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Tricò D, Rebelos E, Astiarraga B, Baldi S, Scozzaro T, Sacchetta L, Chiriacò M, Mari A, Ferrannini E, Muscelli E, Natali A. Effects of Hypertriglyceridemia With or Without NEFA Elevation on β-cell Function and Insulin Clearance and Sensitivity. J Clin Endocrinol Metab 2025; 110:e667-e674. [PMID: 38635405 PMCID: PMC11918624 DOI: 10.1210/clinem/dgae276] [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: 02/27/2024] [Revised: 04/09/2024] [Accepted: 04/16/2024] [Indexed: 04/20/2024]
Abstract
CONTEXT Hypertriglyceridemia is a risk factor for developing type 2 diabetes (T2D) and might contribute to its pathogenesis either directly or through elevation of nonesterified fatty acids (NEFAs). OBJECTIVE This study aimed at comparing the glucometabolic effects of acute hypertriglyceridemia alone or combined with NEFA elevation in subjects without diabetes. METHODS Twenty-two healthy lean volunteers underwent 5-hour intravenous infusions of either saline or Intralipid, without (n = 12) or with heparin (I + H; n = 10) to activate the release of NEFAs. Oral glucose tolerance tests (OGTTs) were performed during the last 3 hours of infusion. Insulin sensitivity, insulin secretion rate (ISR), model-derived β-cell function, and insulin clearance were measured after 2 hours of lipid infusion and during the OGTTs. RESULTS In fasting conditions, both lipid infusions increased plasma insulin and ISR and reduced insulin clearance without affecting plasma glucose and insulin sensitivity. These effects on insulin and ISR were more pronounced for I + H than Intralipid alone. During the OGTT, the lipid infusions markedly impaired glucose tolerance, increased plasma insulin and ISR, and decreased insulin sensitivity and clearance, without significant group differences. Intralipid alone inhibited glucose-stimulated insulin secretion (ie, β-cell glucose sensitivity) and increased β-cell potentiation, whereas I + H had neutral effects on these β-cell functions. CONCLUSION In healthy nonobese subjects, mild acute hypertriglyceridemia directly reduces glucose tolerance and insulin sensitivity and clearance, and has selective and opposite effects on β-cell function that are neutralized by NEFAs. These findings provide new insight into plausible biological signals that generate and sustain insulin resistance and chronic hyperinsulinemia in the development of T2D.
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Affiliation(s)
- Domenico Tricò
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
- Laboratory of Metabolism, Nutrition, and Atherosclerosis, University of Pisa, 56126 Pisa, Italy
| | - Eleni Rebelos
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
- Laboratory of Metabolism, Nutrition, and Atherosclerosis, University of Pisa, 56126 Pisa, Italy
| | - Brenno Astiarraga
- Hospital Universitari Joan XXIII de Tarragona, Institut d'Investigació Sanitària Pere Virgili (IISPV), 43005 Tarragona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Simona Baldi
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
- Laboratory of Metabolism, Nutrition, and Atherosclerosis, University of Pisa, 56126 Pisa, Italy
| | - Tiziana Scozzaro
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
- Laboratory of Metabolism, Nutrition, and Atherosclerosis, University of Pisa, 56126 Pisa, Italy
| | - Luca Sacchetta
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
- Laboratory of Metabolism, Nutrition, and Atherosclerosis, University of Pisa, 56126 Pisa, Italy
| | - Martina Chiriacò
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
- Laboratory of Metabolism, Nutrition, and Atherosclerosis, University of Pisa, 56126 Pisa, Italy
| | - Andrea Mari
- Institute of Neuroscience, National Research Council, 35127 Padua, Italy
| | - Ele Ferrannini
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy
| | - Elza Muscelli
- Department of Internal Medicine, University of Campinas, 13083-887 Campinas, Brazil
| | - Andrea Natali
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
- Laboratory of Metabolism, Nutrition, and Atherosclerosis, University of Pisa, 56126 Pisa, Italy
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Ježek P. Physiological Fatty Acid-Stimulated Insulin Secretion and Redox Signaling Versus Lipotoxicity. Antioxid Redox Signal 2025. [PMID: 39834189 DOI: 10.1089/ars.2024.0799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
Significance: Type 2 diabetes as a world-wide epidemic is characterized by the insulin resistance concomitant to a gradual impairment of β-cell mass and function (prominently declining insulin secretion) with dysregulated fatty acids (FAs) and lipids, all involved in multiple pathological development. Recent Advances: Recently, redox signaling was recognized to be essential for insulin secretion stimulated with glucose (GSIS), branched-chain keto-acids, and FAs. FA-stimulated insulin secretion (FASIS) is a normal physiological event upon postprandial incoming chylomicrons. This contrasts with the frequent lipotoxicity observed in rodents. Critical Issues: Overfeeding causes FASIS to overlap with GSIS providing repeating hyperinsulinemia, initiates prediabetic states by lipotoxic effects and low-grade inflammation. In contrast the protective effects of lipid droplets in human β-cells counteract excessive lipids. Insulin by FASIS allows FATP1 recruitment into adipocyte plasma membranes when postprandial chylomicrons come late at already low glycemia. Future Directions: Impaired states of pancreatic β-cells and peripheral organs at prediabetes and type 2 diabetes should be revealed, including the inter-organ crosstalk by extracellular vesicles. Details of FA/lipid molecular physiology are yet to be uncovered, such as complex phenomena of FA uptake into cells, postabsorptive inactivity of G-protein-coupled receptor 40, carnitine carrier substrate specificity, the role of carnitine-O-acetyltransferase in β-cells, and lipid droplet interactions with mitochondria. Antioxid. Redox Signal. 00, 000-000.
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Affiliation(s)
- Petr Ježek
- Department of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
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Anderson KC, Liu J, Liu Z. Interplay of fatty acids, insulin and exercise in vascular health. Lipids Health Dis 2025; 24:4. [PMID: 39773723 PMCID: PMC11706162 DOI: 10.1186/s12944-024-02421-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 12/26/2024] [Indexed: 01/11/2025] Open
Abstract
Fatty acid metabolism, exercise, and insulin action play critical roles in maintaining vascular health, especially relevant in metabolic disorders such as obesity, type 2 diabetes, and cardiovascular disease. Insulin, a vasoactive hormone, induces arterial vasodilation throughout the arterial tree, increasing arterial compliance and enhancing tissue perfusion. These effects, however, are impaired in individuals with obesity and type 2 diabetes, and evidence suggests that vascular insulin resistance contributes to the pathogenesis of type 2 diabetes and its cardiovascular complications. Elevated plasma levels of free fatty acids in people with insulin resistance engender vascular inflammation, endothelial dysfunction, and vascular insulin resistance. Importantly, these effects are both functionally and structurally dependent, with saturated fatty acids as the primary culprits, while polyunsaturated fatty acids may support insulin sensitivity and endothelial function. Exercise enhances fatty acid oxidation, reduces circulating free fatty acids, and improves insulin sensitivity, thereby mitigating lipotoxicity and promoting endothelial function. Additionally, exercise induces beneficial vascular adaptations. This review examines the complex interplay among fatty acid metabolism, exercise training-induced vascular adaptations, and insulin-mediated vascular changes, highlighting their collective impact on vascular health and underlying mechanisms in both healthy and insulin-resistant states. It also explores the therapeutic potential of targeted exercise prescriptions and fatty acid-focused dietary strategies for enhancing vascular health, emphasizing tailored interventions to maximize metabolic benefits. Future research should investigate the pathways linking fatty acid metabolism to vascular insulin resistance, with a focus on how exercise and dietary modifications can be personalized to enhance vascular insulin sensitivity, optimize vascular health, and reduce the risks of type 2 diabetes and associated cardiovascular complications.
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Affiliation(s)
- Kara C Anderson
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA, USA
| | - Jia Liu
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA, USA
| | - Zhenqi Liu
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA, USA.
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Nemati M, Rostamkhani F, Karbaschi R, Zardooz H. Metabolic Responses to High-Fat Feeding and Chronic Psychological Stress Combination. Endocrinol Diabetes Metab 2024; 7:e487. [PMID: 38867382 PMCID: PMC11168916 DOI: 10.1002/edm2.487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 04/07/2024] [Accepted: 04/17/2024] [Indexed: 06/14/2024] Open
Abstract
INTRODUCTION High-fat diet (HFD) consumption and being exposed to daily psychological stress, common environmental factors in modern lifestyle, play an important role on metabolic disorders such as glucose homeostasis impairment. The aim of this study was to investigate the effects of high-fat diet (HFD) and psychological stress combination on metabolic response to chronic psychological stress in male rats. METHOD Male Wistar rats were divided into HFD, and normal diet (ND) groups and then into stress and nonstress subgroups. The diets were applied for 5 weeks, and psychological stress was induced for 7 consecutive days. Then, blood samples were taken to measure glucose, insulin, free fatty acids (FFA), and leptin and corticosterone concentrations. Subsequently, glucose-stimulated insulin release from pancreatic isolated islets was assessed. RESULTS HFD did not significantly change fasting plasma glucose, insulin and corticosterone levels, whereas increased plasma leptin (7.05 ± 0.33) and FFA (p < 0.01) levels and impaired glucose tolerance. Additionally, HFD and stress combination induced more profound glucose intolerance associated with increased plasma corticosterone (p < 0.01) and leptin (8.63 ± 0.38) levels. However, insulin secretion from isolated islets did not change in the presence of high-fat diet and/or stress. CONCLUSION HFD should be considered as an intensified factor of metabolic impairments caused by chronic psychological stress.
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Affiliation(s)
- Marzieh Nemati
- Department of Physiology, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
- Endocrinology and Metabolism Research CenterShiraz University of Medical ScienceShirazIran
| | - Fatemeh Rostamkhani
- Department of Biology, College of Basic Sciences, Yadegar‐e‐Imam Khomeini (RAH) BranchIslamic Azad UniversityTehranIran
| | - Roxana Karbaschi
- Faculty of Nursing and MidwiferyShahid Beheshti University of Medical SciencesTehranIran
| | - Homeira Zardooz
- Department of Physiology, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
- Neurophysiology Research CenterShahid Beheshti University of Medical SciencesTehranIran
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Kosmalski M, Śliwińska A, Drzewoski J. Non-Alcoholic Fatty Liver Disease or Type 2 Diabetes Mellitus—The Chicken or the Egg Dilemma. Biomedicines 2023; 11:biomedicines11041097. [PMID: 37189715 DOI: 10.3390/biomedicines11041097] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/28/2023] [Accepted: 03/28/2023] [Indexed: 04/08/2023] Open
Abstract
In clinical practice, we often deal with patients who suffer from non-alcoholic fatty liver disease (NAFLD) concurrent with type 2 diabetes mellitus (T2DM). The etiopathogenesis of NAFLD is mainly connected with insulin resistance (IR) and obesity. Similarly, the latter patients are in the process of developing T2DM. However, the mechanisms of NAFLD and T2DM coexistence have not been fully elucidated. Considering that both diseases and their complications are of epidemic proportions and significantly affect the length and quality of life, we aimed to answer which of these diseases appears first and thereby highlight the need for their diagnosis and treatment. To address this question, we present and discuss the epidemiological data, diagnoses, complications and pathomechanisms of these two coexisting metabolic diseases. This question is difficult to answer due to the lack of a uniform procedure for NAFLD diagnosis and the asymptomatic nature of both diseases, especially at their beginning stages. To conclude, most researchers suggest that NAFLD appears as the first disease and starts the sequence of circumstances leading ultimately to the development of T2DM. However, there are also data suggesting that T2DM develops before NAFLD. Despite the fact that we cannot definitively answer this question, it is very important to bring the attention of clinicians and researchers to the coexistence of NAFLD and T2DM in order to prevent their consequences.
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Affiliation(s)
- Marcin Kosmalski
- Department of Clinical Pharmacology, Medical University of Lodz, 90-153 Lodz, Poland
| | - Agnieszka Śliwińska
- Department of Nucleic Acids Biochemistry, Medical University of Lodz, 92-213 Lodz, Poland
| | - Józef Drzewoski
- Central Teaching Hospital of Medical University of Lodz, 92-213 Lodz, Poland
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Mukherjee S, Maheshwari D, Pal R, Sachdeva N. Pancreatic fat in type 2 diabetes: Causal or coincidental? World J Meta-Anal 2023; 11:68-78. [DOI: 10.13105/wjma.v11.i3.68] [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: 09/17/2022] [Revised: 12/27/2022] [Accepted: 02/15/2023] [Indexed: 03/01/2023] Open
Abstract
Type 2 diabetes (T2D) is a multifactorial metabolic disorder affecting more than 450 million people across the globe. With the increasing prevalence of T2D and obesity, the role of fat accumulation at sites other than subcutaneous adipose tissue has received significant attention in the pathophysiology of T2D. Over the past decade and a half, a pressing concern has emerged on investigating the association of pancreatic fat accumulation or pancreatic steatosis with the development of disease. While a few reports have suggested a possible association between pancreatic fat and T2D and/or impaired glucose metabolism, a few reports suggest a lack of such association. Pancreatic fat has also been linked with genetic risk of developing T2D, prediabetes, reduced insulin secretion, and beta cell dysfunction albeit some confounding factors such as age and ethnicity may affect the outcome. With the technological advancements in clinical imaging and progress in assessment of pancreatic beta cell function, our understanding of the role of pancreatic fat in causing insulin resistance and development of various etiologies of T2D has significantly improved. This review summarizes various findings on the possible association of pancreatic fat accumulation with the pathophysiology of T2D.
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Affiliation(s)
- Soham Mukherjee
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Deep Maheshwari
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Rimesh Pal
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Naresh Sachdeva
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
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7
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Narasimhan A, Flores RR, Camell CD, Bernlohr DA, Robbins PD, Niedernhofer LJ. Cellular Senescence in Obesity and Associated Complications: a New Therapeutic Target. Curr Diab Rep 2022; 22:537-548. [PMID: 36239841 PMCID: PMC10123542 DOI: 10.1007/s11892-022-01493-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/11/2022] [Indexed: 01/13/2023]
Abstract
PURPOSE OF REVIEW Obesity has increased worldwide recently and represents a major global health challenge. This review focuses on the obesity-associated cellular senescence in various organs and the role of these senescent cells (SnCs) in driving complications associated with obesity. Also, the ability to target SnCs pharmacologically with drugs termed senotherapeutics as a therapy for these complications is discussed. RECENT FINDINGS Several studies have shown a positive correlation between obesity and SnC burden in organs such as adipose tissue, liver, and pancreatic-β-cells. These SnCs produce several secretory factors which affect other cells and tissues in a paracrine manner resulting in organ dysfunction. The accumulation of SnCs in adipocytes affects their lipid storage and impairs adipogenesis. The inflammatory senescence-associated secretory phenotype (SASP) of SnCs downregulates the antioxidant capacity and mitochondrial function in tissues. Senescent hepatocytes cannot oxidize fatty acids, which leads to lipid deposition and senescence in β-cells decrease function. These and other adverse effects of SnCs contribute to insulin resistance and type-2 diabetes. The reduction in the SnC burden genetically or pharmacologically improves the complications associated with obesity. The accumulation of SnCs with age and disease accelerates aging. Obesity is a key driver of SnC accumulation, and the complications associated with obesity can be controlled by reducing the SnC burden. Thus, senotherapeutic drugs have the potential to be an effective therapeutic option.
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Affiliation(s)
- Akilavalli Narasimhan
- Institute On the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church Street, SE, Minneapolis, MN, 55455, USA
| | - Rafael R Flores
- Institute On the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church Street, SE, Minneapolis, MN, 55455, USA
| | - Christina D Camell
- Institute On the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church Street, SE, Minneapolis, MN, 55455, USA
| | - David A Bernlohr
- Institute On the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church Street, SE, Minneapolis, MN, 55455, USA
| | - Paul D Robbins
- Institute On the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church Street, SE, Minneapolis, MN, 55455, USA.
| | - Laura J Niedernhofer
- Institute On the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church Street, SE, Minneapolis, MN, 55455, USA.
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8
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Reiterer M, Gilani A, Lo JC. Pancreatic Islets as a Target of Adipokines. Compr Physiol 2022; 12:4039-4065. [PMID: 35950650 DOI: 10.1002/cphy.c210044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Rising rates of obesity are intricately tied to the type 2 diabetes epidemic. The adipose tissues can play a central role in protection against or triggering metabolic diseases through the secretion of adipokines. Many adipokines may improve peripheral insulin sensitivity through a variety of mechanisms, thereby indirectly reducing the strain on beta cells and thus improving their viability and functionality. Such effects will not be the focus of this article. Rather, we will focus on adipocyte-secreted molecules that have a direct effect on pancreatic islets. By their nature, adipokines represent potential druggable targets that can reach the islets and improve beta-cell function or preserve beta cells in the face of metabolic stress. © 2022 American Physiological Society. Compr Physiol 12:1-27, 2022.
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Affiliation(s)
- Moritz Reiterer
- Division of Cardiology, Department of Medicine, Weill Center for Metabolic Health, Cardiovascular Research Institute, Weill Cornell Medicine, New York, New York, USA
| | - Ankit Gilani
- Division of Cardiology, Department of Medicine, Weill Center for Metabolic Health, Cardiovascular Research Institute, Weill Cornell Medicine, New York, New York, USA
| | - James C Lo
- Division of Cardiology, Department of Medicine, Weill Center for Metabolic Health, Cardiovascular Research Institute, Weill Cornell Medicine, New York, New York, USA
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Suleiman M, Marselli L, Cnop M, Eizirik DL, De Luca C, Femia FR, Tesi M, Del Guerra S, Marchetti P. The Role of Beta Cell Recovery in Type 2 Diabetes Remission. Int J Mol Sci 2022; 23:7435. [PMID: 35806437 PMCID: PMC9267061 DOI: 10.3390/ijms23137435] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 06/29/2022] [Accepted: 06/30/2022] [Indexed: 12/11/2022] Open
Abstract
Type 2 diabetes (T2D) has been considered a relentlessly worsening disease, due to the progressive deterioration of the pancreatic beta cell functional mass. Recent evidence indicates, however, that remission of T2D may occur in variable proportions of patients after specific treatments that are associated with recovery of beta cell function. Here we review the available information on the recovery of beta cells in (a) non-diabetic individuals previously exposed to metabolic stress; (b) T2D patients following low-calorie diets, pharmacological therapies or bariatric surgery; (c) human islets isolated from non-diabetic organ donors that recover from "lipo-glucotoxic" conditions; and (d) human islets isolated from T2D organ donors and exposed to specific treatments. The improvement of insulin secretion reported by these studies and the associated molecular traits unveil the possibility to promote T2D remission by directly targeting pancreatic beta cells.
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Affiliation(s)
- Mara Suleiman
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.S.); (L.M.); (C.D.L.); (M.T.); (S.D.G.)
| | - Lorella Marselli
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.S.); (L.M.); (C.D.L.); (M.T.); (S.D.G.)
| | - Miriam Cnop
- ULB Center for Diabetes Research, Université Libre de Bruxelles, 1050 Brussels, Belgium; (M.C.); (D.L.E.)
- Division of Endocrinology, ULB Erasmus Hospital, Université Libre de Bruxelles, 1050 Brussels, Belgium
| | - Decio L. Eizirik
- ULB Center for Diabetes Research, Université Libre de Bruxelles, 1050 Brussels, Belgium; (M.C.); (D.L.E.)
| | - Carmela De Luca
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.S.); (L.M.); (C.D.L.); (M.T.); (S.D.G.)
| | - Francesca R. Femia
- Departmental Section of Endocrinology and Metabolism of Transplantation, AOUP Cisanello Hospital, 56124 Pisa, Italy;
| | - Marta Tesi
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.S.); (L.M.); (C.D.L.); (M.T.); (S.D.G.)
| | - Silvia Del Guerra
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.S.); (L.M.); (C.D.L.); (M.T.); (S.D.G.)
| | - Piero Marchetti
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.S.); (L.M.); (C.D.L.); (M.T.); (S.D.G.)
- Departmental Section of Endocrinology and Metabolism of Transplantation, AOUP Cisanello Hospital, 56124 Pisa, Italy;
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Petry SF, Römer A, Rawat D, Brunner L, Lerch N, Zhou M, Grewal R, Sharifpanah F, Sauer H, Eckert GP, Linn T. Loss and Recovery of Glutaredoxin 5 Is Inducible by Diet in a Murine Model of Diabesity and Mediated by Free Fatty Acids In Vitro. Antioxidants (Basel) 2022; 11:antiox11040788. [PMID: 35453472 PMCID: PMC9025089 DOI: 10.3390/antiox11040788] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 03/24/2022] [Accepted: 04/14/2022] [Indexed: 02/05/2023] Open
Abstract
Free fatty acids (FFA), hyperglycemia, and inflammatory cytokines are major mediators of β-cell toxicity in type 2 diabetes mellitus, impairing mitochondrial metabolism. Glutaredoxin 5 (Glrx5) is a mitochondrial protein involved in the assembly of iron–sulfur clusters required for complexes of the respiratory chain. We have provided evidence that islet cells are deprived of Glrx5, correlating with impaired insulin secretion during diabetes in genetically obese mice. In this study, we induced diabesity in C57BL/6J mice in vivo by feeding the mice a high-fat diet (HFD) and modelled the diabetic metabolism in MIN6 cells through exposure to FFA, glucose, or inflammatory cytokines in vitro. qRT-PCR, ELISA, immunohisto-/cytochemistry, bioluminescence, and respirometry were employed to study Glrx5, insulin secretion, and mitochondrial biomarkers. The HFD induced a depletion of islet Glrx5 concomitant with an obese phenotype, elevated FFA in serum and reactive oxygen species in islets, and impaired glucose tolerance. Exposure of MIN6 cells to FFA led to a loss of Glrx5 in vitro. The FFA-induced depletion of Glrx5 coincided with significantly altered mitochondrial biomarkers. In summary, we provide evidence that Glrx5 is regulated by FFA in type 2 diabetes mellitus and is linked to mitochondrial dysfunction and blunted insulin secretion.
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Affiliation(s)
- Sebastian Friedrich Petry
- Clinical Research Unit, Medical Clinic and Polyclinic III, Center of Internal Medicine, Justus Liebig University, 35392 Giessen, Germany; (A.R.); (D.R.); (L.B.); (N.L.); (M.Z.); (T.L.)
- Correspondence: ; Tel.: +49-641-985-57010
| | - Axel Römer
- Clinical Research Unit, Medical Clinic and Polyclinic III, Center of Internal Medicine, Justus Liebig University, 35392 Giessen, Germany; (A.R.); (D.R.); (L.B.); (N.L.); (M.Z.); (T.L.)
| | - Divya Rawat
- Clinical Research Unit, Medical Clinic and Polyclinic III, Center of Internal Medicine, Justus Liebig University, 35392 Giessen, Germany; (A.R.); (D.R.); (L.B.); (N.L.); (M.Z.); (T.L.)
| | - Lara Brunner
- Clinical Research Unit, Medical Clinic and Polyclinic III, Center of Internal Medicine, Justus Liebig University, 35392 Giessen, Germany; (A.R.); (D.R.); (L.B.); (N.L.); (M.Z.); (T.L.)
| | - Nina Lerch
- Clinical Research Unit, Medical Clinic and Polyclinic III, Center of Internal Medicine, Justus Liebig University, 35392 Giessen, Germany; (A.R.); (D.R.); (L.B.); (N.L.); (M.Z.); (T.L.)
| | - Mengmeng Zhou
- Clinical Research Unit, Medical Clinic and Polyclinic III, Center of Internal Medicine, Justus Liebig University, 35392 Giessen, Germany; (A.R.); (D.R.); (L.B.); (N.L.); (M.Z.); (T.L.)
| | - Rekha Grewal
- Laboratory for Nutrition in Prevention & Therapy, Department of Nutritional Sciences, Justus Liebig University, 35392 Giessen, Germany; (R.G.); (G.P.E.)
| | - Fatemeh Sharifpanah
- Faculty of Medicine, Philipps University, 35037 Marburg, Germany;
- Cyntegrity Germany GmbH, 60438 Frankfurt, Germany
| | - Heinrich Sauer
- Department of Physiology, Faculty of Medicine, Justus Liebig University, 35392 Giessen, Germany;
| | - Gunter Peter Eckert
- Laboratory for Nutrition in Prevention & Therapy, Department of Nutritional Sciences, Justus Liebig University, 35392 Giessen, Germany; (R.G.); (G.P.E.)
| | - Thomas Linn
- Clinical Research Unit, Medical Clinic and Polyclinic III, Center of Internal Medicine, Justus Liebig University, 35392 Giessen, Germany; (A.R.); (D.R.); (L.B.); (N.L.); (M.Z.); (T.L.)
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Abstract
The accumulation of an excessive amount of body fat can cause type 2 diabetes, and the risk of type 2 diabetes increases linearly with an increase in body mass index. Accordingly, the worldwide increase in the prevalence of obesity has led to a concomitant increase in the prevalence of type 2 diabetes. The cellular and physiological mechanisms responsible for the link between obesity and type 2 diabetes are complex and involve adiposity-induced alterations in β cell function, adipose tissue biology, and multi-organ insulin resistance, which are often ameliorated and can even be normalized with adequate weight loss.
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Affiliation(s)
- Samuel Klein
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO 63110, USA; Sansum Diabetes Research Institute, Santa Barbara, CA 93105, USA.
| | - Amalia Gastaldelli
- Institute of Clinical Physiology, National Research Council-CNR, Pisa 56100, Italy
| | - Hannele Yki-Järvinen
- Minerva Foundation Institute for Medical Research, 00290 Helsinki, Finland; Department of Medicine, University of Helsinki, Helsinki University Hospital, 00290 Helsinki, Finland
| | - Philipp E Scherer
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; Department of Cell Biology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
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12
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Hamilton JS, Klett EL. Linoleic acid and the regulation of glucose homeostasis: A review of the evidence. Prostaglandins Leukot Essent Fatty Acids 2021; 175:102366. [PMID: 34763302 PMCID: PMC8691379 DOI: 10.1016/j.plefa.2021.102366] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 10/27/2021] [Accepted: 10/27/2021] [Indexed: 12/14/2022]
Abstract
The consumption of linoleic acid (LA, ω-6 18:2), the most common ω-6 polyunsaturated fatty acid (PUFA) in the Modern Western diet (MWD), has significantly increased over the last century in tandem with unprecedented incidence of chronic metabolic diseases like obesity and type 2 diabetes mellitus (T2DM). Although an essential fatty acid for health, LA was a very rare fatty acid in the diet of humans during their evolution. While the intake of other dietary macronutrients (carbohydrates like fructose) has also risen, diets rich in ω-6 PUFAs have been promoted in an effort to reduce cardiovascular disease despite unclear evidence as to how increased dietary LA consumption could promote a proinflammatory state and affect glucose metabolism. Current evidence suggests that sex, genetics, environmental factors, and disease status can differentially modulate how LA influences insulin sensitivity and peripheral glucose uptake as well as insulin secretion and pancreatic beta-cell function. Therefore, the aim of this review will be to summarize recent additions to our knowledge to refine the unique physiological and pathophysiological roles of LA in the regulation of glucose homeostasis.
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Affiliation(s)
- Jakob S Hamilton
- Department of Nutrition, University of North Carolina School of Public Health, Chapel Hill, North Carolina, United States of America
| | - Eric L Klett
- Department of Medicine, Division of Endocrinology, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America; Department of Nutrition, University of North Carolina School of Public Health, Chapel Hill, North Carolina, United States of America.
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13
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Chueire VB, Muscelli E. Effect of free fatty acids on insulin secretion, insulin sensitivity and incretin effect - a narrative review. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2021; 65:24-31. [PMID: 33320449 PMCID: PMC10528699 DOI: 10.20945/2359-3997000000313] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 09/26/2020] [Indexed: 11/23/2022]
Abstract
Deleterious effects of free fatty acids, FFAs, on insulin sensitivity are observed in vivo studies in humans. Mechanisms include impaired insulin signaling, oxidative stress, inflammation, and mitochondrial dysfunction, but the effects on insulin secretion are less well known. Our aim was to review the relationship of increased FFAs with insulin resistance, secretion and mainly with the incretin effect in humans. Narrative review. Increased endogenous or administered FFAs induce insulin resistance. FFAs effects on insulin secretion are debatable; inhibition and stimulation have been reported, depending on the type and duration of lipids exposition and the study subjects. Chronically elevated FFAs seem to decrease insulin biosynthesis, glucose-stimulated insulin secretion and β-cell glucose sensitivity. Lipids infusion decreases the response to incretins with unchanged incretin levels in volunteers with normal glucose tolerance. In contrast, FFAs reduction by acipimox did not restore the incretin effect in type-2 diabetes, probably due to the dysfunctional β-cell. Possible mechanisms of FFAs excess on incretin effect include reduction of the expression and levels of GLP-1 (glucagon like peptide-1) receptor, reduction of connexin-36 expression thus the coordinated secretory activity in response to GLP-1, and GIP (glucose-dependent insulinotropic polypeptide) receptors downregulation in islets cells. Increased circulating FFAs impair insulin sensitivity. Effects on insulin secretion are complex and controversial. Deleterious effects on the incretin-induced potentiation of insulin secretion were reported. More investigation is needed to better understand the extent and mechanisms of β-cell impairment and insulin resistance induced by increased FFAs and how to prevent them.
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Affiliation(s)
- Valeria Bahdur Chueire
- Departamento de Endocrinologia, Hospital da Pontifícia Universidade Católica de Campinas, Campinas, SP, Brasil,
| | - Elza Muscelli
- Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
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14
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Plasma Fatty Acid Composition Was Associated with Apelin Gene Expression in Human Adipose Tissues. BIOMED RESEARCH INTERNATIONAL 2021; 2021:8846483. [PMID: 34660801 PMCID: PMC8514886 DOI: 10.1155/2021/8846483] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 09/13/2021] [Indexed: 11/18/2022]
Abstract
Background Apelin is an adipokine with an intermediatory role in obesity and insulin resistance, which can be modified by dietary intake. Aims In this study, we aimed to determine the association of the plasma fatty acid composition with apelin plasma concentration and gene expression in visceral (VAT) and subcutaneous (SAT) adipose tissues. Methods In this cross-sectional study, we recruited 179 patients aged 19-75 years who were candidates for elective surgery. Through the surgery, SAT and VAT were collected to measure apelin gene expression. Anthropometric measurements, fasting blood samples, and dietary intakes were collected before surgery. Free fatty acids (FFAs) in fasting whole plasma were measured using gas chromatography with flame ionization detection. Linear regression models were used to estimate standardized β (STZ β) showing the association of individual and total FFAs with apelin gene expression after adjustment for potential confounding variables. Results In multivariable analysis, we observed a significant positive association of total plasma free fatty acids (FFAs) (STZ β = 0.241, P = 0.006), saturated fatty acid (SFA) (STZ β = 0.336, P < 0.001), and monounsaturated fatty acid (MUFA) (STZ β = 0.313, P < 0.001) concentrations with apelin gene expression from VAT after controlling for age, sex, body mass index, homeostatic model assessment for insulin resistance (HOMA-IR), physical activity, and energy intake. In the SFA family, there was a direct association with plasma concentration of myristic acid (STZ β = 0.372, P < 0.001), pentadecanoic acid (STZ β = 0.252, P = 0.002), and heptadecanoic acid (STZ β = 0.407, P < 0.001) with apelin mRNA expression in VAT. There was no significant association between FFAs and apelin plasma concentration and SAT mRNA levels. Conclusions In conclusion, circulating plasma FFAs, SFA, and MUFA had a positive association with apelin gene expression in VAT. It seems that plasma fatty acid composition may regulate apelin gene expression in VAT.
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15
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Henquin JC. Non-glucose modulators of insulin secretion in healthy humans: (dis)similarities between islet and in vivo studies. Metabolism 2021; 122:154821. [PMID: 34174327 DOI: 10.1016/j.metabol.2021.154821] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 06/10/2021] [Accepted: 06/18/2021] [Indexed: 12/17/2022]
Abstract
Optimal metabolic homeostasis requires precise temporal and quantitative control of insulin secretion. Both in vivo and in vitro studies have often focused on the regulation by glucose although many additional factors including other nutrients, neurotransmitters, hormones and drugs, modulate the secretory function of pancreatic β-cells. This review is based on the analysis of clinical investigations characterizing the effects of non-glucose modulators of insulin secretion in healthy subjects, and of experimental studies testing the same modulators in islets isolated from normal human donors. The aim was to determine whether the information gathered in vitro can reliably be translated to the in vivo situation. The comparison evidenced both convincing similarities and areas of discordance. The lack of coherence generally stems from the use of exceedingly high concentrations of test agents at too high or too low glucose concentrations in vitro, which casts doubts on the physiological relevance of a number of observations made in isolated islets. Future projects resorting to human islets should avoid extreme experimental conditions, such as oversized stimulations or inhibitions of β-cells, which are unlikely to throw light on normal insulin secretion and contribute to the elucidation of its defects.
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Affiliation(s)
- Jean-Claude Henquin
- Unit of Endocrinology and Metabolism, Faculty of Medicine, University of Louvain, Brussels, Belgium.
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16
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Benito-Vicente A, Jebari-Benslaiman S, Galicia-Garcia U, Larrea-Sebal A, Uribe KB, Martin C. Molecular mechanisms of lipotoxicity-induced pancreatic β-cell dysfunction. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021; 359:357-402. [PMID: 33832653 DOI: 10.1016/bs.ircmb.2021.02.013] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Type 2 diabetes (T2D), a heterogeneous disorder derived from metabolic dysfunctions, leads to a glucose overflow in the circulation due to both defective insulin secretion and peripheral insulin resistance. One of the critical risk factor for T2D is obesity, which represents a global epidemic that has nearly tripled since 1975. Obesity is characterized by chronically elevated free fatty acid (FFA) levels, which cause deleterious effects on glucose homeostasis referred to as lipotoxicity. Here, we review the physiological FFA roles onto glucose-stimulated insulin secretion (GSIS) and the pathological ones affecting many steps of the mechanisms and modulation of GSIS. We also describe in vitro and in vivo experimental evidences addressing lipotoxicity in β-cells and the role of saturation and chain length of FFA on the potency of GSIS stimulation. The molecular mechanisms underpinning lipotoxic-β-cell dysfunction are also reviewed. Among them, endoplasmic reticulum stress, oxidative stress and mitochondrial dysfunction, inflammation, impaired autophagy and β-cell dedifferentiation. Finally therapeutic strategies for the β-cells dysfunctions such as the use of metformin, glucagon-like peptide 1, thiazolidinediones, anti-inflammatory drugs, chemical chaperones and weight are discussed.
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Affiliation(s)
- Asier Benito-Vicente
- Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), Leioa, Spain; Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Shifa Jebari-Benslaiman
- Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), Leioa, Spain; Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Unai Galicia-Garcia
- Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), Leioa, Spain; Department of Molecular Biophysics, Fundación Biofísica Bizkaia, Leioa, Spain
| | - Asier Larrea-Sebal
- Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), Leioa, Spain; Department of Molecular Biophysics, Fundación Biofísica Bizkaia, Leioa, Spain
| | - Kepa B Uribe
- Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Donostia San Sebastián, Spain
| | - Cesar Martin
- Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), Leioa, Spain; Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Leioa, Spain.
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17
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Marselli L, Piron A, Suleiman M, Colli ML, Yi X, Khamis A, Carrat GR, Rutter GA, Bugliani M, Giusti L, Ronci M, Ibberson M, Turatsinze JV, Boggi U, De Simone P, De Tata V, Lopes M, Nasteska D, De Luca C, Tesi M, Bosi E, Singh P, Campani D, Schulte AM, Solimena M, Hecht P, Rady B, Bakaj I, Pocai A, Norquay L, Thorens B, Canouil M, Froguel P, Eizirik DL, Cnop M, Marchetti P. Persistent or Transient Human β Cell Dysfunction Induced by Metabolic Stress: Specific Signatures and Shared Gene Expression with Type 2 Diabetes. Cell Rep 2020; 33:108466. [PMID: 33264613 DOI: 10.1016/j.celrep.2020.108466] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 08/06/2020] [Accepted: 11/10/2020] [Indexed: 12/16/2022] Open
Abstract
Pancreatic β cell failure is key to type 2 diabetes (T2D) onset and progression. Here, we assess whether human β cell dysfunction induced by metabolic stress is reversible, evaluate the molecular pathways underlying persistent or transient damage, and explore the relationships with T2D islet traits. Twenty-six islet preparations are exposed to several lipotoxic/glucotoxic conditions, some of which impair insulin release, depending on stressor type, concentration, and combination. The reversal of dysfunction occurs after washout for some, although not all, of the lipoglucotoxic insults. Islet transcriptomes assessed by RNA sequencing and expression quantitative trait loci (eQTL) analysis identify specific pathways underlying β cell failure and recovery. Comparison of a large number of human T2D islet transcriptomes with those of persistent or reversible β cell lipoglucotoxicity show shared gene expression signatures. The identification of mechanisms associated with human β cell dysfunction and recovery and their overlap with T2D islet traits provide insights into T2D pathogenesis, fostering the development of improved β cell-targeted therapeutic strategies.
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Affiliation(s)
- Lorella Marselli
- Department of Clinical and Experimental Medicine, and AOUP Cisanello University Hospital, University of Pisa, Pisa 56126, Italy.
| | - Anthony Piron
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels 1070, Belgium
| | - Mara Suleiman
- Department of Clinical and Experimental Medicine, and AOUP Cisanello University Hospital, University of Pisa, Pisa 56126, Italy
| | - Maikel L Colli
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels 1070, Belgium
| | - Xiaoyan Yi
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels 1070, Belgium
| | - Amna Khamis
- INSERM UMR 1283, CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille University Hospital, Lille 59000, France
| | - Gaelle R Carrat
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology, and Metabolism, Imperial College, London, UK
| | - Guy A Rutter
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology, and Metabolism, Imperial College, London, UK; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Marco Bugliani
- Department of Clinical and Experimental Medicine, and AOUP Cisanello University Hospital, University of Pisa, Pisa 56126, Italy
| | - Laura Giusti
- Department of Clinical and Experimental Medicine, and AOUP Cisanello University Hospital, University of Pisa, Pisa 56126, Italy; School of Pharmacy, University of Camerino, Camerino, Italy
| | - Maurizio Ronci
- Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Chieti, Italy; Centre for Advanced Studies and Technologies (CAST), University "G. d'Annunzio" of Chieti-Pescara, Chieti, Italy
| | - Mark Ibberson
- Vital-IT Group, Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland
| | | | - Ugo Boggi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56126, Italy; Division of General and Transplant Surgery, Cisanello University Hospital, Pisa 56124, Italy
| | - Paolo De Simone
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56126, Italy; Division of Liver Surgery and Transplantation, Cisanello University Hospital, Pisa 56124, Italy
| | - Vincenzo De Tata
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56126, Italy
| | - Miguel Lopes
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels 1070, Belgium
| | - Daniela Nasteska
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels 1070, Belgium
| | - Carmela De Luca
- Department of Clinical and Experimental Medicine, and AOUP Cisanello University Hospital, University of Pisa, Pisa 56126, Italy
| | - Marta Tesi
- Department of Clinical and Experimental Medicine, and AOUP Cisanello University Hospital, University of Pisa, Pisa 56126, Italy
| | - Emanuele Bosi
- Department of Clinical and Experimental Medicine, and AOUP Cisanello University Hospital, University of Pisa, Pisa 56126, Italy
| | - Pratibha Singh
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels 1070, Belgium
| | - Daniela Campani
- Department of Surgical, Medical and Molecular Pathology and the Critical Areas, University of Pisa, Pisa 56126, Italy
| | - Anke M Schulte
- Sanofi-Aventis Deutschland GmbH, Diabetes Research, Frankfurt, Germany
| | - Michele Solimena
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, TU Dresden, Dresden 01307, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg 85764, Germany
| | - Peter Hecht
- Sanofi-Aventis Deutschland GmbH, Diabetes Research, Frankfurt, Germany
| | | | | | | | | | - Bernard Thorens
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
| | - Mickaël Canouil
- INSERM UMR 1283, CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille University Hospital, Lille 59000, France
| | - Philippe Froguel
- Department of Metabolism, Digestion, and Reproduction, Imperial College London, London, UK
| | - Decio L Eizirik
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels 1070, Belgium; WELBIO, Université Libre de Bruxelles, Brussels, Belgium; Indiana Biosciences Research Institute, Indianapolis, IN, USA; Division of Endocrinology, ULB Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Miriam Cnop
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels 1070, Belgium; Division of Endocrinology, ULB Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium.
| | - Piero Marchetti
- Department of Clinical and Experimental Medicine, and AOUP Cisanello University Hospital, University of Pisa, Pisa 56126, Italy.
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18
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Weir GC. Glucolipotoxicity, β-Cells, and Diabetes: The Emperor Has No Clothes. Diabetes 2020; 69:273-278. [PMID: 31519699 PMCID: PMC7034184 DOI: 10.2337/db19-0138] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 04/08/2019] [Indexed: 12/21/2022]
Abstract
Reduction of β-cell mass and function is central to the pathogenesis of type 2 diabetes. The terms glucotoxicity, lipotoxicity, and glucolipotoxicity are used to describe potentially responsible processes. The premise is that chronically elevated glucose levels are toxic to β-cells, that elevated lipid levels in the form of circulating free fatty acids (FFA) also have toxic effects, and that the combination of the two, glucolipotoxicity, is particularly harmful. Much work has shown that high concentrations of FFA can be very damaging to β-cells when used for in vitro experiments, and when infused in large amounts in humans and rodents they produce suppression of insulin secretion. The purpose of this Perspective is to raise doubts about whether the FFA levels found in real-life situations are ever high enough to cause problems. Evidence supporting the importance of glucotoxicity is strong because there is such a tight correlation between defective insulin secretion and rising glucose levels. However, there is virtually no convincing evidence that the alterations in FFA levels occurring during progression to diabetes are pathogenic. Thus, the terms lipotoxicity and glucolipotoxicity should be used with great caution, if at all, because evidence supporting their importance has not yet emerged.
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Affiliation(s)
- Gordon C Weir
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA
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19
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Lytrivi M, Castell AL, Poitout V, Cnop M. Recent Insights Into Mechanisms of β-Cell Lipo- and Glucolipotoxicity in Type 2 Diabetes. J Mol Biol 2019; 432:1514-1534. [PMID: 31628942 DOI: 10.1016/j.jmb.2019.09.016] [Citation(s) in RCA: 241] [Impact Index Per Article: 40.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 09/15/2019] [Accepted: 09/16/2019] [Indexed: 12/24/2022]
Abstract
The deleterious effects of chronically elevated free fatty acid (FFA) levels on glucose homeostasis are referred to as lipotoxicity, and the concurrent exposure to high glucose may cause synergistic glucolipotoxicity. Lipo- and glucolipotoxicity have been studied for over 25 years. Here, we review the current evidence supporting the role of pancreatic β-cell lipo- and glucolipotoxicity in type 2 diabetes (T2D), including lipid-based interventions in humans, prospective epidemiological studies, and human genetic findings. In addition to total FFA quantity, the quality of FFAs (saturation and chain length) is a key determinant of lipotoxicity. We discuss in vitro and in vivo experimental models to investigate lipo- and glucolipotoxicity in β-cells and describe experimental pitfalls. Lipo- and glucolipotoxicity adversely affect many steps of the insulin production and secretion process. The molecular mechanisms underpinning lipo- and glucolipotoxic β-cell dysfunction and death comprise endoplasmic reticulum stress, oxidative stress and mitochondrial dysfunction, impaired autophagy, and inflammation. Crosstalk between these stress pathways exists at multiple levels and may aggravate β-cell lipo- and glucolipotoxicity. Lipo- and glucolipotoxicity are therapeutic targets as several drugs impact the underlying stress responses in β-cells, potentially contributing to their glucose-lowering effects in T2D.
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Affiliation(s)
- Maria Lytrivi
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium; Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Anne-Laure Castell
- CRCHUM, Montréal, QC, Canada; Department of Medicine, Université de Montréal, Montréal, QC, Canada
| | - Vincent Poitout
- CRCHUM, Montréal, QC, Canada; Department of Medicine, Université de Montréal, Montréal, QC, Canada.
| | - Miriam Cnop
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium; Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium.
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20
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Gerst F, Wagner R, Oquendo MB, Siegel-Axel D, Fritsche A, Heni M, Staiger H, Häring HU, Ullrich S. What role do fat cells play in pancreatic tissue? Mol Metab 2019; 25:1-10. [PMID: 31113756 PMCID: PMC6600604 DOI: 10.1016/j.molmet.2019.05.001] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 04/10/2019] [Accepted: 05/01/2019] [Indexed: 02/07/2023] Open
Abstract
Background It is now generally accepted that obesity is a major risk factor for type 2 diabetes mellitus (T2DM). Hepatic steatosis in particular, as well as visceral and ectopic fat accumulation within tissues, is associated with the development of the disease. We recently presented the first study on isolated human pancreatic adipocytes and their interaction with islets [Gerst, F., Wagner, R., Kaiser, G., Panse, M., Heni, M., Machann, J., et al., 2017. Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion. Diabetologia 60(11):2240–2251.]. The results indicate that the function of adipocytes depends on the overall metabolic status in humans which, in turn, differentially affects islet hormone release. Scope of Review This review summarizes former and recent studies on factors derived from adipocytes and their effects on insulin-secreting β-cells, with particular emphasis on the human pancreas. The adipocyte secretome is discussed with a special focus on its influence on insulin secretion, β-cell survival and apoptotic β-cell death. Major Conclusions Human pancreatic adipocytes store lipids and release adipokines, metabolites, and pro-inflammatory molecules in response to the overall metabolic, humoral, and neuronal status. The differentially regulated adipocyte secretome impacts on endocrine function, i.e., insulin secretion, β-cell survival and death which interferes with glycemic control. This review attempts to explain why the extent of pancreatic steatosis is associated with reduced insulin secretion in some studies but not in others.
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Affiliation(s)
- Felicia Gerst
- German Center for Diabetes Research (DZD), Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Robert Wagner
- German Center for Diabetes Research (DZD), Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard Karls University of Tübingen, Tübingen, Germany; Department of Internal Medicine IV, Division of Endocrinology, Diabetology, and Nephrology, University Hospital Tübingen, Tübingen, Germany
| | - Morgana Barroso Oquendo
- German Center for Diabetes Research (DZD), Tübingen, Germany; Department of Internal Medicine IV, Division of Endocrinology, Diabetology, and Nephrology, University Hospital Tübingen, Tübingen, Germany
| | - Dorothea Siegel-Axel
- German Center for Diabetes Research (DZD), Tübingen, Germany; Department of Internal Medicine IV, Division of Endocrinology, Diabetology, and Nephrology, University Hospital Tübingen, Tübingen, Germany
| | - Andreas Fritsche
- German Center for Diabetes Research (DZD), Tübingen, Germany; Department of Internal Medicine IV, Division of Endocrinology, Diabetology, and Nephrology, University Hospital Tübingen, Tübingen, Germany
| | - Martin Heni
- German Center for Diabetes Research (DZD), Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard Karls University of Tübingen, Tübingen, Germany; Department of Internal Medicine IV, Division of Endocrinology, Diabetology, and Nephrology, University Hospital Tübingen, Tübingen, Germany
| | - Harald Staiger
- German Center for Diabetes Research (DZD), Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard Karls University of Tübingen, Tübingen, Germany; Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Hans-Ulrich Häring
- German Center for Diabetes Research (DZD), Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard Karls University of Tübingen, Tübingen, Germany; Department of Internal Medicine IV, Division of Endocrinology, Diabetology, and Nephrology, University Hospital Tübingen, Tübingen, Germany
| | - Susanne Ullrich
- German Center for Diabetes Research (DZD), Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard Karls University of Tübingen, Tübingen, Germany.
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21
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Mousa A, Naderpoor N, Mellett N, Wilson K, Plebanski M, Meikle PJ, de Courten B. Lipidomic profiling reveals early-stage metabolic dysfunction in overweight or obese humans. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1864:335-343. [PMID: 30586632 DOI: 10.1016/j.bbalip.2018.12.014] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 12/20/2018] [Accepted: 12/21/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Advances in mass spectrometry and lipidomics techniques are providing new insights into the role of lipid metabolism in obesity-related diseases. However, human lipidomic studies have been inconsistent, owing to the use of indirect proxy measures of metabolic outcomes and relatively limited coverage of the lipidome. Here, we employed comprehensive lipid profiling and gold-standard metabolic measures to test the hypothesis that distinct lipid signatures in obesity may signify early stages of pathogenesis toward type 2 diabetes. METHODS Using high-performance liquid chromatography-electrospray tandem mass spectrometry, we profiled >450 lipid species across 26 classes in 65 overweight or obese non-diabetic individuals. Intensive metabolic testing was conducted using direct gold-standard measures of adiposity (% body fat by dual X-ray absorptiometry), insulin sensitivity (hyperinsulinaemic-euglycaemic clamps), and insulin secretion (intravenous glucose tolerance tests), as well as measurement of serum inflammatory cytokines and adipokines (multiplex assays; flow cytometry). Univariable and multivariable linear regression models were computed using Matlab R2011a, and all analyses were corrected for multiple testing using the Benjamini-Hochberg method. RESULTS We present new evidence showing a strong and independent positive correlation between the lysophosphatidylinositol (LPI) lipid class and insulin secretion in vivo in humans (β [95% CI] = 781.9 [353.3, 1210.4], p = 0.01), supporting the insulinotropic effects of LPI demonstrated in mouse islets. Dihydroceramide, a sphingolipid precursor, was independently and negatively correlated with insulin sensitivity (β [95% CI] = -1.9 [-2.9, -0.9], p = 0.01), indicating a possible upregulation in sphingolipid synthesis in obese individuals. These associations remained significant in multivariable models adjusted for age, sex, and % body fat. The dihexosylceramide class correlated positively with interleukin-10 before and after adjustment for age, sex, and % body fat (p = 0.02), while the phosphatidylethanolamine class and its vinyl ether-linked (plasmalogen) derivatives correlated negatively with % body fat in both univariable and age- and sex-adjusted models (all p < 0.04). CONCLUSIONS Our data suggest that these lipid classes may signify early pathogenesis toward type 2 diabetes and could serve as novel therapeutic targets or biomarkers for diabetes prevention.
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Affiliation(s)
- Aya Mousa
- Monash Centre for Health Research and Implementation (MCHRI), School of Public Health and Preventive Medicine, Monash University, 43-51 Kanooka Grove, Clayton, VIC 3168, Australia.
| | - Negar Naderpoor
- Monash Centre for Health Research and Implementation (MCHRI), School of Public Health and Preventive Medicine, Monash University, 43-51 Kanooka Grove, Clayton, VIC 3168, Australia.
| | - Natalie Mellett
- Metabolomics Laboratory, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia.
| | - Kirsty Wilson
- Department of Immunology and Pathology, Monash University, 89 Commercial Road, Melbourne, VIC 3004, Australia.
| | - Magdalena Plebanski
- Department of Immunology and Pathology, Monash University, 89 Commercial Road, Melbourne, VIC 3004, Australia; School of Health and Biomedical Sciences, RMIT University, Corner Janefield Dr and Plenty Road, Bundoora, VIC 3083, Australia.
| | - Peter J Meikle
- Metabolomics Laboratory, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia.
| | - Barbora de Courten
- Monash Centre for Health Research and Implementation (MCHRI), School of Public Health and Preventive Medicine, Monash University, 43-51 Kanooka Grove, Clayton, VIC 3168, Australia.
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22
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Astiarraga B, Chueire VB, Souza AL, Pereira-Moreira R, Monte Alegre S, Natali A, Tura A, Mari A, Ferrannini E, Muscelli E. Effects of acute NEFA manipulation on incretin-induced insulin secretion in participants with and without type 2 diabetes. Diabetologia 2018; 61:1829-1837. [PMID: 29732475 DOI: 10.1007/s00125-018-4633-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 04/04/2018] [Indexed: 01/08/2023]
Abstract
AIMS/HYPOTHESIS Incretin effect-the potentiation of glucose-stimulated insulin release induced by the oral vs the i.v. route-is impaired in dysglycaemic states. Despite evidence from human islet studies that NEFA interfere with incretin function, little information is available about the effect in humans. We tested the impact of acute bidirectional NEFA manipulation on the incretin effect in humans. METHODS Thirteen individuals with type 2 diabetes and ten non-diabetic volunteers had a 3 h OGTT, and, a week later, an i.v. isoglycaemic glucose infusion (ISO; OGTT matched). Both pairs of studies were repeated during an exogenous lipid infusion in the non-diabetic volunteers, and following acipimox administration (to inhibit lipolysis) in people with diabetes. Mathematical modelling of insulin secretion dynamics assessed total insulin secretion (TIS), beta cell glucose sensitivity (β-GS), glucose-induced potentiation (PGLU) and incretin-induced potentiation (PINCR); the oral glucose sensitivity index was used to estimate insulin sensitivity. RESULTS Lipid infusion increased TIS (from 61 [interquartile range 26] to 78 [31] nmol/m2 on OGTT and from 29 nmol/m2 [26] to 57 nmol/m2 [30] on ISO) and induced insulin resistance. PINCR decreased from 1.6 [1.1] to 1.3 [0.1] (p < 0.05). β-GS, PGLU and glucagon, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) responses were unaffected. Acipimox (lowering NEFA by ~55%) reduced plasma glucose and TIS and enhanced insulin sensitivity, but did not change β-GS, PINCR, PGLU or glucagon, GLP-1 or GIP responses. As the per cent difference, incretin effect was decreased in non-diabetic participants and unchanged in those with diabetes. CONCLUSIONS/INTERPRETATION Raising NEFA selectively impairs incretin effect and insulin sensitivity in non-diabetic individuals, while acute NEFA reduction lowers plasma glucose and enhances insulin sensitivity in people with diabetes but does not correct the impaired incretin-induced potentiation.
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Affiliation(s)
- Brenno Astiarraga
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Valéria B Chueire
- Department of Internal Medicine, University of Campinas, Campinas, Brazil
| | - Aglécio L Souza
- Department of Internal Medicine, University of Campinas, Campinas, Brazil
| | | | - Sarah Monte Alegre
- Department of Internal Medicine, University of Campinas, Campinas, Brazil
| | - Andrea Natali
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | | | - Ele Ferrannini
- CNR Institute of Clinical Physiology, Via Savi, 10, 56100, Pisa, Italy.
| | - Elza Muscelli
- Department of Internal Medicine, University of Campinas, Campinas, Brazil
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23
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Wang Y, Liu J, Liu Z, Chen J, Hu X, Hu Y, Yuan Y, Wu G, Dai Z, Xu Y. Sall2 knockdown exacerbates palmitic acid induced dysfunction and apoptosis of pancreatic NIT-1 beta cells. Biomed Pharmacother 2018; 104:375-382. [PMID: 29783189 DOI: 10.1016/j.biopha.2018.05.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 04/25/2018] [Accepted: 05/07/2018] [Indexed: 12/12/2022] Open
Abstract
Spalt-like (Sall) proteins are a class of transcription factors. The role of Sall2 in beta cells remain poorly understood. Here, we aimed to explore whether Sall2 involved in lipotoxicity-mediated dysfunction and apoptosis in pancreatic NIT-1 beta cells. Our results showed that high concentrations of palmitic acid (PA) led to impaired cell viability and decreased Sall2 expression in NIT-1 cells. Knocking down of Sall2 in NIT-1 cells resulted in increased sensitivity to lipotoxicity and caused higher rates of cell apoptosis following PA treatment. Additionally, Sall2 Knockdown impaired insulin synthesis and secretion in response to glucose. Further research indicated Sall2 knockdown attenuate antioxidant capacity and decreased expression level of Peroxiredoxin 2 in NIT-1 cells. These finding implicate that Sall2 may play a significant role in NIT-1 cell function and cell apoptosis under lipotoxic conditions. Therefore, the study of Sall2 in NIT-1 cells provided a new perspective for molecular mechanism of lipotoxicity mediating dysfunction and apoptosis of beta cells.
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Affiliation(s)
- Ye Wang
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China
| | - Jie Liu
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China
| | - Zheng Liu
- Department of Endocrinology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006,China
| | - Jing Chen
- Department of Integrated Wards, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China
| | - Xuemei Hu
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China
| | - Yimeng Hu
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China
| | - Yin Yuan
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China
| | - Guijun Wu
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China
| | - Zhe Dai
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China
| | - Yancheng Xu
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China.
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24
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Velasco C, Comesaña S, Conde-Sieira M, Míguez JM, Soengas JL. The short-term presence of oleate or octanoate alters the phosphorylation status of Akt, AMPK, mTOR, CREB, and FoxO1 in liver of rainbow trout ( Oncorhynchus mykiss ). Comp Biochem Physiol B Biochem Mol Biol 2018; 219-220:17-25. [DOI: 10.1016/j.cbpb.2018.03.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 03/06/2018] [Accepted: 03/13/2018] [Indexed: 01/11/2023]
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25
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Neuman JC, Schaid MD, Brill AL, Fenske RJ, Kibbe CR, Fontaine DA, Sdao SM, Brar HK, Connors KM, Wienkes HN, Eliceiri KW, Merrins MJ, Davis DB, Kimple ME. Enriching Islet Phospholipids With Eicosapentaenoic Acid Reduces Prostaglandin E 2 Signaling and Enhances Diabetic β-Cell Function. Diabetes 2017; 66:1572-1585. [PMID: 28193789 PMCID: PMC5440023 DOI: 10.2337/db16-1362] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Accepted: 02/09/2017] [Indexed: 12/26/2022]
Abstract
Prostaglandin E2 (PGE2) is derived from arachidonic acid, whereas PGE3 is derived from eicosapentaenoic acid (EPA) using the same downstream metabolic enzymes. Little is known about the impact of EPA and PGE3 on β-cell function, particularly in the diabetic state. In this work, we determined that PGE3 elicits a 10-fold weaker reduction in glucose-stimulated insulin secretion through the EP3 receptor as compared with PGE2 We tested the hypothesis that enriching pancreatic islet cell membranes with EPA, thereby reducing arachidonic acid abundance, would positively impact β-cell function in the diabetic state. EPA-enriched islets isolated from diabetic BTBR Leptinob/ob mice produced significantly less PGE2 and more PGE3 than controls, correlating with improved glucose-stimulated insulin secretion. NAD(P)H fluorescence lifetime imaging showed that EPA acts downstream and independently of mitochondrial function. EPA treatment also reduced islet interleukin-1β expression, a proinflammatory cytokine known to stimulate prostaglandin production and EP3 expression. Finally, EPA feeding improved glucose tolerance and β-cell function in a mouse model of diabetes that incorporates a strong immune phenotype: the NOD mouse. In sum, increasing pancreatic islet EPA abundance improves diabetic β-cell function through both direct and indirect mechanisms that converge on reduced EP3 signaling.
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Affiliation(s)
- Joshua C Neuman
- Interdisciplinary Graduate Program in Nutritional Sciences, College of Agriculture and Life Sciences, University of Wisconsin-Madison, Madison, WI
- Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI
| | - Michael D Schaid
- Interdisciplinary Graduate Program in Nutritional Sciences, College of Agriculture and Life Sciences, University of Wisconsin-Madison, Madison, WI
- Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI
| | - Allison L Brill
- Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI
- Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
| | - Rachel J Fenske
- Interdisciplinary Graduate Program in Nutritional Sciences, College of Agriculture and Life Sciences, University of Wisconsin-Madison, Madison, WI
- Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI
| | - Carly R Kibbe
- Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI
- Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
| | - Danielle A Fontaine
- Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI
- Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
| | - Sophia M Sdao
- Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI
- Integrated Program in Biochemistry, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
| | - Harpreet K Brar
- Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI
- Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
| | - Kelsey M Connors
- Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI
- Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
| | - Haley N Wienkes
- Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI
- Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
| | - Kevin W Eliceiri
- Department of Biomedical Engineering, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
- Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
| | - Matthew J Merrins
- Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI
- Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
- Integrated Program in Biochemistry, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
- Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
- Department of Biomolecular Chemistry, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
| | - Dawn B Davis
- Interdisciplinary Graduate Program in Nutritional Sciences, College of Agriculture and Life Sciences, University of Wisconsin-Madison, Madison, WI
- Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
- Medical Service, William S. Middleton Memorial Veterans Hospital, Madison, WI
| | - Michelle E Kimple
- Interdisciplinary Graduate Program in Nutritional Sciences, College of Agriculture and Life Sciences, University of Wisconsin-Madison, Madison, WI
- Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI
- Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
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26
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Roomp K, Kristinsson H, Schvartz D, Ubhayasekera K, Sargsyan E, Manukyan L, Chowdhury A, Manell H, Satagopam V, Groebe K, Schneider R, Bergquist J, Sanchez JC, Bergsten P. Combined lipidomic and proteomic analysis of isolated human islets exposed to palmitate reveals time-dependent changes in insulin secretion and lipid metabolism. PLoS One 2017; 12:e0176391. [PMID: 28448538 PMCID: PMC5407795 DOI: 10.1371/journal.pone.0176391] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 04/10/2017] [Indexed: 01/09/2023] Open
Abstract
Studies on the pathophysiology of type 2 diabetes mellitus (T2DM) have linked the accumulation of lipid metabolites to the development of beta-cell dysfunction and impaired insulin secretion. In most in vitro models of T2DM, rodent islets or beta-cell lines are used and typically focus is on specific cellular pathways or organs. Our aim was to, firstly, develop a combined lipidomics and proteomics approach for lipotoxicity in isolated human islets and, secondly, investigate if the approach could delineate novel and/ or confirm reported mechanisms of lipotoxicity. To this end isolated human pancreatic islets, exposed to chronically elevated palmitate concentrations for 0, 2 and 7 days, were functionally characterized and their levels of multiple targeted lipid and untargeted protein species determined. Glucose-stimulated insulin secretion from the islets increased on day 2 and decreased on day 7. At day 7 islet insulin content decreased and the proinsulin to insulin content ratio doubled. Amounts of cholesterol, stearic acid, C16 dihydroceramide and C24:1 sphingomyelin, obtained from the lipidomic screen, increased time-dependently in the palmitate-exposed islets. The proteomic screen identified matching changes in proteins involved in lipid biosynthesis indicating up-regulated cholesterol and lipid biosynthesis in the islets. Furthermore, proteins associated with immature secretory granules were decreased when palmitate exposure time was increased despite their high affinity for cholesterol. Proteins associated with mature secretory granules remained unchanged. Pathway analysis based on the protein and lipid expression profiles implicated autocrine effects of insulin in lipotoxicity. Taken together the study demonstrates that combining different omics approaches has potential in mapping of multiple simultaneous cellular events. However, it also shows that challenges exist for effectively combining lipidomics and proteomics in primary cells. Our findings provide insight into how saturated fatty acids contribute to islet cell dysfunction by affecting the granule maturation process and confirmation in human islets of some previous findings from rodent islet and cell-line studies.
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Affiliation(s)
- Kirsten Roomp
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-Belval, Luxembourg
- * E-mail:
| | | | - Domitille Schvartz
- Human Protein Sciences Department, Centre Médical Universitaire, University of Geneva, Geneva, Switzerland
| | - Kumari Ubhayasekera
- Analytical Chemistry, Department of Chemistry and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Ernest Sargsyan
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Levon Manukyan
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Azazul Chowdhury
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Hannes Manell
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Venkata Satagopam
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-Belval, Luxembourg
| | | | - Reinhard Schneider
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-Belval, Luxembourg
| | - Jonas Bergquist
- Analytical Chemistry, Department of Chemistry and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Jean-Charles Sanchez
- Human Protein Sciences Department, Centre Médical Universitaire, University of Geneva, Geneva, Switzerland
| | - Peter Bergsten
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
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27
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Templeman NM, Skovsø S, Page MM, Lim GE, Johnson JD. A causal role for hyperinsulinemia in obesity. J Endocrinol 2017; 232:R173-R183. [PMID: 28052999 DOI: 10.1530/joe-16-0449] [Citation(s) in RCA: 109] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 01/03/2017] [Indexed: 12/13/2022]
Abstract
Insulin modulates the biochemical pathways controlling lipid uptake, lipolysis and lipogenesis at multiple levels. Elevated insulin levels are associated with obesity, and conversely, dietary and pharmacological manipulations that reduce insulin have occasionally been reported to cause weight loss. However, the causal role of insulin hypersecretion in the development of mammalian obesity remained controversial in the absence of direct loss-of-function experiments. Here, we discuss theoretical considerations around the causal role of excess insulin for obesity, as well as recent studies employing mice that are genetically incapable of the rapid and sustained hyperinsulinemia that normally accompanies a high-fat diet. We also discuss new evidence demonstrating that modest reductions in circulating insulin prevent weight gain, with sustained effects that can persist after insulin levels normalize. Importantly, evidence from long-term studies reveals that a modest reduction in circulating insulin is not associated with impaired glucose homeostasis, meaning that body weight and lipid homeostasis are actually more sensitive to small changes in circulating insulin than glucose homeostasis in these models. Collectively, the evidence from new studies on genetic loss-of-function models forces a re-evaluation of current paradigms related to obesity, insulin resistance and diabetes. The potential for translation of these findings to humans is briefly discussed.
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Affiliation(s)
- Nicole M Templeman
- Department of Cellular and Physiological SciencesDiabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Søs Skovsø
- Department of Cellular and Physiological SciencesDiabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Melissa M Page
- Department of Cellular and Physiological SciencesDiabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Gareth E Lim
- Department of Cellular and Physiological SciencesDiabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - James D Johnson
- Department of Cellular and Physiological SciencesDiabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
- Institute for Personalized Therapeutic NutritionVancouver, British Columbia, Canada
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28
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Tzeng CY, Lee YC, Chung JJ, Tsai JC, Chen YI, Hsu TH, Lin JG, Lee KR, Chang SL. 15 hz Electroacupuncture at St36 Improves Insulin Sensitivity and Reduces Free Fatty Acid Levels in Rats with Chronic Dexamethasone-Induced Insulin Resistance. Acupunct Med 2016; 34:296-301. [DOI: 10.1136/acupmed-2015-010956] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/23/2016] [Indexed: 02/01/2023]
Abstract
Objective To evaluate the effect of electroacupuncture (EA) in a rat model of chronic steroid-induced insulin resistance (SIIR). Methods An SIIR rat model was created using daily intraperitoneal injections of clinically relevant doses of dexamethasone (1 mg/kg) for 5 days to induce chronic insulin resistance. Thirty-six SIIR rats were randomly divided into the SIIR+EA group (n=18), which received 15 Hz EA at ST36 for 60 min, and the SIIR group (n=18), which remained untreated. Plasma glucose and free fatty acid (FFA) levels were measured in serial blood samples taken without further manipulation (n=6 per group) and during insulin challenge test (ICT, n=6 per group) and intravenous glucose tolerance test (ivGTT, n=6 per group). Insulin receptor substrate (IRS)-1 and glucose transporter (GLUT)-4 were measured using Western blotting and expressed relative to β-actin. Results Following EA, area-under-the-curve (AUC) for glucose was reduced (7340±291 vs 10 705±1474 mg/dL/min, p=0.049) and FFA levels significantly lower at 30/60 min in the SIIR+EA versus SIIR groups. Similar effects on glucose AUC were seen during the ICT (5568±275 vs 7136±594 mg/dL/min, p<0.05) and igVTT (11 498±1398 vs 16 652±1217 mg/dL/min, p<0.01). FFA levels were lower at 30 and/or 60 min in SIIR+EA versus SIIR groups (p<0.01). Relative expression of IRS-1 and GLUT4 were significantly increased by EA (p<0.01). Conclusions EA decreased the FFA level and increased insulin sensitivity in SIIR rats. Further clinical studies are needed to determine whether EA is an effective alternative treatment for the reduction of insulin resistance in patients requiring chronic use of dexamethasone.
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Affiliation(s)
- Chung-Yuh Tzeng
- Department of Orthopedics, Taichung Veterans General Hospital, Taichung City, Taiwan
- Institute of Molecular Medicine, College of Life Science, National Tsing Hua University, Hsinchu City, Taiwan
- Department of Nursing, Hung-Kuang University, Taichung city, Taiwan
| | - Yu-Chen Lee
- Department of Acupuncture, China Medical University Hospital, Taichung City, Taiwan
| | - Jui-Jung Chung
- Department of Pharmacy, Cheng-Ching Hospital, Taichung City, Taiwan
| | - Jen-Chieh Tsai
- Department of Medicinal Botanicals and Health Applications, Da-Yeh University, Changhua County, Taiwan
| | - Ying-I Chen
- Department of Medicinal Botanicals and Health Applications, Da-Yeh University, Changhua County, Taiwan
| | - Tai-Hao Hsu
- Department of BioIndustry Technology, Da-Yeh University, Changhua County, Taiwan
| | - Jaung-Geng Lin
- School of Chinese Medicine, China Medical University, Taichung City, Taiwan
| | - Kuan-Rong Lee
- Institute of Molecular Medicine, College of Life Science, National Tsing Hua University, Hsinchu City, Taiwan
| | - Shih-Liang Chang
- Department of Medicinal Botanicals and Health Applications, Da-Yeh University, Changhua County, Taiwan
- School of Chinese Medicine, China Medical University, Taichung City, Taiwan
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29
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Lombardo GE, Arcidiacono B, De Rose RF, Lepore SM, Costa N, Montalcini T, Brunetti A, Russo D, De Sarro G, Celano M. Normocaloric Diet Restores Weight Gain and Insulin Sensitivity in Obese Mice. Front Endocrinol (Lausanne) 2016; 7:49. [PMID: 27303363 PMCID: PMC4882321 DOI: 10.3389/fendo.2016.00049] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 05/09/2016] [Indexed: 12/17/2022] Open
Abstract
An increased incidence of obesity is registered worldwide, and its association with insulin resistance and type 2 diabetes is closely related with increased morbidity and mortality for cardiovascular diseases. A major clinical problem in the management of obesity is the non-adherence or low adherence of patients to a hypocaloric dietetic restriction. In this study, we evaluated in obese mice the effects of shifting from high-calorie foods to normal diet on insulin sensitivity. Male C57BL/6JOlaHsd mice (n = 20) were fed with high fat diet (HFD) for a 24-week period. Afterward, body weight, energy, and food intake were measured in all animals, together with parameters of insulin sensitivity by homeostatic model assessment of insulin resistance and plasma glucose levels in response to insulin administration. Moreover, in half of these mice, Glut4 mRNA levels were measured in muscle at the end of the high fat treatment, whereas the rest of the animals (n = 10) were shifted to normocaloric diet (NCD) for 10 weeks, after which the same analyses were carried out. A significant reduction of body weight was found after the transition from high to normal fat diet, and this decrease correlated well with an improvement in insulin sensitivity. In fact, we found a reduction in serum insulin levels and the recovery of insulin responsiveness in terms of glucose disposal measured by insulin tolerance test and Glut4 mRNA and protein expression. These results indicate that obesity-related insulin resistance may be rescued by shifting from HFD to NCD.
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Affiliation(s)
| | - Biagio Arcidiacono
- Department of Health Sciences, University “Magna Graecia” of Catanzaro, Catanzaro, Italy
| | | | - Saverio Massimo Lepore
- Department of Health Sciences, University “Magna Graecia” of Catanzaro, Catanzaro, Italy
| | - Nicola Costa
- Department of Health Sciences, University “Magna Graecia” of Catanzaro, Catanzaro, Italy
| | - Tiziana Montalcini
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, Catanzaro, Italy
| | - Antonio Brunetti
- Department of Health Sciences, University “Magna Graecia” of Catanzaro, Catanzaro, Italy
- *Correspondence: Antonio Brunetti, ; Diego Russo,
| | - Diego Russo
- Department of Health Sciences, University “Magna Graecia” of Catanzaro, Catanzaro, Italy
- *Correspondence: Antonio Brunetti, ; Diego Russo,
| | | | - Marilena Celano
- Department of Health Sciences, University “Magna Graecia” of Catanzaro, Catanzaro, Italy
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Erion KA, Berdan CA, Burritt NE, Corkey BE, Deeney JT. Chronic Exposure to Excess Nutrients Left-shifts the Concentration Dependence of Glucose-stimulated Insulin Secretion in Pancreatic β-Cells. J Biol Chem 2015; 290:16191-201. [PMID: 25934392 DOI: 10.1074/jbc.m114.620351] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Indexed: 01/21/2023] Open
Abstract
Hyperinsulinemia (HI) is elevated plasma insulin at basal glucose. Impaired glucose tolerance is associated with HI, although the exact cause and effect relationship remains poorly defined. We tested the hypothesis that HI can result from an intrinsic response of the β-cell to chronic exposure to excess nutrients, involving a shift in the concentration dependence of glucose-stimulated insulin secretion. INS-1 (832/13) cells were cultured in either a physiological (4 mm) or high (11 mm) glucose concentration with or without concomitant exposure to oleate. Isolated rat islets were also cultured with or without oleate. A clear hypersensitivity to submaximal glucose concentrations was evident in INS-1 cells cultured in excess nutrients such that the 25% of maximal (S0.25) glucose-stimulated insulin secretion was significantly reduced in cells cultured in 11 mm glucose (S0.25 = 3.5 mm) and 4 mm glucose with oleate (S0.25 = 4.5 mm) compared with 4 mm glucose alone (S0.25 = 5.7 mm). The magnitude of the left shift was linearly correlated with intracellular lipid stores in INS-1 cells (r(2) = 0.97). We observed no significant differences in the dose responses for glucose stimulation of respiration, NAD(P)H autofluorescence, or Ca(2+) responses between left- and right-shifted β-cells. However, a left shift in the sensitivity of exocytosis to Ca(2+) was documented in permeabilized INS-1 cells cultured in 11 versus 4 mm glucose (S0.25 = 1.1 and 1.7 μm, respectively). Our results suggest that the sensitivity of exocytosis to triggering is modulated by a lipid component, the levels of which are influenced by the culture nutrient environment.
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Affiliation(s)
- Karel A Erion
- From the Obesity Research Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118
| | - Charles A Berdan
- From the Obesity Research Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118
| | - Nathan E Burritt
- From the Obesity Research Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118
| | - Barbara E Corkey
- From the Obesity Research Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118
| | - Jude T Deeney
- From the Obesity Research Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118
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Bellini L, Campana M, Mahfouz R, Carlier A, Véret J, Magnan C, Hajduch E, Le Stunff H. Targeting sphingolipid metabolism in the treatment of obesity/type 2 diabetes. Expert Opin Ther Targets 2015; 19:1037-50. [PMID: 25814122 DOI: 10.1517/14728222.2015.1028359] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
INTRODUCTION Obesity is a major factor that is linked to the development of type 2 diabetes (T2D). Excess circulating fatty acids (FAs), which characterize obesity, induce insulin resistance, steatosis, β cells dysfunction and apoptosis. These deleterious effects have been defined as lipotoxicity. AREAS COVERED FAs are metabolized to different lipid species, including ceramides which play a crucial role in lipotoxicity. The action of ceramides on tissues, such as muscle, liver, adipose tissue and pancreatic β cells, during the development of T2D will also be reviewed. In addition, the potential antagonist action of other sphingolipids, namely sphingoid base phosphates, on lipotoxicity in skeletal muscle and β cells will be addressed. EXPERT OPINION Ceramide is a critical mediator to the development of T2D linked to obesity. Targeting proteins involved in ceramide's deleterious action has not been possible due to their involvement in many other intracellular signaling pathways. A possible means of counteracting ceramide action would be to prevent the accumulation of the specific ceramide species involved in both insulin resistance and β-cell apoptosis/dysfunction. Another possibility would be to adjust the dynamic balance between ceramide and sphingoid base phosphate, both known to display opposing properties on the development of T2D-linked obesity.
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Affiliation(s)
- Lara Bellini
- Université PARIS-DIDEROT (7), Unité Biologie Fonctionnelle et Adaptative - UMR CNRS 8251, Équipe Régulation de la glycémie par le système nerveux central (REGLYS) , 4, rue Marie-Andrée Lagroua Weill-Halle, 75205 PARIS Cedex 13 , France +01 57 27 77 97 ; +01 57 27 77 96 ;
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Oh YS. Mechanistic insights into pancreatic beta-cell mass regulation by glucose and free fatty acids. Anat Cell Biol 2015; 48:16-24. [PMID: 25806118 PMCID: PMC4371177 DOI: 10.5115/acb.2015.48.1.16] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2014] [Accepted: 02/04/2015] [Indexed: 01/14/2023] Open
Abstract
Pancreatic islets are responsible for blood glucose homeostasis. Reduced numbers of functional (insulin-secreting) beta-cells in pancreatic islets underlies diabetes. Restoration of the secretion of the proper amount of insulin is a goal. Beta-cell mass is increased by neogenesis, proliferation and cell hypertrophy, and is decreased by beta-cell death primarily through apoptosis. Many hormones and nutrients affect beta-cell mass, and glucose and free fatty acid are thought to be the most important determinants of beta-cell equilibrium. A number of molecular pathways have been implicated in beta-cell mass regulation and have been studied. This review will focus on the role of the principle metabolites, glucose and free fatty acid, and the downstream signaling pathways regulating beta-cell mass by these metabolites.
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Affiliation(s)
- Yoon Sin Oh
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea. ; Gachon Medical Research Institute, Gil Hospital, Incheon, Korea
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Narendran P, Solomon TP, Kennedy A, Chimen M, Andrews RC. The time has come to test the beta cell preserving effects of exercise in patients with new onset type 1 diabetes. Diabetologia 2015; 58:10-8. [PMID: 25367458 DOI: 10.1007/s00125-014-3412-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 09/22/2014] [Indexed: 12/14/2022]
Abstract
Type 1 diabetes is characterised by immune-mediated destruction of insulin-producing beta cells. Significant beta cell function is usually present at the time of diagnosis with type 1 diabetes, and preservation of this function has important clinical benefits. The last 30 years have seen a number of largely unsuccessful trials for beta cell preservation, some of which have been of therapies that have potential for significant harm. There is a need to explore new, more tolerable approaches to preserving beta cell function that can be implemented on a large clinical scale. Here we review the evidence for physical exercise as a therapy for the preservation of beta cell function in patients with newly diagnosed type 1 diabetes. We highlight possible mechanisms by which exercise could preserve beta cell function and then present evidence from other models of diabetes that demonstrate that exercise preserves beta cell function. We conclude by proposing that there is now a need for studies to explore whether exercise can preserve beta cell in patients newly diagnosed with type 1 diabetes.
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Affiliation(s)
- Parth Narendran
- The Institute of Biomedical Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK,
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Johns I, Goff L, Bluck LJ, Griffin BA, Jebb SA, Lovegrove JA, Sanders TAB, Frost G, Dornhorst A. Plasma free fatty acids do not provide the link between obesity and insulin resistance or β-cell dysfunction: results of the Reading, Imperial, Surrey, Cambridge, Kings (RISCK) study. Diabet Med 2014; 31:1310-5. [PMID: 25047698 DOI: 10.1111/dme.12550] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Revised: 05/13/2014] [Accepted: 07/17/2014] [Indexed: 12/15/2022]
Abstract
AIMS To investigate the relationship between adiposity and plasma free fatty acid levels and the influence of total plasma free fatty acid level on insulin sensitivity and β-cell function. METHODS An insulin sensitivity index, acute insulin response to glucose and a disposition index, derived from i.v. glucose tolerance minimal model analysis and total fasting plasma free fatty acid levels were available for 533 participants in the Reading, Imperial, Surrey, Cambridge, Kings study. Bivariate correlations were made between insulin sensitivity index, acute insulin response to glucose and disposition index and both adiposity measures (BMI, waist circumference and body fat mass) and total plasma free fatty acid levels. Multivariate linear regression analysis was performed, controlling for age, sex, ethnicity and adiposity. RESULTS After adjustment, all adiposity measures were inversely associated with insulin sensitivity index (BMI: β = -0.357; waist circumference: β = -0.380; body fat mass: β = -0.375) and disposition index (BMI: β = -0.215; waist circumference: β = -0.248; body fat mass: β = -0.221) and positively associated with acute insulin response to glucose [BMI: β = 0.200; waist circumference: β = 0.195; body fat mass β = 0.209 (P values <0.001)]. Adiposity explained 13, 4 and 5% of the variation in insulin sensitivity index, acute insulin response to glucose and disposition index, respectively. After adjustment, no adiposity measure was associated with free fatty acid level, but total plasma free fatty acid level was inversely associated with insulin sensitivity index (β = -0.133), acute insulin response to glucose (β = -0.148) and disposition index [β = -0.218 (P values <0.01)]. Plasma free fatty acid concentration accounted for 1.5, 2 and 4% of the variation in insulin sensitivity index, acute insulin response to glucose and disposition index, respectively. CONCLUSIONS Plasma free fatty acid levels have a modest negative association with insulin sensitivity, β-cell secretion and disposition index but no association with adiposity measures. It is unlikely that plasma free fatty acids are the primary mediators of obesity-related insulin resistance or β-cell dysfunction.
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Affiliation(s)
- I Johns
- Nutrition and Dietetic Research Group, Imperial College London, London, UK
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Hatanaka M, Maier B, Sims EK, Templin AT, Kulkarni RN, Evans-Molina C, Mirmira RG. Palmitate induces mRNA translation and increases ER protein load in islet β-cells via activation of the mammalian target of rapamycin pathway. Diabetes 2014; 63:3404-15. [PMID: 24834975 PMCID: PMC4171659 DOI: 10.2337/db14-0105] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Saturated free fatty acids (FFAs) have complex effects on the islet β-cell, acutely promoting adaptive hyperplasia but chronically impairing insulin release. The acute effects of FFAs remain incompletely defined. To elucidate these early molecular events, we incubated mouse β-cells and islets with palmitate and then studied mRNA translation by polyribosomal profiling and analyzed signaling pathways by immunoblot analysis. We found that palmitate acutely increases polyribosome occupancy of total RNA, consistent with an increase in mRNA translation. This effect on translation was attributable to activation of mammalian target of rapamycin (mTOR) pathways via L-type Ca(2+) channels but was independent of insulin signaling. Longer incubations led to depletion of polyribosome-associated RNA, consistent with activation of the unfolded protein response (UPR). Pharmacologic inhibition of mTOR suppressed both the acute effects of palmitate on mRNA translation and the chronic effects on the UPR. Islets from mice fed a high-fat diet for 7 days showed increases in polyribosome-associated RNA and phosphorylation of S6K, both consistent with activation of mTOR. Our results suggest that palmitate acutely activates mRNA translation and that this increase in protein load contributes to the later UPR.
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Affiliation(s)
- Masayuki Hatanaka
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN
| | - Bernhard Maier
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN
| | - Emily K Sims
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN
| | - Andrew T Templin
- Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN
| | - Rohit N Kulkarni
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, MA
| | - Carmella Evans-Molina
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN Department of Medicine, Indiana University School of Medicine, Indianapolis, IN Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN
| | - Raghavendra G Mirmira
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN Department of Medicine, Indiana University School of Medicine, Indianapolis, IN Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN
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Nunemaker CS, Chung HG, Verrilli GM, Corbin KL, Upadhye A, Sharma PR. Increased serum CXCL1 and CXCL5 are linked to obesity, hyperglycemia, and impaired islet function. J Endocrinol 2014; 222:267-76. [PMID: 24928936 PMCID: PMC4135511 DOI: 10.1530/joe-14-0126] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Proinflammatory cytokines are thought to play a significant role in the pathogenesis of type 2 diabetes (T2D) and are elevated in the circulation even before the onset of the disease. However, the full complement of cytokines involved in the development of T2D is not known. In this study, 32 serum cytokines were measured from diabetes-prone BKS.Cg-m+/+Lepr(db)/J (db/db) mice and heterozygous age-matched control mice at 5 weeks (non-diabetic/non-obese), 6-7 weeks (transitional-to-diabetes), or 11 weeks (hyperglycemic/obese) and then correlated with body weight, blood glucose, and fat content. Among these 32 cytokines, C-X-C motif ligand 1 (CXCL1) showed the greatest increase (+78%) in serum levels between db/db mice that were hyperglycemic (blood glucose: 519±23 mg/dl, n=6) and those that were non-hyperglycemic (193±13 mg/dl, n=8). Similarly, increased CXCL1 (+68%) and CXCL5 (+40%) were associated with increased obesity in db/db mice; note that these effects could not be entirely separated from age. We then examined whether islets could be a source of these chemokines. Exposure to cytokines mimicking low-grade systemic inflammation (10 pg/ml IL1β+20 pg/ml IL6) for 48 h upregulated islet CXCL1 expression by 53±3-fold and CXCL5 expression by 83±10-fold (n=4, P<0.001). Finally, overnight treatment with the combination of CXCL1 and CXCL5 at serum levels was sufficient to produce a significant decrease in the peak calcium response to glucose stimulation, suggesting reduced islet function. Our findings demonstrated that CXCL1 and CXCL5 i) are increased in the circulation with the onset of T2D, ii) are produced by islets under stress, and iii) synergistically affect islet function, suggesting that these chemokines participate in the pathogenesis of T2D.
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Affiliation(s)
- Craig S Nunemaker
- Division of Endocrinology and MetabolismDepartment of MedicineDepartment of Biomedical EngineeringDepartment of BiologyUniversity of Virginia, PO Box 801413, Charlottesville, Virginia 22908, USA
| | - H Grace Chung
- Division of Endocrinology and MetabolismDepartment of MedicineDepartment of Biomedical EngineeringDepartment of BiologyUniversity of Virginia, PO Box 801413, Charlottesville, Virginia 22908, USADivision of Endocrinology and MetabolismDepartment of MedicineDepartment of Biomedical EngineeringDepartment of BiologyUniversity of Virginia, PO Box 801413, Charlottesville, Virginia 22908, USA
| | - Gretchen M Verrilli
- Division of Endocrinology and MetabolismDepartment of MedicineDepartment of Biomedical EngineeringDepartment of BiologyUniversity of Virginia, PO Box 801413, Charlottesville, Virginia 22908, USADivision of Endocrinology and MetabolismDepartment of MedicineDepartment of Biomedical EngineeringDepartment of BiologyUniversity of Virginia, PO Box 801413, Charlottesville, Virginia 22908, USA
| | - Kathryn L Corbin
- Division of Endocrinology and MetabolismDepartment of MedicineDepartment of Biomedical EngineeringDepartment of BiologyUniversity of Virginia, PO Box 801413, Charlottesville, Virginia 22908, USA
| | - Aditi Upadhye
- Division of Endocrinology and MetabolismDepartment of MedicineDepartment of Biomedical EngineeringDepartment of BiologyUniversity of Virginia, PO Box 801413, Charlottesville, Virginia 22908, USA
| | - Poonam R Sharma
- Division of Endocrinology and MetabolismDepartment of MedicineDepartment of Biomedical EngineeringDepartment of BiologyUniversity of Virginia, PO Box 801413, Charlottesville, Virginia 22908, USA
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Shimodaira M, Niwa T, Nakajima K, Kobayashi M, Hanyu N, Nakayama T. Serum Triglyceride Levels Correlated with the Rate of Change in Insulin Secretion Over Two Years in Prediabetic Subjects. ANNALS OF NUTRITION AND METABOLISM 2014; 64:38-43. [DOI: 10.1159/000360012] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Accepted: 01/26/2014] [Indexed: 11/19/2022]
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Sherwani SI, Aldana C, Usmani S, Adin C, Kotha S, Khan M, Eubank T, Scherer PE, Parinandi N, Magalang UJ. Intermittent hypoxia exacerbates pancreatic β-cell dysfunction in a mouse model of diabetes mellitus. Sleep 2013; 36:1849-58. [PMID: 24293759 DOI: 10.5665/sleep.3214] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
STUDY OBJECTIVES The effects of intermittent hypoxia (IH) on pancreatic function in the presence of diabetes and the underlying mechanisms are unclear. We hypothesized that IH would exacerbate pancreatic β-cell dysfunction and alter the fatty acids in the male Tallyho/JngJ (TH) mouse, a rodent model of type 2 diabetes. DESIGN TH mice were exposed for 14 d to either 8 h of IH or intermittent air (IA), followed by an intraperitoneal glucose tolerance test (IPGTT) and tissue harvest. The effect of IH on insulin release was determined by using a β3-adrenergic receptor (AR) agonist. MEASUREMENTS AND RESULTS During IH, pancreatic tissue pO2 decreased from 20.4 ± 0.9 to 5.7 ± 2.6 mm Hg, as determined by electron paramagnetic resonance oximetry. TH mice exposed to IH exhibited higher plasma glucose levels during the IPGTT (P < 0.001) while the insulin levels tended to be lower (P = 0.06). Pancreatic islets of the IH group showed an enhancement of the caspase-3 staining (P = 0.002). IH impaired the β-AR agonist-mediated insulin release (P < 0.001). IH increased the levels of the total free fatty acids and saturated fatty acids (palmitic and stearic acids), and decreased levels of the monounsaturated fatty acids in the pancreas and plasma. Ex vivo exposure of pancreatic islets to palmitic acid suppressed insulin secretion and decreased islet cell viability. CONCLUSIONS Intermittent hypoxia increases pancreatic apoptosis and exacerbates dysfunction in a polygenic rodent model of diabetes. An increase in free fatty acids and a shift in composition towards long chain saturated fatty acid species appear to mediate these effects.
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Affiliation(s)
- Shariq I Sherwani
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH ; Dorothy M. Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH
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Michaliszyn SF, Bonadonna RC, Sjaarda LA, Lee S, Farchoukh L, Arslanian SA. β-Cell lipotoxicity in response to free fatty acid elevation in prepubertal youth: African American versus Caucasian contrast. Diabetes 2013; 62:2917-22. [PMID: 23557704 PMCID: PMC3717834 DOI: 10.2337/db12-1664] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Prepubertal African American (AA) youth compared with their Caucasian (C) peers have higher insulin secretion, which correlates positively with free fatty acid (FFA) concentration. In our continued efforts to explain the racial disparity in insulinemia, and because FFAs modulate insulin secretion, we hypothesized that AA youth would have a greater response to FFA-induced β-cell insulin secretion than C youth. We compared the short-term effects of FFA elevation on fasting and glucose-stimulated C-peptide-modeled insulin secretion in prepubertal normal-weight AA versus C peers during a 2-h hyperglycemic clamp (12.5 mmol/L) on two occasions: 1) infusion of normal saline and 2) infusion of 20% intralipid (IL). During IL infusion, insulin sensitivity (IS) declined comparably in AA and C youth. Glucose sensitivity of first- and second-phase insulin secretion showed a significant condition × race interaction being higher in AA youth. Disposition index, β-cell function relative to IS, declined with IL infusion in AA and C youth, with a significantly greater decrease in Cs compared with AAs. In conclusion, AA and C prepubertal youth both demonstrated a decline in β-cell function relative to IS during IL infusion, indicative of acute lipotoxicity. The greater decline in C youth compared with AAs may suggest that C youth are more susceptible to β-cell lipotoxicity than AA youth, or alternatively, that AA youth are hypersensitive to FFA stimulation of β-cell insulin secretion, consistent with our theory.
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Affiliation(s)
- Sara F. Michaliszyn
- Division of Weight Management, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Riccardo C. Bonadonna
- Division of Endocrinology and Metabolic Disease, University of Verona School of Medicine, and Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Lindsey A. Sjaarda
- Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, Maryland
| | - SoJung Lee
- Division of Weight Management, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Lama Farchoukh
- Division of Weight Management, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Silva A. Arslanian
- Division of Weight Management, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
- Division of Pediatric Endocrinology, Metabolism & Diabetes Mellitus, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania
- Corresponding author: Silva A. Arslanian,
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Wagner R, Kaiser G, Gerst F, Christiansen E, Due-Hansen ME, Grundmann M, Machicao F, Peter A, Kostenis E, Ulven T, Fritsche A, Häring HU, Ullrich S. Reevaluation of fatty acid receptor 1 as a drug target for the stimulation of insulin secretion in humans. Diabetes 2013; 62:2106-11. [PMID: 23378609 PMCID: PMC3661642 DOI: 10.2337/db12-1249] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The role of free fatty acid receptor 1 (FFAR1/GPR40) in glucose homeostasis is still incompletely understood. Small receptor agonists stimulating insulin secretion are undergoing investigation for the treatment of type 2 diabetes. Surprisingly, genome-wide association studies did not discover diabetes risk variants in FFAR1. We reevaluated the role of FFAR1 in insulin secretion using a specific agonist, FFAR1-knockout mice and human islets. Nondiabetic individuals were metabolically phenotyped and genotyped. In vitro experiments indicated that palmitate and a specific FFAR1 agonist, TUG-469, stimulate glucose-induced insulin secretion through FFAR1. The proapoptotic effect of chronic exposure of β-cells to palmitate was independent of FFAR1. TUG-469 was protective, whereas inhibition of FFAR1 promoted apoptosis. In accordance with the proapoptotic effect of palmitate, in vivo cross-sectional observations demonstrated a negative association between fasting free fatty acids (NEFAs) and insulin secretion. Because NEFAs stimulate secretion through FFAR1, we examined the interaction of genetic variation in FFAR1 with NEFA and insulin secretion. The inverse association of NEFA and secretion was modulated by rs1573611 and became steeper for carriers of the minor allele. In conclusion, FFAR1 agonists support β-cell function, but variation in FFAR1 influences NEFA effects on insulin secretion and therefore could affect therapeutic efficacy of FFAR1 agonists.
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Affiliation(s)
- Robert Wagner
- University of Tübingen, Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholz Centre Munich at the University of Tübingen, Partner in the German Center for Diabetes Research, Tübingen, Germany
| | - Gabriele Kaiser
- University of Tübingen, Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, Tübingen, Germany
| | - Felicia Gerst
- University of Tübingen, Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholz Centre Munich at the University of Tübingen, Partner in the German Center for Diabetes Research, Tübingen, Germany
| | - Elisabeth Christiansen
- University of Southern Denmark, Department of Physics, Chemistry and Pharmacy, Odense M, Denmark
| | - Maria E. Due-Hansen
- University of Southern Denmark, Department of Physics, Chemistry and Pharmacy, Odense M, Denmark
| | - Manuel Grundmann
- University of Bonn, Institute for Pharmaceutical Biology, Bonn, Germany
| | - Fausto Machicao
- University of Tübingen, Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholz Centre Munich at the University of Tübingen, Partner in the German Center for Diabetes Research, Tübingen, Germany
| | - Andreas Peter
- University of Tübingen, Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholz Centre Munich at the University of Tübingen, Partner in the German Center for Diabetes Research, Tübingen, Germany
| | - Evi Kostenis
- University of Bonn, Institute for Pharmaceutical Biology, Bonn, Germany
| | - Trond Ulven
- University of Southern Denmark, Department of Physics, Chemistry and Pharmacy, Odense M, Denmark
| | - Andreas Fritsche
- University of Tübingen, Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholz Centre Munich at the University of Tübingen, Partner in the German Center for Diabetes Research, Tübingen, Germany
| | - Hans-Ulrich Häring
- University of Tübingen, Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholz Centre Munich at the University of Tübingen, Partner in the German Center for Diabetes Research, Tübingen, Germany
| | - Susanne Ullrich
- University of Tübingen, Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholz Centre Munich at the University of Tübingen, Partner in the German Center for Diabetes Research, Tübingen, Germany
- Corresponding author: Susanne Ullrich,
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Hughan KS, Bonadonna RC, Lee S, Michaliszyn SF, Arslanian SA. β-Cell lipotoxicity after an overnight intravenous lipid challenge and free fatty acid elevation in African American versus American white overweight/obese adolescents. J Clin Endocrinol Metab 2013; 98:2062-9. [PMID: 23526462 PMCID: PMC3644601 DOI: 10.1210/jc.2012-3492] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVE Overweight/obese (OW/OB) African American (AA) adolescents have a more diabetogenic insulin secretion/sensitivity pattern compared with their American white (AW) peers. The present study investigated β-cell lipotoxicity to test whether increased free fatty acid (FFA) levels result in greater β-cell dysfunction in AA vs AW OW/OB adolescents. RESEARCH DESIGN AND METHODS Glucose-stimulated insulin secretion was modeled, from glucose and C-peptide concentrations during a 2-hour hyperglycemic (225 mg/dL) clamp in 22 AA and 24 AW OW/OB adolescents, on 2 occasions after a 12-hour overnight infusion of either normal saline or intralipid (IL) in a random sequence. β-Cell function relative to insulin sensitivity, the disposition index (DI), was examined during normal saline and IL conditions. Substrate oxidation was evaluated with indirect calorimetry and body composition and abdominal adiposity with dual-energy X-ray absorptiometry and magnetic resonance imaging at L4-L5, respectively. RESULTS Age, sex, body mass index, total and sc adiposity were similar between racial groups, but visceral adiposity was significantly lower in AAs. During IL infusion, FFAs and fat oxidation increased and insulin sensitivity decreased similarly in AAs and AWs. β-Cell glucose sensitivity of first- and second-phase insulin secretion did not change significantly during IL infusion in either group, but DI in each phase decreased significantly and similarly in AAs and AWs. CONCLUSIONS Overweight/obese AA and AW adolescents respond to an overnight fat infusion with significant declines in insulin sensitivity, DI, and β-cell function relative to insulin sensitivity, suggestive of β-cell lipotoxicity. However, contrary to our hypothesis, there does not seem to be a race differential in β-cell lipotoxicity. Longer durations of FFA elevation may unravel such race-related contrasts.
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Affiliation(s)
- Kara S Hughan
- Division of Weight Management and Wellness, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224, USA
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Librán-Pérez M, López-Patiño MA, Míguez JM, Soengas JL. In vitro response of putative fatty acid-sensing systems in rainbow trout liver to increased levels of oleate or octanoate. Comp Biochem Physiol A Mol Integr Physiol 2013; 165:288-94. [PMID: 23542747 DOI: 10.1016/j.cbpa.2013.03.024] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Revised: 03/20/2013] [Accepted: 03/21/2013] [Indexed: 12/25/2022]
Abstract
In a previous study we provided evidence for the presence in liver of rainbow trout of fatty acid (FA) sensing systems responding to changes in levels of oleate (long-chain FA) or octanoate (medium-chain FA). Since those effects could be attributed to an indirect effect, we have evaluated in the present study in vitro (in the absence of extrahepatic regulatory mechanisms) whether or not liver responds to changes in FA concentration in a way similar to that previously observed in vivo. Accordingly, liver slices were exposed to increased oleate or octanoate concentrations to evaluate changes in parameters related to FA metabolism, FA transport, nuclear receptors and transcription factors, ROS effectors, and glucose metabolism. The responses observed in vitro in liver were in general not coincident with those previously observed in vivo allowing us to suggest that FA sensing capacity of liver in vivo is of indirect nature and could be related among other reasons to an interaction with other endocrine systems and/or to FA sensing in hypothalamus.
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Affiliation(s)
- Marta Librán-Pérez
- Laboratorio de Fisioloxía Animal, Departamento de Bioloxía Funcional e Ciencias da Saúde, Facultade de Bioloxía, Universidade de Vigo, E-36310 Vigo, Spain
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Cui W, Ma J, Wang X, Yang W, Zhang J, Ji Q. Free fatty acid induces endoplasmic reticulum stress and apoptosis of β-cells by Ca2+/calpain-2 pathways. PLoS One 2013; 8:e59921. [PMID: 23527285 PMCID: PMC3604010 DOI: 10.1371/journal.pone.0059921] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2012] [Accepted: 02/19/2013] [Indexed: 12/28/2022] Open
Abstract
Dysfunction of β-cells is a major characteristic in the pathogenesis of type 2 diabetes mellitus (T2DM). The combination of obesity and T2DM is associated with elevated plasma free fatty acids (FFAs). However, molecular mechanisms linking FFAs to β-cell dysfunction remain poorly understood. In the present study, we identified that the major endoplasmic reticulum stress (ERS) marker, Grp78 and ERS-induced apoptotic factor, CHOP, were time-dependently increased by exposure of β-TC3 cells to FFA. The expression of ATF6 and the phosphorylation levels of PERK and IRE1, which trigger ERS signaling, markedly increased after FFA treatments. FFA treatments increased cell apoptosis by inducing ERS in β-TC3 cells. We also found that FFA-induced ERS was mediated by the store-operated Ca2+ entry through promoting the association of STIM1 and Orai1. Moreover, calpain-2 was required for FFA-induced expression of CHOP and activation of caspase-12 and caspase-3, thus promoting cell apoptosis in β-TC3 cells. Together, these results reveal pivotal roles for Ca2+/calpain-2 pathways in modulating FFA-induced β-TC3 cell ERS and apoptosis.
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Affiliation(s)
- Wei Cui
- Department of Endocrinology and Metabolism, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Jie Ma
- Department of Neurosurgery, Tangdu Hospital, Forth Military Medical University, Xi’an, China
| | - Xingqin Wang
- Department of Neurosurgery, Tangdu Hospital, Forth Military Medical University, Xi’an, China
| | - Wenjuan Yang
- Department of Endocrinology and Metabolism, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Jing Zhang
- No. 371 Central Hospital of People’s Liberation Army, Xinxiang, China
| | - Qiuhe Ji
- Department of Endocrinology and Metabolism, Xijing Hospital, Fourth Military Medical University, Xi’an, China
- * E-mail:
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Osto M, Zini E, Reusch CE, Lutz TA. Diabetes from humans to cats. Gen Comp Endocrinol 2013; 182:48-53. [PMID: 23247272 DOI: 10.1016/j.ygcen.2012.11.019] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2012] [Revised: 11/27/2012] [Accepted: 11/30/2012] [Indexed: 01/04/2023]
Abstract
Diabetes mellitus is a common endocrinopathy in humans and in cats. The general prevalence of diabetes mellitus, and in particular of type 2 diabetes, has risen dramatically in recent years. This increase has often been linked to the rise in the obesity pandemic because obesity and the ensuing metabolic consequences constitute major risk factors for human type 2 and for feline diabetes. Feline diabetes shares many features of human type 2 diabetes in respect to its pathophysiology, underlying risk factors and treatment strategies. This review will briefly summarize major characteristics in the human and the feline disease and where available, point out the current knowledge on similarities and differences.
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Affiliation(s)
- M Osto
- Vetsuisse Faculty, Institute of Veterinary Physiology, University of Zurich, Switzerland.
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Response of hepatic lipid and glucose metabolism to a mixture or single fatty acids: Possible presence of fatty acid-sensing mechanisms. Comp Biochem Physiol A Mol Integr Physiol 2012; 164:241-8. [PMID: 23010243 DOI: 10.1016/j.cbpa.2012.09.012] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2012] [Revised: 09/17/2012] [Accepted: 09/17/2012] [Indexed: 12/22/2022]
Abstract
To assess the hypothesis that an acute dietary fatty acid (FA) supply may improve glucose tolerance in rainbow trout, we orally administered fish with fish oil (FO; 10mL.kg(-1), one time), which were then subjected to a glucose tolerance test and sampled 6h after injection. Parameters related to glucose and lipid metabolism were then assessed. The results suggest that when both nutrients were administered at the same time, an increased potential for lipogenesis occurred concomitantly with a lower level of glycaemia. In a second experiment we administered intraperitoneally a single FA present in the FO mixture such as oleic acid (60 or 300μg.kg(-1)) whereas octanoic acid (60 or 300μg.kg(-1)) was used as negative control (absent from the FO). However, the effects of both FA were similar in reducing the potential of lipid synthesis and oxidation, and in enhancing the potential of glucose synthesis and glycogenesis. Differences found between FO and single FA administration show that response to FA was dependent on the treatment (mixture vs. single FA) but also comply with the idea that an interaction between FA and glucose rather than FA alone are in the origin of the results reported. The administration of individual FA such as oleic and octanoic acid failed in enhancing lipogenesis and reducing plasma glucose levels and thus in explaining results obtained with FO. However, results provide evidence that FA even provided at a low dose play a key role in the regulation of several putative components of a FA sensing system present in rainbow trout liver.
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Salgin B, Ong KK, Thankamony A, Emmett P, Wareham NJ, Dunger DB. Higher fasting plasma free fatty acid levels are associated with lower insulin secretion in children and adults and a higher incidence of type 2 diabetes. J Clin Endocrinol Metab 2012; 97:3302-9. [PMID: 22740706 DOI: 10.1210/jc.2012-1428] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
CONTEXT There are limited data in humans on the association between fasting free fatty acid (FFA) levels and pancreatic β-cell function. OBJECTIVE Our objective was to examine this association in children and adults with normal glucose tolerance and to explore fasting FFA levels in relation to subsequent risk of impaired glucose tolerance (IGT) and type 2 diabetes (T2D). DESIGN We measured FFA, glucose, and insulin levels after an overnight fast and 30 min after an oral glucose load in 797 children aged 8 yr in the Avon Longitudinal Study of Parents and Children and 770 adults aged 44-71 yr in the Medical Research Council Ely Study. We calculated the homeostasis model assessment to estimate fasting insulin sensitivity, the insulinogenic index to estimate insulin secretion, and the disposition index to assess insulin secretion corrected for insulin sensitivity. RESULTS Higher fasting FFA levels were associated with lower insulin secretion in children (boys, P = 0.03; girls, P = 0.001) and adults (men, P = 0.03, women, P = 0.04). Associations with insulin sensitivity were more variable, but after adjustment for insulin sensitivity, higher fasting FFA levels remained associated with lower insulin secretion (disposition index). Compared with adults in the lowest tertile of fasting FFA levels, those in the middle and highest tertiles had a 3-fold higher incidence of IGT or T2D over the following 5-8 yr. CONCLUSIONS Higher fasting FFA levels were consistently associated with lower insulin secretion in children and adults with normal glucose tolerance. Furthermore, higher fasting FFA levels were prospectively associated with a greater risk of subsequent IGT and T2D.
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Affiliation(s)
- Burak Salgin
- University Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
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Piro S, Rabuazzo AM, Renis M, Purrello F. Effects of metformin on oxidative stress, adenine nucleotides balance, and glucose-induced insulin release impaired by chronic free fatty acids exposure in rat pancreatic islets. J Endocrinol Invest 2012; 35:504-10. [PMID: 21750398 DOI: 10.3275/7866] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND In rat pancreatic islets, chronic exposure to high free fatty acid (FFA) levels impairs insulin secretion and β cell mass. The mechanisms underlying this defect are not completely understood. Since islets have intrinsically low anti-oxidant enzyme defense, oxidative stress might be responsible for β cell damage. AIM In this study, we investigated if FFA could induce oxidative stress in rat pancreatic islets and if metformin might reverse adverse effects. MATERIAL AND METHODS We cultured rat pancreatic islets in the presence or absence of FFA (oleate/palmitate 2:1, 2 mM) for 72 h. In some experiments, we used metformin (2.5 μg/ml) during the last 24 h. RESULTS In our model, glucosestimu lated insulin release was markedly reduced (p<0.005) after chronic FFA exposure, and the ATP/ADP ratio was altered (p<0.05). We observed a significant increase of reactive oxygen species (ROS) (p<0.001), malondialdehyde a lipid peroxidation product (p<0.01) and nitric oxide (NO) levels in the culture media (p<0.001). Inducible NO synthase (iNOS) and heat shock protein-70 (HSP-70) protein expression were also increased (p<0.001 and p<0.01, respectively). When metformin was present during the last 24 h of culture, insulin secretion was restored, and the ATP/ADP ratio was normalized. ROS production, NO production, lipid peroxidation, iNOS and HSP-70 protein expression levels had decreased. CONCLUSIONS These data indicate that, in rat pancreatic islets, chronic exposure to high FFA induces oxidative stress and that metformin, by reducing this effect, may have a direct beneficial effect on insulin secretion impaired by lipotoxicity.
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Affiliation(s)
- S Piro
- Department of Clinical and Molecular Biomedicine, Laboratory of Molecular Medicine, University of Catania, Garibaldi-Nesima Hospital, Via Palermo 636-95122, Catania, Italy
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FSP27 promotes lipid droplet clustering and then fusion to regulate triglyceride accumulation. PLoS One 2011; 6:e28614. [PMID: 22194867 PMCID: PMC3237475 DOI: 10.1371/journal.pone.0028614] [Citation(s) in RCA: 98] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Accepted: 11/11/2011] [Indexed: 02/08/2023] Open
Abstract
Fat Specific Protein 27 (FSP27), a lipid droplet (LD) associated protein in adipocytes, regulates triglyceride (TG) storage. In the present study we demonstrate that FSP27 plays a key role in LD morphology to accumulate TGs. We show here that FSP27 promotes clustering of the LDs which is followed by their fusion into fewer and enlarged droplets. To map the domains of FSP27 responsible for these events, we generated GFP-fusion constructs of deletion mutants of FSP27. Microscopic analysis revealed that amino acids 173–220 of FSP27 are necessary and sufficient for both the targeting of FSP27 to LDs and the initial clustering of the droplets. Amino acids 120–140 are essential but not sufficient for LD enlargement, whereas amino acids 120–210 are necessary and sufficient for both clustering and fusion of LDs to form enlarged droplets. In addition, we found that FSP27-mediated enlargement of LDs, but not their clustering, is associated with triglyceride accumulation. These results suggest a model in which FSP27 facilitates LD clustering and then promotes their fusion to form enlarged droplets in two discrete, sequential steps, and a subsequent triglyceride accumulation.
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Lopez X, Cypess A, Manning R, O'Shea S, Kulkarni RN, Goldfine AB. Exogenous insulin enhances glucose-stimulated insulin response in healthy humans independent of changes in free fatty acids. J Clin Endocrinol Metab 2011; 96:3811-21. [PMID: 21956413 PMCID: PMC3232618 DOI: 10.1210/jc.2011-0627] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Islet β-cells express both insulin receptors and insulin signaling proteins. Recent studies suggest insulin signaling is physiologically important for glucose sensing. OBJECTIVE Preexposure to insulin enhances glucose-stimulated insulin secretion (GSIS) in healthy humans. We evaluated whether the effect of insulin to potentiate GSIS is modulated through regulation of free fatty acids (FFA). DESIGN AND SETTING Subjects were studied on three occasions in this single-site study at an academic institution clinical research center. PATIENTS Subjects included nine healthy volunteers. INTERVENTIONS Glucose-induced insulin response was assessed on three occasions after 4 h saline (low insulin/sham) or isoglycemic-hyperinsulinemic (high insulin) clamps with or without intralipid and heparin infusion, using B28 Asp-insulin that could be distinguished from endogenous insulin immunologically. During the last 80 min of all three clamps, additional glucose was administered to stimulate insulin secretion (GSIS) with glucose concentrations maintained at similar concentrations during all studies. MAIN OUTCOME MEASURE β-Cell response to glucose stimulation was assessed. RESULTS Preexposure to exogenous insulin increased the endogenous insulin-secretory response to glucose by 32% compared with sham clamp (P = 0.001). This was accompanied by a drop in FFA during hyperinsulinemic clamp compared with the sham clamp (0.06 ± 0.02 vs. 0.60 ± 0.09 mEq/liter, respectively), which was prevented during the hyperinsulinemic clamp with intralipid/heparin infusion (1.27 ± 0.17 mEq/liter). After preexposure to insulin with intralipid/heparin infusion to maintain FFA concentration, GSIS was 21% higher compared with sham clamp (P < 0.04) and similar to preexposure to insulin without intralipid/heparin (P = 0.2). CONCLUSIONS Insulin potentiates glucose-stimulated insulin response independent of FFA concentrations in healthy humans.
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Affiliation(s)
- Ximena Lopez
- Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts 02215, USA
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van Raalte DH, Diamant M. Glucolipotoxicity and beta cells in type 2 diabetes mellitus: target for durable therapy? Diabetes Res Clin Pract 2011; 93 Suppl 1:S37-46. [PMID: 21864750 DOI: 10.1016/s0168-8227(11)70012-2] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is characterised by beta-cell failure in the setting of obesity-related insulin resistance. Progressive beta-cell dysfunction determines the course of the disease, regardless of the treatment used. There is mounting evidence that chronically elevated circulating levels of glucose and fatty acids contribute to relentless beta-cell function decline, by endorsing processes commonly referred to as glucolipotoxicity. Mechanisms related to glucolipotoxicity include endoplasmic reticulum (ER) stress, oxidative stress, mitochondrial dysfunction and islet inflammation. The most commonly prescribed blood-glucose lowering agents, metformin and sul-fonylurea, may temporarily improve glycaemic control, however, these drugs do not alter the continuous decline in beta-cell function in T2DM patients. Evidence exists that novel classes of drugs, the thiazolidinediones (TZDs) and incretin-based therapies, may be able to preserve beta-cell function and functional beta-cell mass, amongst others by reducing glucolipotoxicity in the beta cell. The durability of the effects of TZDs and incretin-based therapies on beta-cell function, whether given as monotherapy or combined with other treatment, should be addressed in future, long-term clinical studies.
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Affiliation(s)
- Daniel H van Raalte
- Diabetes Centre, Department of Internal Medicine, VU University Medical Centre, Amsterdam, The Netherlands.
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