl transferase and phosphoribosyl pyrophosphate, which occurs by the following mechanisms. First, phosphoribosyl pyrophosphate synthesis from pentose phosphate pathway is compromised by a decrease in plasma thiamine and transketolase activity. Second, nicotinamide phosphoribosyl transferase expression is decreased because of reduced adenosine monophosphate‐activated protein kinase activity, which occurs in type 2 diabetes. The adenosine monophosphate‐activated protein kinase inhibition is caused by an activation of protein kinase C and D1 as a result of enhanced diacylglycerol synthesis caused by pseudohypoxia and increased fatty acids levels. In this regard, nicotinamide‐related compounds should be given with caution to treat diabetes. To minimize the risk and maximize the benefit, nicotinamide‐related compounds should be taken with insulin sensitizers (for type 2 diabetes), polyphenols, benfotiamine, acetyl‐L‐carnitine and aldose reductase inhibitors. The efficacy of these regimens can be monitored by measuring serum NAD+ and urinary nicotinamide catabolites.
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Affiliation(s)
- Lan Fan
- Boston University School of Medicine, Boston, Massachusetts, USA
| | - Jose M Cacicedo
- Boston University School of Medicine, Boston, Massachusetts, USA
| | - Yasuo Ido
- Boston University School of Medicine, Boston, Massachusetts, USA
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Guasch-Ferré M, Santos JL, Martínez-González MA, Clish CB, Razquin C, Wang D, Liang L, Li J, Dennis C, Corella D, Muñoz-Bravo C, Romaguera D, Estruch R, Santos-Lozano JM, Castañer O, Alonso-Gómez A, Serra-Majem L, Ros E, Canudas S, Asensio EM, Fitó M, Pierce K, Martínez JA, Salas-Salvadó J, Toledo E, Hu FB, Ruiz-Canela M. Glycolysis/gluconeogenesis- and tricarboxylic acid cycle-related metabolites, Mediterranean diet, and type 2 diabetes. Am J Clin Nutr 2020; 111:835-844. [PMID: 32060497 PMCID: PMC7138680 DOI: 10.1093/ajcn/nqaa016] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 01/23/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Glycolysis/gluconeogenesis and tricarboxylic acid (TCA) cycle metabolites have been associated with type 2 diabetes (T2D). However, the associations of these metabolites with T2D incidence and the potential effect of dietary interventions remain unclear. OBJECTIVES We aimed to evaluate the association of baseline and 1-y changes in glycolysis/gluconeogenesis and TCA cycle metabolites with insulin resistance and T2D incidence, and the potential modifying effect of Mediterranean diet (MedDiet) interventions. METHODS We included 251 incident T2D cases and 638 noncases in a nested case-cohort study within the PREDIMED Study during median follow-up of 3.8 y. Participants were allocated to MedDiet + extra-virgin olive oil, MedDiet + nuts, or control diet. Plasma metabolites were measured using a targeted approach by LC-tandem MS. We tested the associations of baseline and 1-y changes in glycolysis/gluconeogenesis and TCA cycle metabolites with subsequent T2D risk using weighted Cox regression models and adjusting for potential confounders. We designed a weighted score combining all these metabolites and applying the leave-one-out cross-validation approach. RESULTS Baseline circulating concentrations of hexose monophosphate, pyruvate, lactate, alanine, glycerol-3 phosphate, and isocitrate were significantly associated with higher T2D risk (17-44% higher risk for each 1-SD increment). The weighted score including all metabolites was associated with a 30% (95% CI: 1.12, 1.51) higher relative risk of T2D for each 1-SD increment. Baseline lactate and alanine were associated with baseline and 1-y changes of homeostasis model assessment of insulin resistance. One-year increases in most metabolites and in the weighted score were associated with higher relative risk of T2D after 1 y of follow-up. Lower risks were observed in the MedDiet groups than in the control group although no significant interactions were found after adjusting for multiple comparisons. CONCLUSIONS We identified a panel of glycolysis/gluconeogenesis-related metabolites that was significantly associated with T2D risk in a Mediterranean population at high cardiovascular disease risk. A MedDiet could counteract the detrimental effects of these metabolites.This trial was registered at controlled-trials.com as ISRCTN35739639.
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Affiliation(s)
- Marta Guasch-Ferré
- Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA
- Human Nutrition Unit, Faculty of Medicine and Health Sciences, Pere Virgili Health Research Institute, Rovira i Virgili University, Reus, Spain
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - José L Santos
- Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Miguel A Martínez-González
- Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA
- Department of Preventive Medicine and Public Health, IdiSNA (Health Research Institute of Navarra), University of Navarra, Pamplona, Spain
- The Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition, Health Institute Carlos III, Madrid, Spain
| | - Clary B Clish
- Broad Institute of MIT and Harvard University, Cambridge, MA, USA
| | - Cristina Razquin
- Department of Preventive Medicine and Public Health, IdiSNA (Health Research Institute of Navarra), University of Navarra, Pamplona, Spain
- The Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition, Health Institute Carlos III, Madrid, Spain
| | - Dong Wang
- Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA
| | - Liming Liang
- Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, MA, USA
| | - Jun Li
- Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA
| | - Courtney Dennis
- Broad Institute of MIT and Harvard University, Cambridge, MA, USA
| | - Dolores Corella
- The Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition, Health Institute Carlos III, Madrid, Spain
- Department of Preventive Medicine, University of Valencia, Valencia, Spain
| | - Carlos Muñoz-Bravo
- Department of Public Health and Psychiatry, University of Málaga, Málaga, Spain
| | - Dora Romaguera
- The Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition, Health Institute Carlos III, Madrid, Spain
- Health Research Institute of the Balearic Islands (IdISBa), University Hospital Son Espases, Mallorca, Spain
| | - Ramón Estruch
- The Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition, Health Institute Carlos III, Madrid, Spain
- Department of Internal Medicine, Department of Endocrinology and Nutrition Biomedical Research Institute August Pi Sunyer (IDI-BAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - José Manuel Santos-Lozano
- The Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition, Health Institute Carlos III, Madrid, Spain
- Department of Family Medicine, Primary Care Division of Sevilla, San Pablo Health Center, Sevilla, Spain
| | - Olga Castañer
- The Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition, Health Institute Carlos III, Madrid, Spain
- Cardiovascular and Nutrition Research Group, Hospital del Mar Research Institute (IMIM), Barcelona, Spain
| | - Angel Alonso-Gómez
- The Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition, Health Institute Carlos III, Madrid, Spain
- Bioaraba Health Research Institute; Osakidetza Baseque Health Service, Araba University Hospital; Unibersity of the Basque Country UPV/EHU; Vitoria-Gasteiz, Spain
| | - Luis Serra-Majem
- The Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition, Health Institute Carlos III, Madrid, Spain
- Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria and Service of Preventive Medicine, Complejo Hospitalario Universitario Insular Materno Infantil (CHUIMI), Canary Health Service, Las Palmas de Gran Canaria, Spain
| | - Emilio Ros
- The Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition, Health Institute Carlos III, Madrid, Spain
- Lipid Clinic, Department of Endocrinology and Nutrition Biomedical Research Institute August Pi Sunyer (IDI-BAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Sílvia Canudas
- Human Nutrition Unit, Faculty of Medicine and Health Sciences, Pere Virgili Health Research Institute, Rovira i Virgili University, Reus, Spain
- The Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition, Health Institute Carlos III, Madrid, Spain
| | - Eva M Asensio
- Department of Preventive Medicine, University of Valencia, Valencia, Spain
| | - Montserrat Fitó
- The Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition, Health Institute Carlos III, Madrid, Spain
- Cardiovascular and Nutrition Research Group, Hospital del Mar Research Institute (IMIM), Barcelona, Spain
| | - Kerry Pierce
- Broad Institute of MIT and Harvard University, Cambridge, MA, USA
| | - J Alfredo Martínez
- The Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition, Health Institute Carlos III, Madrid, Spain
- Department of Nutrition, Food Sciences, and Physiology, Center for Nutrition Research, University of Navarra, Pamplona, IMDEA Food, Madrid, Spain
| | - Jordi Salas-Salvadó
- Human Nutrition Unit, Faculty of Medicine and Health Sciences, Pere Virgili Health Research Institute, Rovira i Virgili University, Reus, Spain
- The Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition, Health Institute Carlos III, Madrid, Spain
| | - Estefanía Toledo
- Department of Preventive Medicine and Public Health, IdiSNA (Health Research Institute of Navarra), University of Navarra, Pamplona, Spain
- The Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition, Health Institute Carlos III, Madrid, Spain
| | - Frank B Hu
- Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Miguel Ruiz-Canela
- Department of Preventive Medicine and Public Health, IdiSNA (Health Research Institute of Navarra), University of Navarra, Pamplona, Spain
- The Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition, Health Institute Carlos III, Madrid, Spain
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Gilijamse PW, Hartstra AV, Levin E, Wortelboer K, Serlie MJ, Ackermans MT, Herrema H, Nederveen AJ, Imangaliyev S, Aalvink S, Sommer M, Levels H, Stroes ESG, Groen AK, Kemper M, de Vos WM, Nieuwdorp M, Prodan A. Treatment with Anaerobutyricum soehngenii: a pilot study of safety and dose-response effects on glucose metabolism in human subjects with metabolic syndrome. NPJ Biofilms Microbiomes 2020; 6:16. [PMID: 32221294 PMCID: PMC7101376 DOI: 10.1038/s41522-020-0127-0] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 03/09/2020] [Indexed: 01/25/2023] Open
Abstract
Dysbiosis of the intestinal microbiota has been implicated in insulin resistance, although evidence regarding causality in humans is scarce. We performed a phase I/II dose-finding and safety study on the effect of oral intake of the anaerobic butyrogenic strain Anaerobutyricum soehngenii on glucose metabolism in 24 subjects with metabolic syndrome. We found that treatment with A. soehngenii was safe and observed a significant correlation between the measured fecal abundance of administered A. soehngenii and improvement in peripheral insulin sensitivity after 4 weeks of treatment. This was accompanied by an altered microbiota composition and a change in bile acid metabolism. Finally, we show that metabolic response upon administration of A. soehngenii (defined as improved insulin sensitivity 4 weeks after A. soehngenii intake) is dependent on microbiota composition at baseline. These data in humans are promising, but additional studies are needed to reproduce our findings and to investigate long-term effects, as well as other modes of delivery.
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Affiliation(s)
- Pim W Gilijamse
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands.,Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Annick V Hartstra
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Evgeni Levin
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Koen Wortelboer
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Mireille J Serlie
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Mariette T Ackermans
- Laboratory of Endocrinology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Hilde Herrema
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Aart J Nederveen
- Department of Radiology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Sultan Imangaliyev
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Steven Aalvink
- Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands
| | | | - Han Levels
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Erik S G Stroes
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Albert K Groen
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Marleen Kemper
- Department of Clinical Pharmacy, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Willem M de Vos
- Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands.,Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Max Nieuwdorp
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Andrei Prodan
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
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Relationships between plasma lactate, plasma alanine, genetic variations in lactate transporters and type 2 diabetes in the Japanese population. Drug Metab Pharmacokinet 2020; 35:131-138. [DOI: 10.1016/j.dmpk.2019.10.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 08/28/2019] [Accepted: 10/03/2019] [Indexed: 01/17/2023]
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Krycer JR, Quek LE, Francis D, Fazakerley DJ, Elkington SD, Diaz-Vegas A, Cooke KC, Weiss FC, Duan X, Kurdyukov S, Zhou PX, Tambar UK, Hirayama A, Ikeda S, Kamei Y, Soga T, Cooney GJ, James DE. Lactate production is a prioritized feature of adipocyte metabolism. J Biol Chem 2020; 295:83-98. [PMID: 31690627 PMCID: PMC6952601 DOI: 10.1074/jbc.ra119.011178] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/31/2019] [Indexed: 12/14/2022] Open
Abstract
Adipose tissue is essential for whole-body glucose homeostasis, with a primary role in lipid storage. It has been previously observed that lactate production is also an important metabolic feature of adipocytes, but its relationship to adipose and whole-body glucose disposal remains unclear. Therefore, using a combination of metabolic labeling techniques, here we closely examined lactate production of cultured and primary mammalian adipocytes. Insulin treatment increased glucose uptake and conversion to lactate, with the latter responding more to insulin than did other metabolic fates of glucose. However, lactate production did not just serve as a mechanism to dispose of excess glucose, because we also observed that lactate production in adipocytes did not solely depend on glucose availability and even occurred independently of glucose metabolism. This suggests that lactate production is prioritized in adipocytes. Furthermore, knocking down lactate dehydrogenase specifically in the fat body of Drosophila flies lowered circulating lactate and improved whole-body glucose disposal. These results emphasize that lactate production is an additional metabolic role of adipose tissue beyond lipid storage and release.
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Affiliation(s)
- James R Krycer
- School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia
| | - Lake-Ee Quek
- Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia; School of Mathematics and Statistics, The University of Sydney, Sydney, New South Wales 2006, Australia
| | - Deanne Francis
- School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia
| | - Daniel J Fazakerley
- School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia; Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom
| | - Sarah D Elkington
- School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia
| | - Alexis Diaz-Vegas
- School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia
| | - Kristen C Cooke
- School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia
| | - Fiona C Weiss
- School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia
| | - Xiaowen Duan
- School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia
| | - Sergey Kurdyukov
- School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia
| | - Ping-Xin Zhou
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9038; School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Uttam K Tambar
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9038
| | - Akiyoshi Hirayama
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan; AMED-CREST, Japan Agency for Medical Research and Development (AMED), 1-7-1 Otemachi, Chiyoda-Ku, Tokyo 100-0004, Japan
| | - Satsuki Ikeda
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan
| | - Yushi Kamei
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan; AMED-CREST, Japan Agency for Medical Research and Development (AMED), 1-7-1 Otemachi, Chiyoda-Ku, Tokyo 100-0004, Japan
| | - Gregory J Cooney
- Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia; Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia.
| | - David E James
- School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia; Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia.
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48
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Borghi F, Morais CL, Silva C, da Silva PC, Ishizu LY, Costa GT, Grassi-Kassisse DM. A new perspective of lactatogenesis by isolated adipocytes. Mol Cell Endocrinol 2019; 498:110560. [PMID: 31442545 DOI: 10.1016/j.mce.2019.110560] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 07/02/2019] [Accepted: 08/19/2019] [Indexed: 11/24/2022]
Abstract
Increased adipose tissue mass exhibited greater capacity of glucose transformation in lactate, highlighting lactatogenesis as a crucial factor in body size. Classically, lactate produced by isolated adipocytes are expressed per million of cells and were never correlated with their size. Spontaneously hypertensive rats (SHR) have a lower body weight and smaller adipocytes when compared to Wistar-Kyoto. We evaluated basal lactate by epididymal 15-weeks-old isolated adipocytes of SHR, Wistar-Kyoto and Wistar. Basal lactate was similar when expressed by one million cells. However, SHR adipocytes were smaller, so we adjusted the results by cell volume and SHR showed higher basal lactate production which was directly endorsed by hyperlactatemia in the presented conditions. Thereby, we suggest a new perspective on lactatogenesis analysis by adipocytes, which could be linked to the receptors density and associate enzymes. Moreover, we showed that the thin and hypertensive rats can be hyperlactemic in fasting conditions.
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Affiliation(s)
- Filipy Borghi
- LABEEST - Laboratory of Stress Study, Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, 13083-862, Campinas, SP, Brazil
| | - Camila L Morais
- LABEEST - Laboratory of Stress Study, Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, 13083-862, Campinas, SP, Brazil
| | - Carolina Silva
- LABEEST - Laboratory of Stress Study, Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, 13083-862, Campinas, SP, Brazil
| | - Priscila C da Silva
- LABEEST - Laboratory of Stress Study, Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, 13083-862, Campinas, SP, Brazil
| | - Larissa Y Ishizu
- LABEEST - Laboratory of Stress Study, Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, 13083-862, Campinas, SP, Brazil
| | - Gustavo T Costa
- LABEEST - Laboratory of Stress Study, Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, 13083-862, Campinas, SP, Brazil
| | - Dora M Grassi-Kassisse
- LABEEST - Laboratory of Stress Study, Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, 13083-862, Campinas, SP, Brazil.
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49
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Mizgier ML, Fernández-Verdejo R, Cherfan J, Pinget M, Bouzakri K, Galgani JE. Insights on the Role of Putative Muscle-Derived Factors on Pancreatic Beta Cell Function. Front Physiol 2019; 10:1024. [PMID: 31440170 PMCID: PMC6694406 DOI: 10.3389/fphys.2019.01024] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 07/24/2019] [Indexed: 01/02/2023] Open
Abstract
Skeletal muscle is a main target of insulin action that plays a pivotal role in postprandial glucose disposal. Importantly, skeletal muscle insulin sensitivity relates inversely with pancreatic insulin secretion, which prompted the hypothesis of the existence of a skeletal muscle-pancreas crosstalk mediated through an endocrine factor. The observation that changes in skeletal muscle glucose metabolism are accompanied by altered insulin secretion supports this hypothesis. Meanwhile, a muscle-derived circulating factor affecting in vivo insulin secretion remains elusive. This factor may correspond to peptides/proteins (so called myokines), exosomes and their cargo, and metabolites. We hereby review the most remarkable evidence encouraging the possibility of such inter-organ communication, with special focus on muscle-derived factors that may potentially mediate such skeletal muscle-pancreas crosstalk.
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Affiliation(s)
- Maria L Mizgier
- UMR DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Strasbourg, France
| | - Rodrigo Fernández-Verdejo
- Departamento de Ciencias de la Salud, Nutrición y Dietética, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Julien Cherfan
- UMR DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Strasbourg, France
| | - Michel Pinget
- UMR DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Strasbourg, France
| | - Karim Bouzakri
- UMR DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Strasbourg, France
| | - Jose E Galgani
- Departamento de Ciencias de la Salud, Nutrición y Dietética, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.,Departamento de Nutrición, Diabetes y Metabolismo, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
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50
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Plasma lactate as a marker of metabolic health: Implications of elevated lactate for impairment of aerobic metabolism in the metabolic syndrome. Surgery 2019; 166:861-866. [PMID: 31253418 DOI: 10.1016/j.surg.2019.04.017] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 04/16/2019] [Accepted: 04/24/2019] [Indexed: 01/15/2023]
Abstract
BACKGROUND Fasting lactate is elevated in metabolic diseases and could possibly be predictive of the risk of developing the metabolic syndrome. METHODS Plasma samples were analyzed for fasting lactate to compare lean subjects, nondiabetic subjects with severe obesity, and metabolically impaired subjects. Subjects with severe obesity were studied 1 week before and 1 week to 9 months after gastric bypass surgery. Subjects with components of the metabolic syndrome were studied before and after 6 months of an exercise intervention. RESULTS Metabolically impaired subjects had higher fasting lactate concentrations (P < .0001) and respond to a glucose or insulin challenge with higher lactates than non-obese subjects (P < .004). Lactate was significantly reduced a week after gastric bypass surgery (P < .05) and further reduced 1 to 9 months after surgery (0.95 ± 0.04 mM in non-obese, 1.26 ± 0.12 mM in subjects with severe obesity, and 0.68 ± 0.03 mM 1-3 months after gastric bypass). Six months of chronic exercise resulted in a 16% reduction (P = .028) in fasting lactate. CONCLUSION Fasting plasma lactate was elevated in obese subjects with the metabolic syndrome compared with healthy lean individuals. Lactate was reduced by exercise and bariatric surgery, interventions that improve metabolic health and risk for subsequent disease. The results of this study and those previously published by our research group suggest that elevated lactate may be caused by an impairment in aerobic metabolism and may offer a metric assessing the severity of the metabolic syndrome.
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