|
1
|
Hyder A, Sheta B, Eissa M, Schrezenmeir J. Silencing the FABP3 gene in insulin-secreting cells reduces fatty acid uptake and protects against lipotoxicity. Acta Diabetol 2024; 61:1577-1588. [PMID: 38960943 PMCID: PMC11628584 DOI: 10.1007/s00592-024-02325-x] [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: 02/20/2024] [Accepted: 06/18/2024] [Indexed: 07/05/2024]
Abstract
BACKGROUND Long-term exposure of pancreatic islets to fatty acids (FAs), common in obesity, metabolic syndrome, and type 2 diabetes, leads to a compensatory hyperactivity followed by inflammation, apoptosis, dysfunctional beta cells, and results in insulin dependence of the patient. Restriction of fatty uptake by islet beta cells may protect them from lipotoxicity. PURPOSE Pancreatic islet beta cells express the fatty acid binding protein 3 (FABP3) to bind FAs and to orchestrate lipid signals. Based on this, we investigated whether downregulation of FABP3, by Fabp3 silencing, might slow lipid metabolism and protect against lipotoxicity in insulin-secreting cells. RESULTS Neither Fabp3 silencing, nor overexpression affected the glucose-stimulated insulin secretion in absence of FAs. Fabp3 silencing decreased FA-uptake, lipid droplets formation, and the expression of the lipid accumulation-regulating gene Dgat1 in Ins1E cells. It reduced FA-induced inflammation by deactivation of NF-κB, which was associated with upregulation of IκBα and deactivation of the NF-κB p65 nuclear translocation, and the downregulation of the cytokines ILl-6, IL-1β, and TNFα. Ins1E cells were protected from the FA-induced apoptosis as assessed by different parameters including DNA degradation and cleaved caspase-3 immunoblotting. Furthermore, FABP3 silencing improved the viability, Pdx1 gene expression, and the insulin-secreting function in cells long-term cultured with palmitic acid. All results were confirmed by the opposite action rendered by FABP3 overexpression. CONCLUSION The present data reveals that pancreatic beta cells can be protected from lipotoxicity by inhibition of FA-uptake, intracellular utilization and accumulation. FABP3 inhibition, hence, may be a useful pharmaceutical approach in obesity, metabolic syndrome, and type 2 diabetes.
Collapse
Affiliation(s)
- Ayman Hyder
- Faculty of Science, Damietta University, New Damietta, 34517, Egypt.
| | - Basma Sheta
- Faculty of Science, Damietta University, New Damietta, 34517, Egypt
| | - Manar Eissa
- Faculty of Science, Damietta University, New Damietta, 34517, Egypt
| | | |
Collapse
|
|
2
|
Jiménez-Sánchez C, Oberhauser L, Maechler P. Role of fatty acids in the pathogenesis of ß-cell failure and Type-2 diabetes. Atherosclerosis 2024; 398:118623. [PMID: 39389828 DOI: 10.1016/j.atherosclerosis.2024.118623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 10/02/2024] [Accepted: 10/03/2024] [Indexed: 10/12/2024]
Abstract
Pancreatic ß-cells are glucose sensors in charge of regulated insulin delivery to the organism, achieving glucose homeostasis and overall energy storage. The latter function promotes obesity when nutrient intake chronically exceeds daily expenditure. In case of ß-cell failure, such weight gain may pave the way for the development of Type-2 diabetes. However, the causal link between excessive body fat mass and potential degradation of ß-cells remains largely unknown and debated. Over the last decades, intensive research has been conducted on the role of lipids in the pathogenesis of ß-cells, also referred to as lipotoxicity. Among various lipid species, the usual suspects are essentially the non-esterified fatty acids (NEFA), in particular the saturated ones such as palmitate. This review describes the fundamentals and the latest advances of research on the role of fatty acids in ß-cells. This includes intracellular pathways and receptor-mediated signaling, both participating in regulated glucose-stimulated insulin secretion as well as being implicated in ß-cell dysfunction. The discussion extends to the contribution of high glucose exposure, or glucotoxicity, to ß-cell defects. Combining glucotoxicity and lipotoxicity results in the synergistic and more deleterious glucolipotoxicity effect. In recent years, alternative roles for intracellular lipids have been uncovered, pointing to a protective function in case of nutrient overload. This requires dynamic storage of NEFA as neutral lipid droplets within the ß-cell, along with active glycerolipid/NEFA cycle allowing subsequent recruitment of lipid species supporting glucose-stimulated insulin secretion. Overall, the latest studies have revealed the two faces of the same coin.
Collapse
Affiliation(s)
- Cecilia Jiménez-Sánchez
- Department of Cell Physiology and Metabolism & Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland
| | - Lucie Oberhauser
- Department of Cell Physiology and Metabolism & Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland
| | - Pierre Maechler
- Department of Cell Physiology and Metabolism & Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland.
| |
Collapse
|
|
3
|
Velagapudi S, Karsai G, Karsai M, Mohammed SA, Montecucco F, Liberale L, Lee H, Carbone F, Adami GF, Yang K, Crucet M, Stein S, Paneni F, Lapikova-Bryhinska T, Jang HD, Kraler S, Vdovenko D, Züllig RA, Camici GG, Kim HS, Laaksonen R, Gerber PA, Hornemann T, Akhmedov A, Lüscher TF. Inhibition of de novo ceramide synthesis by sirtuin-1 improves beta-cell function and glucose metabolism in type 2 diabetes. Cardiovasc Res 2024; 120:1265-1278. [PMID: 38739545 DOI: 10.1093/cvr/cvae100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 03/03/2024] [Accepted: 03/26/2024] [Indexed: 05/16/2024] Open
Abstract
AIMS Obesity and type 2 diabetes (T2D) are major risk factors for cardiovascular (CV) diseases. Dysregulated pro-apoptotic ceramide synthesis reduces β-cell insulin secretion, thereby promoting hyperglycaemic states that may manifest as T2D. Pro-apoptotic ceramides modulate insulin sensitivity and glucose tolerance while being linked to poor CV outcomes. Sirtuin-1 (SIRT1) is a NAD + -dependent deacetylase that protects against pancreatic β-cell dysfunction; however, systemic levels are decreased in obese-T2D mice and may promote pro-apoptotic ceramide synthesis and hyperglycaemia. Herein, we aimed to assess the effects of restoring circulating SIRT1 levels to prevent metabolic imbalance in obese and diabetic mice. METHODS AND RESULTS Circulating SIRT1 levels were reduced in obese-diabetic mice (db/db) as compared to age-matched non-diabetic db/+ controls. Restoration of SIRT1 plasma levels with recombinant murine SIRT1 for 4 weeks prevented body weight gain and improved glucose tolerance, insulin sensitivity, and vascular function in mice models of obesity and T2D. Untargeted lipidomics revealed that SIRT1 restored insulin secretory function of β-cells by reducing synthesis and accumulation of pro-apoptotic ceramides. Molecular mechanisms involved direct binding to and deacetylation of Toll-like receptor 4 (TLR4) by SIRT1 in β-cells, thereby decreasing the rate-limiting enzymes of sphingolipid synthesis SPTLC1/2 via AKT/NF-κB. Among patients with T2D, those with high baseline plasma levels of SIRT1 prior to metabolic surgery displayed restored β-cell function (HOMA2-β) and were more likely to have T2D remission during follow-up. CONCLUSION Acetylation of TLR4 promotes β-cell dysfunction via ceramide synthesis in T2D, which is blunted by systemic SIRT1 replenishment. Hence, restoration of systemic SIRT1 may provide a novel therapeutic strategy to counteract toxic ceramide synthesis and mitigate CV complications of T2D.
Collapse
Affiliation(s)
- Srividya Velagapudi
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
| | - Gergely Karsai
- Institute of Clinical Chemistry, University Hospital Zürich, Zürich, Switzerland
| | - Maria Karsai
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zürich and University of Zürich, Zürich, Switzerland
| | - Shafeeq A Mohammed
- Department of Cardiology, Center for Translational and Experimental Cardiology (CTEC), Zurich University Hospital and University of Zürich, Zürich, Switzerland
| | - Fabrizio Montecucco
- Department of Internal Medicine, First Clinic of Internal Medicine, University of Genoa School of Medicine, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genoa-Italian Cardiovascular Network, Genoa, Italy
| | - Luca Liberale
- Department of Internal Medicine, First Clinic of Internal Medicine, University of Genoa School of Medicine, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genoa-Italian Cardiovascular Network, Genoa, Italy
| | - Hwan Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Federico Carbone
- Department of Internal Medicine, First Clinic of Internal Medicine, University of Genoa School of Medicine, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genoa-Italian Cardiovascular Network, Genoa, Italy
| | - Giovanni Francesco Adami
- Department of Internal Medicine, First Clinic of Internal Medicine, University of Genoa School of Medicine, Genoa, Italy
| | - Kangmin Yang
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
| | - Margot Crucet
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
| | - Sokrates Stein
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
| | - Franceso Paneni
- Department of Cardiology, Center for Translational and Experimental Cardiology (CTEC), Zurich University Hospital and University of Zürich, Zürich, Switzerland
| | | | - Hyun-Duk Jang
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Simon Kraler
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
| | - Daria Vdovenko
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
| | - Richard Arnold Züllig
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zürich and University of Zürich, Zürich, Switzerland
| | - Giovanni G Camici
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
| | - Hyo-Soo Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Reijo Laaksonen
- Zora Biosciences and Finnish Cardiovascular Research Center, Finland Medical School, Tampere University, Tampere, Finland
| | - Philipp A Gerber
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zürich and University of Zürich, Zürich, Switzerland
| | - Thorsten Hornemann
- Institute of Clinical Chemistry, University Hospital Zürich, Zürich, Switzerland
| | - Alexander Akhmedov
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
| | - Thomas F Lüscher
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
- Royal Brompton and Harefield Hospitals, Imperial College and King's College, London, United Kingdom
| |
Collapse
|
|
4
|
Sadafi S, Azizi A, Najafi F, Pasdar Y. Lipid accumulation product and type 2 diabetes risk: a population-based study. BMC Endocr Disord 2024; 24:147. [PMID: 39134995 PMCID: PMC11318136 DOI: 10.1186/s12902-024-01682-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Accepted: 08/07/2024] [Indexed: 08/16/2024] Open
Abstract
BACKGROUND The Lipid Accumulation Product (LAP) is a measure that indicates excessive fat accumulation in the body. LAP has been the focus of research in epidemiological studies aimed at forecasting chronic and metabolic diseases. This study aimed to evaluate the association between LAP and type 2 diabetes mellitus (T2DM) among adults in western Iran. METHODS The study involved 9,065 adults who participated in the initial phase of the Ravansar non-communicable diseases study (RaNCD) cohort. To investigate the association between LAP and T2DM, multiple logistic regressions were employed. Additionally, the receiver operating characteristic (ROC) curve was used to evaluate LAP's predictive ability concerning T2DM. RESULTS The participants had an average age of 47.24 ± 8.27 years, comprising 49.30% men and 50.70% women. The mean LAP was 53.10 ± 36.60 for the healthy group and 75.51 ± 51.34 for the diabetic group (P < 0.001). The multiple regression analysis revealed that the odds of T2DM in the second quartile of LAP were 1.69 (95% CI: 1.25, 2.29) times greater than in the first quartile. Furthermore, the odds in the third and fourth quartiles were 2.67 (95% CI: 2.01, 3.55) and 3.73 (95% CI: 2.83, 4.92) times higher, respectively. The ROC analysis for predicting T2DM showed that the LAP index had an area under the curve (AUC) of 0.66 (95% CI: 0.64, 0.68). CONCLUSION A strong association was identified between elevated LAP levels and T2DM in the adult population of western Iran. LAP is recommended as a potential tool for screening diabetes susceptibility.
Collapse
Affiliation(s)
- Sepehr Sadafi
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Social Development and Health Promotion Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ali Azizi
- Social Development and Health Promotion Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
- Department of Community and Family Medicine, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Farid Najafi
- Research Center for Environmental Determinants of Health (RCEDH), Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Yahya Pasdar
- Research Center for Environmental Determinants of Health (RCEDH), Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| |
Collapse
|
|
5
|
Rivera Nieves AM, Wauford BM, Fu A. Mitochondrial bioenergetics, metabolism, and beyond in pancreatic β-cells and diabetes. Front Mol Biosci 2024; 11:1354199. [PMID: 38404962 PMCID: PMC10884328 DOI: 10.3389/fmolb.2024.1354199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 01/17/2024] [Indexed: 02/27/2024] Open
Abstract
In Type 1 and Type 2 diabetes, pancreatic β-cell survival and function are impaired. Additional etiologies of diabetes include dysfunction in insulin-sensing hepatic, muscle, and adipose tissues as well as immune cells. An important determinant of metabolic health across these various tissues is mitochondria function and structure. This review focuses on the role of mitochondria in diabetes pathogenesis, with a specific emphasis on pancreatic β-cells. These dynamic organelles are obligate for β-cell survival, function, replication, insulin production, and control over insulin release. Therefore, it is not surprising that mitochondria are severely defective in diabetic contexts. Mitochondrial dysfunction poses challenges to assess in cause-effect studies, prompting us to assemble and deliberate the evidence for mitochondria dysfunction as a cause or consequence of diabetes. Understanding the precise molecular mechanisms underlying mitochondrial dysfunction in diabetes and identifying therapeutic strategies to restore mitochondrial homeostasis and enhance β-cell function are active and expanding areas of research. In summary, this review examines the multidimensional role of mitochondria in diabetes, focusing on pancreatic β-cells and highlighting the significance of mitochondrial metabolism, bioenergetics, calcium, dynamics, and mitophagy in the pathophysiology of diabetes. We describe the effects of diabetes-related gluco/lipotoxic, oxidative and inflammation stress on β-cell mitochondria, as well as the role played by mitochondria on the pathologic outcomes of these stress paradigms. By examining these aspects, we provide updated insights and highlight areas where further research is required for a deeper molecular understanding of the role of mitochondria in β-cells and diabetes.
Collapse
Affiliation(s)
- Alejandra María Rivera Nieves
- Diabetes Center of Excellence, University of Massachusetts Chan Medical School, Worcester, MA, United States
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, United States
| | - Brian Michael Wauford
- Diabetes Center of Excellence, University of Massachusetts Chan Medical School, Worcester, MA, United States
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, United States
| | - Accalia Fu
- Diabetes Center of Excellence, University of Massachusetts Chan Medical School, Worcester, MA, United States
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, United States
| |
Collapse
|
|
6
|
Yildirim V, Sheraton VM, Brands R, Crielaard L, Quax R, van Riel NA, Stronks K, Nicolaou M, Sloot PM. A data-driven computational model for obesity-driven diabetes onset and remission through weight loss. iScience 2023; 26:108324. [PMID: 38026205 PMCID: PMC10665812 DOI: 10.1016/j.isci.2023.108324] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 08/22/2023] [Accepted: 10/20/2023] [Indexed: 12/01/2023] Open
Abstract
Obesity is a major risk factor for the development of type 2 diabetes (T2D), where a sustained weight loss may result in T2D remission in individuals with obesity. To design effective and feasible intervention strategies to prevent or reverse T2D, it is imperative to study the progression of T2D and remission together. Unfortunately, this is not possible through experimental and observational studies. To address this issue, we introduce a data-driven computational model and use human data to investigate the progression of T2D with obesity and remission through weight loss on the same timeline. We identify thresholds for the emergence of T2D and necessary conditions for remission. We explain why remission is only possible within a window of opportunity and the way that window depends on the progression history of T2D, individual's metabolic state, and calorie restrictions. These findings can help to optimize therapeutic intervention strategies for T2D prevention or treatment.
Collapse
Affiliation(s)
- Vehpi Yildirim
- Department of Public and Occupational Health, Amsterdam University Medical Centers, University of Amsterdam, 1081 BT Amsterdam, the Netherlands
- Institute for Advanced Study, University of Amsterdam, 1012 GC Amsterdam, the Netherlands
| | - Vivek M. Sheraton
- Institute for Advanced Study, University of Amsterdam, 1012 GC Amsterdam, the Netherlands
- Computational Science Lab, University of Amsterdam, 1098 XH Amsterdam, the Netherlands
- Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers, 1100 DD Amsterdam, the Netherlands
| | - Ruud Brands
- AMRIF B.V., Agro Business Park, 6708 PW Wageningen, the Netherlands
- Institute for Risk Assessment Sciences, Utrecht University, 3584 CL Utrecht, the Netherlands
| | - Loes Crielaard
- Department of Public and Occupational Health, Amsterdam University Medical Centers, University of Amsterdam, 1081 BT Amsterdam, the Netherlands
- Institute for Advanced Study, University of Amsterdam, 1012 GC Amsterdam, the Netherlands
| | - Rick Quax
- Institute for Advanced Study, University of Amsterdam, 1012 GC Amsterdam, the Netherlands
- Computational Science Lab, University of Amsterdam, 1098 XH Amsterdam, the Netherlands
| | - Natal A.W. van Riel
- Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, the Netherlands
- Department of Experimental and Vascular Medicine, Amsterdam University Medical Centers, 1100 DD Amsterdam, the Netherlands
| | - Karien Stronks
- Department of Public and Occupational Health, Amsterdam University Medical Centers, University of Amsterdam, 1081 BT Amsterdam, the Netherlands
- Institute for Advanced Study, University of Amsterdam, 1012 GC Amsterdam, the Netherlands
| | - Mary Nicolaou
- Department of Public and Occupational Health, Amsterdam University Medical Centers, University of Amsterdam, 1081 BT Amsterdam, the Netherlands
- Institute for Advanced Study, University of Amsterdam, 1012 GC Amsterdam, the Netherlands
| | - Peter M.A. Sloot
- Institute for Advanced Study, University of Amsterdam, 1012 GC Amsterdam, the Netherlands
- Computational Science Lab, University of Amsterdam, 1098 XH Amsterdam, the Netherlands
| |
Collapse
|
|
7
|
Zeng Y, Yin L, Yin X, Zhao D. Association of triglyceride-glucose index levels with gestational diabetes mellitus in the US pregnant women: a cross-sectional study. Front Endocrinol (Lausanne) 2023; 14:1241372. [PMID: 37881497 PMCID: PMC10597685 DOI: 10.3389/fendo.2023.1241372] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 09/25/2023] [Indexed: 10/27/2023] Open
Abstract
Objective This investigation aimed to assess the correlation between the triglyceride-glucose (TyG) index and gestational diabetes mellitus (GDM) in pregnant women in the United States. Methods We calculated the TyG index utilizing data from pregnant women who participated in the National Health and Nutrition Examination Survey (NHANES) through 1999 to March 2020, and then employed multivariate logistic regression, smoothed curve fitting, and subgroup analysis to investigate the association between the TyG index and gestational diabetes during pregnancy. Results Logistic regression models revealed a positive association between the TyG index and GDM, remaining significant even after adjusting for all confounding variables (OR=3.43, 95% CI: 1.20-9.85, P = 0.0216). Subgroup analysis demonstrated consistent correlations and showed that there is no difference in the TyG index among first trimester subgroup. The TyG index had limited diagnostic efficacy for GDM (AUC=0.57, 95% CI: 0.50-0.63). Conclusion The TyG index correlates positively with the GDM, however its diagnostic efficacy is limited. Further research on the TyG index as an early predictor of GDM is required.
Collapse
Affiliation(s)
- Yan Zeng
- Department of Obstetrics and Gynecology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
- Guiyang Maternal and Child Health Care Hospital, Guiyang Children’s Hospital, Guizhou Medical University, Guiyang, China
| | - Li Yin
- Department of Obstetrics and Gynecology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Xiaoping Yin
- Department of Obstetrics and Gynecology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Danqing Zhao
- Department of Obstetrics and Gynecology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| |
Collapse
|
|
8
|
Liu T, Lu W, Zhao X, Yao T, Song B, Fan H, Gao G, Liu C. Relationship between lipid accumulation product and new-onset diabetes in the Japanese population: a retrospective cohort study. Front Endocrinol (Lausanne) 2023; 14:1181941. [PMID: 37265697 PMCID: PMC10230034 DOI: 10.3389/fendo.2023.1181941] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 05/04/2023] [Indexed: 06/03/2023] Open
Abstract
Background Diabetes has become a global public health problem. Obesity has been established as a risk factor for diabetes. However, it remains unclear which of the obesity indicators (BMI, WC, WhtR, ABSI, BRI, LAP, VAI) is more appropriate for monitoring diabetes. Therefore, the objective of this investigation is to compare the strength of the association of these indicators and diabetes and reveal the relationship between LAP and diabetes. Methods 15,252 people took part in this research. LAP was quartered and COX proportional risk model was applied to explore the relationship between LAP and new-onset diabetes. Smooth curve fitting was employed to investigate the non-linear link between LAP and diabetes mellitus. Finally, the receiver operating characteristic (ROC) curve was used to evaluate the predictive ability of the aforementioned indicators for diabetes. Results After adjusting for confounding factors, multiple linear regression analysis showed that each unit increase in LAP was associated with a 76.8% increase in the risk of developing diabetes (HR=1.768, 95% CI: 1.139 to 2.746, P=0.011). In addition, LAP predicted new-onset diabetes better than other indicators, and the AUC was the largest [HR: 0.713, 95% CI: 0.6806-0.7454, P<0.001, in women; HR: 0.7922, 95% CI: 0.7396-0.8447; P<0.001, in men]. When LAP was used as a lone predictor, its AUC area was largest both men and women. However, after adding classical predictors (FPG, HbA1c, SBP, exercise, age) to the model, the LAP is better than the ABSI, but not better than the other indicators when compared in pairs. Conclusions High levels of LAP correlate very strongly with diabetes and are an important risk factor for diabetes, especially in women, those with fatty liver and current smokers. LAP was superior to other indicators when screening for diabetes susceptibility using a single indicator of obesity, both in men and in women. However, when obesity indicators were added to the model together with classical predictors, LAP did not show a significant advantage over other indicators, except ABSI.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | - Chengyun Liu
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
9
|
von Hanstein AS, Tsikas D, Lenzen S, Jörns A, Plötz T. Potentiation of Lipotoxicity in Human EndoC-βH1 β-Cells by Glucose is Dependent on the Structure of Free Fatty Acids. Mol Nutr Food Res 2023; 67:e2200582. [PMID: 36629272 DOI: 10.1002/mnfr.202200582] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 11/28/2022] [Indexed: 01/12/2023]
Abstract
SCOPE Lipotoxicity is a significant element in the development of type 2 diabetes mellitus (T2DM). Since pro-diabetic nutritional patterns are associated with hyperglycemia as well as hyperlipidemia, the study analyzes the effects of combining these lipid and carbohydrate components with a special focus on the structural fatty acid properties such as increasing chain length (C16-C20) and degree of saturation with regard to the role of glucolipotoxicity in human EndoC-βH1 β-cells. METHODS AND RESULTS β-cell death induced by saturated FFAs is potentiated by high concentrations of glucose in a chain length-dependent manner starting with stearic acid (C18:0), whereas toxicity remains unchanged in the case of monounsaturated FFAs. Interference with FFA desaturation by overexpression and inhibition of stearoyl-CoA-desaturase, which catalyzes the rate-limiting step in the conversion of long-chain saturated into corresponding monounsaturated FFAs, does not affect the potentiating effect of glucose, but FFA desaturation reduces lipotoxicity and plays an important role in the formation of lipid droplets. Crucial elements underlying glucolipotoxicity are ER stress induction and cardiolipin peroxidation in the mitochondria. CONCLUSION In the context of nutrition, the data emphasize the importance of the lipid component in glucolipotoxicity related to the development of β-cell dysfunction and death in the manifestation of T2DM.
Collapse
Affiliation(s)
- Anna-Sophie von Hanstein
- Institute of Experimental Diabetes Research, Hannover Medical School, 30625, Hannover, Germany.,Institute of Clinical Biochemistry, Hannover Medical School, 30625, Hannover, Germany
| | - Dimitrios Tsikas
- Core Unit Proteomics, Institute of Toxicology, Hannover Medical School, 30625, Hannover, Germany
| | - Sigurd Lenzen
- Institute of Experimental Diabetes Research, Hannover Medical School, 30625, Hannover, Germany.,Institute of Clinical Biochemistry, Hannover Medical School, 30625, Hannover, Germany
| | - Anne Jörns
- Institute of Clinical Biochemistry, Hannover Medical School, 30625, Hannover, Germany
| | - Thomas Plötz
- Institute of Clinical Biochemistry, Hannover Medical School, 30625, Hannover, Germany
| |
Collapse
|
|
10
|
Massimino M, Monea G, Marinaro G, Rubino M, Mancuso E, Mannino GC, Andreozzi F. The Triglycerides and Glucose (TyG) Index Is Associated with 1-Hour Glucose Levels during an OGTT. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 20:787. [PMID: 36613109 PMCID: PMC9819897 DOI: 10.3390/ijerph20010787] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 12/20/2022] [Accepted: 12/21/2022] [Indexed: 06/17/2023]
Abstract
BACKGROUND AND OBJECTIVES Among individuals with normal glucose tolerance (NGT), subjects with high levels of plasma glucose (≥155 mg/dL) at sixty minutes during an oral glucose tolerance test (1h-OGTT) are at an increased risk of developing type 2 diabetes. We investigated the association between the triglycerides and glucose (TyG) index, a novel marker of insulin resistance, with 1h-OGTT glucose plasma concentrations. MATERIAL AND METHODS 1474 non-diabetic Caucasian subjects underwent a 75 g OGTT and were divided into two groups according to the cutoff 1h-OGTT plasma glucose < 155 mg/dL (NGT-1h-low) and ≥ 155 mg/dL (NGT-1h-high). The TyG index was calculated as ln [fasting triglycerides (milligrams per deciliter) × fasting blood glucose (milligrams per deciliter)/2]. Multivariable linear and logistic regression analyses were used to establish the contribution of the TyG index to the variability of 1h-OGTT glucose, and how the former affected the risk of being NGT-1h-high. RESULTS 1004 individuals were NGT-1h-low and 470 were NGT-1h-high. The TyG index was higher for NGT-1h-high (p = 0.001) individuals, and it was an independent factor influencing 1h-OGTT glycemia (β = 0.191, p < 0.001) after correcting for age, sex, and BMI. The TyG index was the strongest marker associated with the risk of being NGT-1h-high (OR = 1.703, CI 95% 1.34-2.17, p < 0.001) when compared with FPG (OR = 1.054, CI 95% 1.04-1.07, p < 0.001) and the HOMA-IR (OR = 1.156, CI 95% 1.08-1.23, p < 0.001). CONCLUSIONS Our study demonstrated that the TyG index, an efficient and cost-effective marker of insulin resistance, is associated with the variability of early post-challenge glucose levels and is an independent marker of being NGT-1h-high.
Collapse
Affiliation(s)
- Mattia Massimino
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Giuseppe Monea
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Giuseppe Marinaro
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Mariangela Rubino
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Elettra Mancuso
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Gaia Chiara Mannino
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Francesco Andreozzi
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
- Research Center for the Prevention and Treatment of Metabolic Diseases (CR METDIS), University Magna Grecia of Catanzaro, 88100 Catanzaro, Italy
| |
Collapse
|
|
11
|
Castell AL, Goubault C, Ethier M, Fergusson G, Tremblay C, Baltz M, Dal Soglio D, Ghislain J, Poitout V. β Cell mass expansion during puberty involves serotonin signaling and determines glucose homeostasis in adulthood. JCI Insight 2022; 7:160854. [PMID: 36107617 PMCID: PMC9675460 DOI: 10.1172/jci.insight.160854] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 09/14/2022] [Indexed: 01/07/2023] Open
Abstract
Puberty is associated with transient insulin resistance that normally recedes at the end of puberty; however, in overweight children, insulin resistance persists, leading to an increased risk of type 2 diabetes. The mechanisms whereby pancreatic β cells adapt to pubertal insulin resistance, and how they are affected by the metabolic status, have not been investigated. Here, we show that puberty is associated with a transient increase in β cell proliferation in rats and humans of both sexes. In rats, β cell proliferation correlated with a rise in growth hormone (GH) levels. Serum from pubertal rats and humans promoted β cell proliferation, suggesting the implication of a circulating factor. In pubertal rat islets, expression of genes of the GH/serotonin (5-hydroxytryptamine [5-HT]) pathway underwent changes consistent with a proliferative effect. Inhibition of the pro-proliferative 5-HT receptor isoform HTR2B blocked the increase in β cell proliferation in pubertal islets ex vivo and in vivo. Peripubertal metabolic stress blunted β cell proliferation during puberty and led to altered glucose homeostasis later in life. This study identifies a role of GH/GH receptor/5-HT/HTR2B signaling in the control of β cell mass expansion during puberty and identifies a mechanistic link between pubertal obesity and the risk of developing type 2 diabetes.
Collapse
Affiliation(s)
- Anne-Laure Castell
- Montreal Diabetes Research Center, Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, Canada.,Department of Medicine and
| | - Clara Goubault
- Montreal Diabetes Research Center, Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, Canada.,Department of Pharmacology and Physiology, University of Montreal, Quebec, Canada
| | - Mélanie Ethier
- Montreal Diabetes Research Center, Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, Canada
| | - Grace Fergusson
- Montreal Diabetes Research Center, Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, Canada
| | - Caroline Tremblay
- Montreal Diabetes Research Center, Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, Canada
| | - Marie Baltz
- Montreal Diabetes Research Center, Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, Canada
| | - Dorothée Dal Soglio
- CHU Sainte-Justine, Montreal, Quebec, Canada.,Department of Pathology and Cell Biology, University of Montreal, Montreal, Quebec, Canada
| | - Julien Ghislain
- Montreal Diabetes Research Center, Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, Canada
| | - Vincent Poitout
- Montreal Diabetes Research Center, Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, Canada.,Department of Medicine and
| |
Collapse
|
|
12
|
Castell AL, Vivoli A, Tippetts TS, Frayne IR, Angeles ZE, Moullé VS, Campbell SA, Ruiz M, Ghislain J, Des Rosiers C, Holland WL, Summers SA, Poitout V. Very-Long-Chain Unsaturated Sphingolipids Mediate Oleate-Induced Rat β-Cell Proliferation. Diabetes 2022; 71:1218-1232. [PMID: 35287172 PMCID: PMC9163557 DOI: 10.2337/db21-0640] [Citation(s) in RCA: 3] [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: 07/16/2021] [Accepted: 03/09/2022] [Indexed: 11/13/2022]
Abstract
Fatty acid (FA) signaling contributes to β-cell mass expansion in response to nutrient excess, but the underlying mechanisms are poorly understood. In the presence of elevated glucose, FA metabolism is shifted toward synthesis of complex lipids, including sphingolipids. Here, we tested the hypothesis that sphingolipids are involved in the β-cell proliferative response to FA. Isolated rat islets were exposed to FA and 16.7 mmol/L glucose for 48-72 h, and the contribution of the de novo sphingolipid synthesis pathway was tested using the serine palmitoyltransferase inhibitor myriocin, the sphingosine kinase (SphK) inhibitor SKI II, or knockdown of SphK, fatty acid elongase 1 (ELOVL1) and acyl-CoA-binding protein (ACBP). Rats were infused with glucose and the lipid emulsion ClinOleic and received SKI II by gavage. β-Cell proliferation was assessed by immunochemistry or flow cytometry. Sphingolipids were analyzed by liquid chromatography-tandem mass spectrometry. Among the FAs tested, only oleate increased β-cell proliferation. Myriocin, SKI II, and SphK knockdown all decreased oleate-induced β-cell proliferation. Oleate exposure did not increase the total amount of sphingolipids but led to a specific rise in 24:1 species. Knockdown of ACBP or ELOVL1 inhibited oleate-induced β-cell proliferation. We conclude that unsaturated very-long-chain sphingolipids produced from the available C24:1 acyl-CoA pool mediate oleate-induced β-cell proliferation in rats.
Collapse
Affiliation(s)
- Anne-Laure Castell
- Montreal Diabetes Research Center, CRCHUM, Montreal, Quebec, Canada
- Department of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Alexis Vivoli
- Montreal Diabetes Research Center, CRCHUM, Montreal, Quebec, Canada
- Department of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Trevor S. Tippetts
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT
| | | | - Zuraya Elisa Angeles
- Montreal Diabetes Research Center, CRCHUM, Montreal, Quebec, Canada
- Department of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Valentine S. Moullé
- Montreal Diabetes Research Center, CRCHUM, Montreal, Quebec, Canada
- Department of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Scott A. Campbell
- Montreal Diabetes Research Center, CRCHUM, Montreal, Quebec, Canada
- Department of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Matthieu Ruiz
- Metabolomic Platform, Montreal Heart Institute Research Center, Montreal, Quebec, Canada
| | - Julien Ghislain
- Montreal Diabetes Research Center, CRCHUM, Montreal, Quebec, Canada
| | - Christine Des Rosiers
- Metabolomic Platform, Montreal Heart Institute Research Center, Montreal, Quebec, Canada
- Department of Nutrition, Université de Montréal, Montreal, Quebec, Canada
| | - William L. Holland
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT
| | - Scott A. Summers
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT
| | - Vincent Poitout
- Montreal Diabetes Research Center, CRCHUM, Montreal, Quebec, Canada
- Department of Medicine, Université de Montréal, Montreal, Quebec, Canada
- Corresponding author: Vincent Poitout,
| |
Collapse
|
|
13
|
Fu X, Liu H, Liu J, Li N, Li L, Ke D, Liu M, Lu Y, Duan L, Ma L, Huo Y, Lei Q, Yan S. Association Between Triglyceride-Glucose Index and the Risk of Type 2 Diabetes Mellitus in an Older Chinese Population Aged Over 75 Years. Front Public Health 2022; 9:796663. [PMID: 35399348 PMCID: PMC8989963 DOI: 10.3389/fpubh.2021.796663] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 12/14/2021] [Indexed: 01/19/2023] Open
Abstract
Background The association between the triglyceride–glucose (TyG) index and type 2 diabetes mellitus (T2DM) in older adults has not been fully understood. This research aims to explore the association between the TyG index and the incidence of T2DM in an older Chinese population aged over 75 years. Methods This longitudinal analysis study was performed based on a database from a health check screening program in China. The participants were stratified based on the quintile ranges of the TyG index (Q1 to Q5 groups). T2DM was defined as fasting plasma glucose (FPG) ≥ 7.00 mmol/L and/or self-reported T2DM. The cumulative incidences of T2DM in various quintile groups were estimated by the Kaplan–Meier method. The Cox proportional hazard model was used to examine the independent impact of the TyG index on the risk of T2DM during the follow-up period. Subgroup analysis was performed by gender and BMI to further validate the credibility of the results. Results During the follow-up period, a total of 231 new-onset T2DM cases were recorded among the 2,571 individuals aged over 75 years. After adjusting confounding factors, elevated TyG index independently indicated a higher risk of T2DM (HR = 1.89; 95% CI, 1.47–2.44; p < 0.01). Higher TyG index quintile groups (Q3 to Q5) also presented with a higher risk of T2DM (hazard ratio (HR) = 1.36, 1.44, and 2.12, respectively) as compared with the lowest quintile group (Q1). Subgroup analysis showed that increased TyG index led to a higher risk of T2DM with HR = 2.35 (95% CI, 1.73–3.19), 1.90 (95% CI, 1.27–2.83), 2.95 (95% CI, 1.94–4.50), and 1.72 (95% CI, 1.25–2.35) in male subgroup, female subgroup, BMI < 24 kg/m2 subgroup, and BMI ≥ 24 kg/m2 subgroup, respectively. Conclusions Triglyceride–glucose index independently correlated with the risk of incident T2DM in Chinese adults aged over 75 years. The TyG index might be useful in monitoring T2DM in the older populations.
Collapse
Affiliation(s)
- Xiaomin Fu
- Department of Endocrinology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Hongzhou Liu
- Department of Endocrinology, The First Medical Center, Chinese PLA General Hospital, Beijing, China.,Department of Endocrinology, First Hospital of Handan City, Handan, China
| | - Jing Liu
- Clinics of Cadre, Department of Outpatient, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Nan Li
- Department of Endocrinology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Lele Li
- Department of Endocrinology, Genetics, Metabolism and Adolescent Medicine, National Center for Children's Health, Beijing Children's Hospital, The Capital Medical University, Beijing, China
| | - Dianshan Ke
- Department of Orthopedics, Fujian Provincial Hospital, Fuzhou, China
| | - Minyan Liu
- Department of Endocrinology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Yanhui Lu
- Department of Endocrinology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Lihua Duan
- Department of Ultrasound Medicine, Handan Central Hospital, Handan, China
| | - Linlin Ma
- General Surgery Department 5, Handan Central Hospital, Handan, China
| | - Yanfei Huo
- Physical Examination Center, Handan Central Hospital, Handan, China
| | - Qinghua Lei
- Physical Examination Center, Handan Central Hospital, Handan, China
| | - Shuangtong Yan
- Department of Endocrinology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| |
Collapse
|
|
14
|
Lipke K, Kubis-Kubiak A, Piwowar A. Molecular Mechanism of Lipotoxicity as an Interesting Aspect in the Development of Pathological States-Current View of Knowledge. Cells 2022; 11:cells11050844. [PMID: 35269467 PMCID: PMC8909283 DOI: 10.3390/cells11050844] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 02/22/2022] [Accepted: 02/25/2022] [Indexed: 02/06/2023] Open
Abstract
Free fatty acids (FFAs) play numerous vital roles in the organism, such as contribution to energy generation and reserve, serving as an essential component of the cell membrane, or as ligands for nuclear receptors. However, the disturbance in fatty acid homeostasis, such as inefficient metabolism or intensified release from the site of storage, may result in increased serum FFA levels and eventually result in ectopic fat deposition, which is unfavorable for the organism. The cells are adjusted for the accumulation of FFA to a limited extent and so prolonged exposure to elevated FFA levels results in deleterious effects referred to as lipotoxicity. Lipotoxicity contributes to the development of diseases such as insulin resistance, diabetes, cardiovascular diseases, metabolic syndrome, and inflammation. The nonobvious organs recognized as the main lipotoxic goal of action are the pancreas, liver, skeletal muscles, cardiac muscle, and kidneys. However, lipotoxic effects to a significant extent are not organ-specific but affect fundamental cellular processes occurring in most cells. Therefore, the wider perception of cellular lipotoxic mechanisms and their interrelation may be beneficial for a better understanding of various diseases’ pathogenesis and seeking new pharmacological treatment approaches.
Collapse
|
|
15
|
Oberhauser L, Maechler P. Lipid-Induced Adaptations of the Pancreatic Beta-Cell to Glucotoxic Conditions Sustain Insulin Secretion. Int J Mol Sci 2021; 23:324. [PMID: 35008750 PMCID: PMC8745448 DOI: 10.3390/ijms23010324] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 12/22/2021] [Accepted: 12/27/2021] [Indexed: 12/16/2022] Open
Abstract
Over the last decades, lipotoxicity and glucotoxicity emerged as established mechanisms participating in the pathophysiology of obesity-related type 2 diabetes in general, and in the loss of β-cell function in particular. However, these terms hold various potential biological processes, and it is not clear what precisely they refer to and to what extent they might be clinically relevant. In this review, we discuss the basis and the last advances of research regarding the role of free fatty acids, their metabolic intracellular pathways, and receptor-mediated signaling related to glucose-stimulated insulin secretion, as well as lipid-induced β-cell dysfunction. We also describe the role of chronically elevated glucose, namely, glucotoxicity, which promotes failure and dedifferentiation of the β cell. Glucolipotoxicity combines deleterious effects of exposures to both high glucose and free fatty acids, supposedly provoking synergistic defects on the β cell. Nevertheless, recent studies have highlighted the glycerolipid/free fatty acid cycle as a protective pathway mediating active storage and recruitment of lipids. Finally, we discuss the putative correspondence of the loss of functional β cells in type 2 diabetes with a natural, although accelerated, aging process.
Collapse
Affiliation(s)
| | - Pierre Maechler
- Department of Cell Physiology and Metabolism, Faculty Diabetes Center, University of Geneva Medical Center, 1206 Geneva, Switzerland;
| |
Collapse
|
|
16
|
Ye S, Ran H, Zhang H, Wu H, Li W, Du S, Su Q. Elevated Serum Triglycerides are Associated with Ketosis-Prone Type 2 Diabetes in Young Individuals. Diabetes Metab Syndr Obes 2021; 14:497-504. [PMID: 33568926 PMCID: PMC7869714 DOI: 10.2147/dmso.s296085] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 01/20/2021] [Indexed: 11/23/2022] Open
Abstract
PURPOSE Ketosis-prone type 2 diabetes (KPT2D) is increasingly recognized in young adults. However, the role of blood lipids in KPT2D, especially serum triglycerides (TGs), is not yet clearly understood. PATIENTS AND METHODS We retrospectively evaluated 409 young patients diagnosed with KPT2D or classical type 2 diabetes (T2D) attending an academic tertiary hospital. Clinical characteristics and laboratory findings were compared between KPT2D and T2D patients. ANOVA or a non-parametric test analyses were used to evaluate differences in clinical characteristics and laboratory findings. Multivariate regression analyses and stratified analyses were used to further investigate differences in serum TGs levels between KPT2D and T2D individuals. RESULTS KPT2D is a subtype of T2D with traits of overweight or obesity. However, hyperglycemia and impaired β-cell functions were more severe in KPT2D patients. Serum TGs levels were significantly higher (P = 0.0003) in KPT2D individuals. Furthermore, the proportion of very high serum TGs levels was 6-fold higher (P < 0.0001) in KPT2D than in T2D patients. Elevated serum TGs were associated with young KPT2D patients. CONCLUSION Lifestyle changes as well as lipid-lowering treatments might be effective in lowering the incidence of ketosis as well as stabilizing disease progression.
Collapse
Affiliation(s)
- Shu Ye
- Department of Endocrinology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai200092, People’s Republic of China
| | - Hui Ran
- Department of Endocrinology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai200092, People’s Republic of China
| | - Hongmei Zhang
- Department of Endocrinology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai200092, People’s Republic of China
| | - Hui Wu
- Department of Endocrinology, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, 310014, People’s Republic of China
| | - Wen Li
- Department of Endocrinology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai200092, People’s Republic of China
| | - Shichun Du
- Department of Endocrinology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai200092, People’s Republic of China
- Correspondence: Shichun Du Department of Endocrinology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Kong Jiang Road 1665#, Shanghai, 200092, People’s Republic of China Email
| | - Qing Su
- Department of Endocrinology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai200092, People’s Republic of China
| |
Collapse
|
|
17
|
Li X, Li G, Cheng T, Liu J, Song G, Ma H. Association between triglyceride-glucose index and risk of incident diabetes: a secondary analysis based on a Chinese cohort study : TyG index and incident diabetes. Lipids Health Dis 2020; 19:236. [PMID: 33161902 PMCID: PMC7649000 DOI: 10.1186/s12944-020-01403-7] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 10/14/2020] [Indexed: 01/29/2023] Open
Abstract
Background Recent studies have suggested the triglyceride-glucose index (TyG index) may serve as a suitable substitute for insulin resistance. However, evidence for the relationship between TyG index and risk of diabetes remains limited. This study sought to explore the association of baseline TyG index with risk of developing diabetes in Chinese adults. Methods This retrospective cohort study was conducted using data from the health screening program in China. A total of 201,298 non-diabetic individuals were included. TyG index was calculated as Ln [fasting plasma glucose (mg/dL) × fasting triglyceride level (mg/dL) / 2]. Diabetes was defined as fasting plasma glucose ≥126 mg/dL and/or self-reported diabetes. Cox proportion-hazard model was employed to evaluate the independent impact of baseline TyG index on future diabetes risk. Sensitivity and subgroup analyses were implemented to verify the reliability of results. Notably, data were downloaded from the DATADRYAD website, and used only for secondary analyses. Results During an average follow-up of 3.12 years, among 201,298 individuals aged ≥20 years, 3389 subjects developed diabetes. After adjusting for potential confounders, elevated TyG index were independently correlated with greater risk of incident diabetes (hazard ratio (HR), 3.34; 95% confidence interval (CI), 3.11–3.60). Compared with the lowest quartile (Q1), increasing TyG index (Q2, Q3, and Q4) was related to increased HR estimates of incident diabetes [HR (95% CI), 1.83 (1.49–2.26); 3.29 (2.70–4.01), and 6.26 (5.15–7.60), respectively]. Moreover, a nonlinear relationship was observed between TyG index and risk of diabetes and the slope of the curve increased accompanying the rise of TyG index. Subgroup analysis revealed the positive association was stronger among subjects with age < 40 years, body mass index ≥18.5 kg/m2 and < 24 kg/m2, or systolic blood pressure < 140 mmHg, or in females. Conclusions Elevated TyG index is independently correlated with increased risk of incident diabetes in Chinese adults, indicating it may represent a reliable predictor of diabetes in high-risk populations. Supplementary information Supplementary information accompanies this paper at 10.1186/s12944-020-01403-7.
Collapse
Affiliation(s)
- Xiaoli Li
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, 050017, Hebei, China.,Department of Endocrinology and Metabolic Diseases, Hebei General Hospital, Shijiazhuang, 050051, Hebei, China
| | - Guilong Li
- Department of Cardiology, Xingtai Third Hospital, Xingtai, 054000, Hebei, China
| | - Tiantian Cheng
- Department of Endocrinology and Metabolic Diseases, Hebei General Hospital, Shijiazhuang, 050051, Hebei, China.,Clinical Medical College, North China University of Science and Technology, Tangshan, 063210, Hebei, China
| | - Jing Liu
- Department of Endocrinology and Metabolic Diseases, Hebei General Hospital, Shijiazhuang, 050051, Hebei, China
| | - Guangyao Song
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, 050017, Hebei, China.,Department of Endocrinology and Metabolic Diseases, Hebei General Hospital, Shijiazhuang, 050051, Hebei, China
| | - Huijuan Ma
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, 050017, Hebei, China. .,Hebei Key Laboratory of Metabolic Diseases, Hebei General Hospital, Shijiazhuang, 050051, Hebei, China.
| |
Collapse
|
|
18
|
Bovolini A, Garcia J, Andrade MA, Duarte JA. Metabolic Syndrome Pathophysiology and Predisposing Factors. Int J Sports Med 2020; 42:199-214. [PMID: 33075830 DOI: 10.1055/a-1263-0898] [Citation(s) in RCA: 163] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Metabolic syndrome (MetS) is a cluster of cardiometabolic risk factors with high prevalence among adult populations and elevated costs for public health systems worldwide. Despite the lack of consensus regarding the syndrome definition and diagnosis criteria, it is characterized by the coexistence of risk factors such as abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, a prothrombotic and pro-inflammatory state, insulin resistance (IR), and higher glucose levels, factors indubitably linked to an increased risk of developing chronic conditions, such as type 2 diabetes (T2D) and cardiovascular disease (CVD). The syndrome has a complex and multifaceted origin not fully understood; however, it has been strongly suggested that sedentarism and unbalanced dietary patterns might play a fundamental role in its development. The purpose of this review is to provide an overview from the syndrome epidemiology, costs, and main etiological traits from its relationship with unhealthy diet patterns and sedentary lifestyles.
Collapse
Affiliation(s)
| | - Juliana Garcia
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences, University of Trás-os-Montes and Alto Douro, Vila Real
| | | | - José Alberto Duarte
- CIAFEL Faculty of Sport, University of Porto, Porto.,University Institute of Health Sciences (IUCS), Rua Central de Gandra, 1317 4585-116 Gandra Paredes, Portugal
| |
Collapse
|
|
19
|
Das D, Das A, Sahu M, Mishra SS, Khan S, Bejugam PR, Rout PK, Das A, Bano S, Mishra GP, Raghav SK, Dixit A, Panda AC. Identification and Characterization of Circular Intronic RNAs Derived from Insulin Gene. Int J Mol Sci 2020; 21:ijms21124302. [PMID: 32560282 PMCID: PMC7352490 DOI: 10.3390/ijms21124302] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/02/2020] [Accepted: 06/09/2020] [Indexed: 01/09/2023] Open
Abstract
Circular RNAs (circRNAs) are a large family of noncoding RNAs that have emerged as novel regulators of gene expression. However, little is known about the function of circRNAs in pancreatic β-cells. Here, transcriptomic analysis of mice pancreatic islet RNA-sequencing data identified 77 differentially expressed circRNAs between mice fed with a normal diet and a high-fat diet. Surprisingly, multiple circRNAs were derived from the intron 2 of the preproinsulin 2 (Ins2) gene and are termed as circular intronic (ci)-Ins2. The expression of ci-Ins2 transcripts in mouse pancreatic islets, and βTC6 cells were confirmed by reverse transcription PCR, DNA sequencing, and RNase R treatment experiments. The level of ci-Ins2 was altered in βTC6 cells upon exposure to elevated levels of palmitate and glucose. Computational analysis predicted the interaction of several RNA-binding proteins with ci-Ins2 and their flanking region, suggesting their role in the ci-Ins2 function or biogenesis. Additionally, bioinformatics analysis predicted the association of several microRNAs with ci-Ins2. Gene ontology and pathway analysis of genes targeted by miRNAs associated with ci-Ins2 suggested the regulation of several key biological processes. Together, our findings indicate that differential expression of circRNAs, especially ci-Ins2 transcripts, may regulate β-cell function and may play a critical role in the development of diabetes.
Collapse
Affiliation(s)
- Debojyoti Das
- Institute of Life Sciences (ILS), Nalco Square, Bhubaneswar, Odisha 751023, India; (D.D.); (A.D.); (M.S.); (S.S.M.); (S.K.); (P.R.B.); (P.K.R.); (A.D.); (G.P.M.); (S.K.R.); (A.D.)
- School of Biotechnology, KIIT University, Bhubaneswar, Odisha 751024, India
| | - Aniruddha Das
- Institute of Life Sciences (ILS), Nalco Square, Bhubaneswar, Odisha 751023, India; (D.D.); (A.D.); (M.S.); (S.S.M.); (S.K.); (P.R.B.); (P.K.R.); (A.D.); (G.P.M.); (S.K.R.); (A.D.)
- School of Biotechnology, KIIT University, Bhubaneswar, Odisha 751024, India
| | - Mousumi Sahu
- Institute of Life Sciences (ILS), Nalco Square, Bhubaneswar, Odisha 751023, India; (D.D.); (A.D.); (M.S.); (S.S.M.); (S.K.); (P.R.B.); (P.K.R.); (A.D.); (G.P.M.); (S.K.R.); (A.D.)
| | - Smruti Sambhav Mishra
- Institute of Life Sciences (ILS), Nalco Square, Bhubaneswar, Odisha 751023, India; (D.D.); (A.D.); (M.S.); (S.S.M.); (S.K.); (P.R.B.); (P.K.R.); (A.D.); (G.P.M.); (S.K.R.); (A.D.)
| | - Shaheerah Khan
- Institute of Life Sciences (ILS), Nalco Square, Bhubaneswar, Odisha 751023, India; (D.D.); (A.D.); (M.S.); (S.S.M.); (S.K.); (P.R.B.); (P.K.R.); (A.D.); (G.P.M.); (S.K.R.); (A.D.)
| | - Pruthvi R. Bejugam
- Institute of Life Sciences (ILS), Nalco Square, Bhubaneswar, Odisha 751023, India; (D.D.); (A.D.); (M.S.); (S.S.M.); (S.K.); (P.R.B.); (P.K.R.); (A.D.); (G.P.M.); (S.K.R.); (A.D.)
| | - Pranita K. Rout
- Institute of Life Sciences (ILS), Nalco Square, Bhubaneswar, Odisha 751023, India; (D.D.); (A.D.); (M.S.); (S.S.M.); (S.K.); (P.R.B.); (P.K.R.); (A.D.); (G.P.M.); (S.K.R.); (A.D.)
| | - Arundhati Das
- Institute of Life Sciences (ILS), Nalco Square, Bhubaneswar, Odisha 751023, India; (D.D.); (A.D.); (M.S.); (S.S.M.); (S.K.); (P.R.B.); (P.K.R.); (A.D.); (G.P.M.); (S.K.R.); (A.D.)
- School of Biotechnology, KIIT University, Bhubaneswar, Odisha 751024, India
| | - Shehnaz Bano
- National Center for Cell Sciences (NCCS), Pune, Maharashtra 411007, India;
| | - Gyan Prakash Mishra
- Institute of Life Sciences (ILS), Nalco Square, Bhubaneswar, Odisha 751023, India; (D.D.); (A.D.); (M.S.); (S.S.M.); (S.K.); (P.R.B.); (P.K.R.); (A.D.); (G.P.M.); (S.K.R.); (A.D.)
| | - Sunil K. Raghav
- Institute of Life Sciences (ILS), Nalco Square, Bhubaneswar, Odisha 751023, India; (D.D.); (A.D.); (M.S.); (S.S.M.); (S.K.); (P.R.B.); (P.K.R.); (A.D.); (G.P.M.); (S.K.R.); (A.D.)
| | - Anshuman Dixit
- Institute of Life Sciences (ILS), Nalco Square, Bhubaneswar, Odisha 751023, India; (D.D.); (A.D.); (M.S.); (S.S.M.); (S.K.); (P.R.B.); (P.K.R.); (A.D.); (G.P.M.); (S.K.R.); (A.D.)
| | - Amaresh C. Panda
- Institute of Life Sciences (ILS), Nalco Square, Bhubaneswar, Odisha 751023, India; (D.D.); (A.D.); (M.S.); (S.S.M.); (S.K.); (P.R.B.); (P.K.R.); (A.D.); (G.P.M.); (S.K.R.); (A.D.)
- Correspondence: ; Tel.: +91-674-230-43-14
| |
Collapse
|
|
20
|
VEGF-B ablation in pancreatic β-cells upregulates insulin expression without affecting glucose homeostasis or islet lipid uptake. Sci Rep 2020; 10:923. [PMID: 31969592 PMCID: PMC6976647 DOI: 10.1038/s41598-020-57599-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 12/18/2019] [Indexed: 02/07/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) affects millions of people and is linked with obesity and lipid accumulation in peripheral tissues. Increased lipid handling and lipotoxicity in insulin producing β-cells may contribute to β-cell dysfunction in T2DM. The vascular endothelial growth factor (VEGF)-B regulates uptake and transcytosis of long-chain fatty acids over the endothelium to tissues such as heart and skeletal muscle. Systemic inhibition of VEGF-B signaling prevents tissue lipid accumulation, improves insulin sensitivity and glucose tolerance, as well as reduces pancreatic islet triglyceride content, under T2DM conditions. To date, the role of local VEGF-B signaling in pancreatic islet physiology and in the regulation of fatty acid trans-endothelial transport in pancreatic islet is unknown. To address these questions, we have generated a mouse strain where VEGF-B is selectively depleted in β-cells, and assessed glucose homeostasis, β-cell function and islet lipid content under both normal and high-fat diet feeding conditions. We found that Vegfb was ubiquitously expressed throughout the pancreas, and that β-cell Vegfb deletion resulted in increased insulin gene expression. However, glucose homeostasis and islet lipid uptake remained unaffected by β-cell VEGF-B deficiency.
Collapse
|
|
21
|
Li YX, Sang YQ, Sun Y, Liu XK, Geng HF, Zha M, Wang B, Teng F, Sun HJ, Wang Y, Qiu QQ, Zang X, Wang Y, Wu TT, Jones PM, Liang J, Xu W. Pancreatic Fat is not significantly correlated with β-cell Dysfunction in Patients with new-onset Type 2 Diabetes Mellitus using quantitative Computed Tomography. Int J Med Sci 2020; 17:1673-1682. [PMID: 32714070 PMCID: PMC7378671 DOI: 10.7150/ijms.46395] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 06/19/2020] [Indexed: 12/14/2022] Open
Abstract
Objective: Type 2 diabetes mellitus (T2DM) is a chronic condition resulting from insulin resistance and insufficient β-cell secretion, leading to improper glycaemic regulation. Previous studies have found that excessive fat deposits in organs such as the liver and muscle can cause insulin resistance through lipotoxicity that affects β-cell function. The relationships between fat deposits in pancreatic tissue, the function of β-cells, the method of visceral fat evaluation and T2DM have been sought by researchers. This study aims to elucidate the role of pancreatic fat deposits in the development of T2DM using quantitative computed tomography (QCT), especially their effects on islet β-cell function. Methods: We examined 106 subjects at the onset of T2DM who had undergone abdominal QCT. Estimated pancreatic fat and liver fat were quantified using QCT and calculated. We analysed the correlations with Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) scores and other oral glucose tolerance test-derived parameters that reflect islet function. Furthermore, correlations of estimated pancreatic fat and liver fat with the area under the curve for insulin (AUCINS) and HOMA-IR were assessed with partial correlation analysis and demonstrated by scatter plots. Results: Associations were found between estimated liver fat and HOMA-IR, AUCINS, the modified β-cell function index (MBCI) and Homeostatic Model Assessment β (HOMA-β). However, no significant differences existed between estimated pancreas fat and those parameters. Similarly, after adjustment for sex, age and body mass index, only estimated liver fat was correlated with HOMA-IR and AUCINS. Conclusions: This study suggests no significant correlation between pancreatic fat deposition and β-cell dysfunction in the early stages of T2DM using QCT as a screening tool. The deposits of fat in the pancreas and the resulting lipotoxicity may play an important role in the late stage of islet cell function dysfunction as the course of T2DM progresses.
Collapse
Affiliation(s)
- Y X Li
- Graduate School of Bengbu Medical College, Bengbu, Anhui, China.,Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Xuzhou Clinical School of Nanjing Medical University, Affiliated Hospital of Medical School of Southeast University, Jiangsu, China
| | - Y Q Sang
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Xuzhou Clinical School of Nanjing Medical University, Affiliated Hospital of Medical School of Southeast University, Jiangsu, China
| | - Yan Sun
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Xuzhou Clinical School of Nanjing Medical University, Affiliated Hospital of Medical School of Southeast University, Jiangsu, China
| | - X K Liu
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Xuzhou Clinical School of Nanjing Medical University, Affiliated Hospital of Medical School of Southeast University, Jiangsu, China
| | - H F Geng
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Xuzhou Clinical School of Nanjing Medical University, Affiliated Hospital of Medical School of Southeast University, Jiangsu, China
| | - Min Zha
- Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Jiangsu, China
| | - Ben Wang
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Xuzhou Clinical School of Nanjing Medical University, Affiliated Hospital of Medical School of Southeast University, Jiangsu, China
| | - Fei Teng
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Xuzhou Clinical School of Nanjing Medical University, Affiliated Hospital of Medical School of Southeast University, Jiangsu, China
| | - H J Sun
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Xuzhou Clinical School of Nanjing Medical University, Affiliated Hospital of Medical School of Southeast University, Jiangsu, China
| | - Yu Wang
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Xuzhou Clinical School of Nanjing Medical University, Affiliated Hospital of Medical School of Southeast University, Jiangsu, China
| | - Q Q Qiu
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Xuzhou Clinical School of Nanjing Medical University, Affiliated Hospital of Medical School of Southeast University, Jiangsu, China
| | - Xiu Zang
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Xuzhou Clinical School of Nanjing Medical University, Affiliated Hospital of Medical School of Southeast University, Jiangsu, China
| | - Yun Wang
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Xuzhou Clinical School of Nanjing Medical University, Affiliated Hospital of Medical School of Southeast University, Jiangsu, China
| | - T T Wu
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Xuzhou Clinical School of Nanjing Medical University, Affiliated Hospital of Medical School of Southeast University, Jiangsu, China
| | - Peter M Jones
- Diabetes Research Group, Division of Diabetes & Nutritional Sciences, School of Medicine, King's College London, London, UK
| | - Jun Liang
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Xuzhou Clinical School of Nanjing Medical University, Affiliated Hospital of Medical School of Southeast University, Jiangsu, China
| | - Wei Xu
- Graduate School of Bengbu Medical College, Bengbu, Anhui, China.,Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Xuzhou Clinical School of Nanjing Medical University, Affiliated Hospital of Medical School of Southeast University, Jiangsu, China.,Diabetes Research Group, Division of Diabetes & Nutritional Sciences, School of Medicine, King's College London, London, UK
| |
Collapse
|
|
22
|
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.
Collapse
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.
| |
Collapse
|
|
23
|
Moullé VS, Tremblay C, Castell AL, Vivot K, Ethier M, Fergusson G, Alquier T, Ghislain J, Poitout V. The autonomic nervous system regulates pancreatic β-cell proliferation in adult male rats. Am J Physiol Endocrinol Metab 2019; 317:E234-E243. [PMID: 31013146 PMCID: PMC6732465 DOI: 10.1152/ajpendo.00385.2018] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The pancreatic β-cell responds to changes in the nutrient environment to maintain glucose homeostasis by adapting its function and mass. Nutrients can act directly on the β-cell and also indirectly through the brain via autonomic nerves innervating islets. Despite the importance of the brain-islet axis in insulin secretion, relatively little is known regarding its involvement in β-cell proliferation. We previously demonstrated that prolonged infusions of nutrients in rats provoke a dramatic increase in β-cell proliferation in part because of the direct action of nutrients. Here, we addressed the contribution of the autonomic nervous system. In isolated islets, muscarinic stimulation increased, whereas adrenergic stimulation decreased, glucose-induced β-cell proliferation. Blocking α-adrenergic receptors reversed the effect of epinephrine on glucose + nonesterified fatty acids (NEFA)-induced β-cell proliferation, whereas activation of β-adrenergic receptors was without effect. Infusion of glucose + NEFA toward the brain stimulated β-cell proliferation, and this effect was abrogated following celiac vagotomy. The increase in β-cell proliferation following peripheral infusions of glucose + NEFA was not inhibited by vagotomy or atropine treatment but was blocked by coinfusion of epinephrine. We conclude that β-cell proliferation is stimulated by parasympathetic and inhibited by sympathetic signals. Whereas glucose + NEFA in the brain stimulates β-cell proliferation through the vagus nerve, β-cell proliferation in response to systemic nutrient excess does not involve parasympathetic signals but may be associated with decreased sympathetic tone.
Collapse
Affiliation(s)
- Valentine S Moullé
- Montreal Diabetes Research Center , Montreal, Quebec , Canada
- CRCHUM, Montreal, Quebec , Canada
| | - Caroline Tremblay
- Montreal Diabetes Research Center , Montreal, Quebec , Canada
- CRCHUM, Montreal, Quebec , Canada
| | - Anne-Laure Castell
- Montreal Diabetes Research Center , Montreal, Quebec , Canada
- CRCHUM, Montreal, Quebec , Canada
| | - Kevin Vivot
- Montreal Diabetes Research Center , Montreal, Quebec , Canada
- CRCHUM, Montreal, Quebec , Canada
| | - Mélanie Ethier
- Montreal Diabetes Research Center , Montreal, Quebec , Canada
- CRCHUM, Montreal, Quebec , Canada
| | - Grace Fergusson
- Montreal Diabetes Research Center , Montreal, Quebec , Canada
- CRCHUM, Montreal, Quebec , Canada
| | - Thierry Alquier
- Montreal Diabetes Research Center , Montreal, Quebec , Canada
- CRCHUM, Montreal, Quebec , Canada
- Department of Medicine, University of Montreal , Quebec , Canada
| | - Julien Ghislain
- Montreal Diabetes Research Center , Montreal, Quebec , Canada
- CRCHUM, Montreal, Quebec , Canada
| | - Vincent Poitout
- Montreal Diabetes Research Center , Montreal, Quebec , Canada
- CRCHUM, Montreal, Quebec , Canada
- Department of Medicine, University of Montreal , Quebec , Canada
| |
Collapse
|
|
24
|
Hedgehog Interacting Protein (Hhip) Regulates Insulin Secretion in Mice Fed High Fat Diets. Sci Rep 2019; 9:11183. [PMID: 31371780 PMCID: PMC6673691 DOI: 10.1038/s41598-019-47633-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 07/15/2019] [Indexed: 12/15/2022] Open
Abstract
Hedgehog interacting protein (Hhip) is essential for islet formation and beta-cell proliferation during pancreatic development; abnormally elevated Hhip expression has been linked to human pancreatitis. Here, we investigate the role of Hhip in modulating insulin secretion in adult Hhip mice (Hhip +/− vs. Hhip+/+) fed high fat diets (HFD). Both sexes of HFD-Hhip +/+ mice developed impaired glucose intolerance, that was only ameliorated in male HFD-Hhip +/− mice that had high levels of circulating plasma insulin, but not in female HFD-Hhip +/− mice. HFD stimulated Hhip gene expression, mainly in beta cells. Male HFD-Hhip +/+ mice had more large islets in which insulin content was reduced; islet architecture was disordered; and markers of oxidative stress (8-OHdG and Nox 2) were increased. In contrast, male HFD-Hhip +/− mice had more small islets with increased beta cell proliferation, enhanced GSIS, less oxidative stress and preserved islet integrity. In vitro, recombinant Hhip increased Nox2 and NADPH activity and decreased insulin-positive beta cells. siRNA-Hhip increased GSIS and abolished the stimulation of sodium palmitate (PA)-BSA on Nox2 gene expression. We conclude that pancreatic Hhip gene inhibits insulin secretion by altering islet integrity and promoting Nox2 gene expression in beta cells in response to HDF-mediated beta cell dysfunction, a novel finding.
Collapse
|
|
25
|
Li Z, Zhou M, Cai Z, Liu H, Zhong W, Hao Q, Cheng D, Hu X, Hou J, Xu P, Xue Y, Zhou Y, Xu T. RNA-binding protein DDX1 is responsible for fatty acid-mediated repression of insulin translation. Nucleic Acids Res 2019; 46:12052-12066. [PMID: 30295850 PMCID: PMC6294501 DOI: 10.1093/nar/gky867] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Accepted: 09/14/2018] [Indexed: 01/13/2023] Open
Abstract
The molecular mechanism in pancreatic β cells underlying hyperlipidemia and insulin insufficiency remains unclear. Here, we find that the fatty acid-induced decrease in insulin levels occurs due to a decrease in insulin translation. Since regulation at the translational level is generally mediated through RNA-binding proteins, using RNA antisense purification coupled with mass spectrometry, we identify a novel insulin mRNA-binding protein, namely, DDX1, that is sensitive to palmitate treatment. Notably, the knockdown or overexpression of DDX1 affects insulin translation, and the knockdown of DDX1 eliminates the palmitate-induced repression of insulin translation. Molecular mechanism studies show that palmitate treatment causes DDX1 phosphorylation at S295 and dissociates DDX1 from insulin mRNA, thereby leading to the suppression of insulin translation. In addition, DDX1 may interact with the translation initiation factors eIF3A and eIF4B to regulate translation. In high-fat diet mice, the inhibition of insulin translation happens at an early prediabetic stage before the elevation of glucose levels. We speculate that the DDX1-mediated repression of insulin translation worsens the situation of insulin resistance and contributes to the elevation of blood glucose levels in obese animals.
Collapse
Affiliation(s)
- Zonghong Li
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics & University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China.,Jilin Province Key Laboratory on Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, China
| | - Maoge Zhou
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics & University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China
| | - Zhaokui Cai
- Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Hongyang Liu
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics & University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China
| | - Wen Zhong
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics & University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China
| | - Qiang Hao
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics & University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China
| | - Dongwan Cheng
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics & University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China
| | - Xihao Hu
- Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Junjie Hou
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics & University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China
| | - Pingyong Xu
- Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Yuanchao Xue
- Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Yifa Zhou
- Jilin Province Key Laboratory on Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, China
| | - Tao Xu
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics & University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China
| |
Collapse
|
|
26
|
Jeon J, Jung KJ, Jee SH. Waist circumference trajectories and risk of type 2 diabetes mellitus in Korean population: the Korean genome and epidemiology study (KoGES). BMC Public Health 2019; 19:741. [PMID: 31196038 PMCID: PMC6567400 DOI: 10.1186/s12889-019-7077-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 05/30/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND To classify waist circumference (WC) trajectories and examine each trajectory's association with risk of incident type 2 diabetes mellitus (T2DM). METHODS In Korean Genome and Epidemiology Study (KoGES 2001-2014), 4992 participants aged 40 years and above who received biennial health examinations from wave 1 to wave 4 (2001-2008) were selected. Five distinct trajectory groups were identified for WC using group-based trajectory modeling methods such as censored normal model. Cox proportional hazards model was used to examine the association of trajectories with risk of T2DM. RESULTS During 31,118 person-years of follow-up (mean follow-up duration, 6.2 years), 276 incident cases of T2DM were identified. Through trajectory analysis, 5 distinct WC patterns were found during wave1 to wave 4, which were "Group A" was stable on very low levels, "Group B" was stable on low levels, "Group C" was stable on moderate levels, "Group D" had increasing pattern on elevated levels, "Group E" was shown increasing on high levels. Age-standardized incidences rates per 100,000 person-years were increased with WC expanding trajectory group (193.9 for Group A, 498.4 for Group B, 661.9 for Group C, 1845.9 for Group D, and 2045.0 for Group E). In multivariate analysis after adjusting for confounding variable at wave 4, Group B (Hazard ratio (HR), 2.2; 95% confidence interval (CI), and 1.1-4.6), Group C (HR: 2.5, 95% CI: 1.2-5.0), Group D (HR: 5.4, 95% CI: 2.7-10.9), Group E (HR: 7.3, 95% CI: 3.5-15.4) had a higher risk of T2DM than Group A. After further adjusting for body mass index strongly correlated with WC, the association was attenuated. CONCLUSIONS WC trajectory was a significant predictor of T2DM risk in increasing trajectories on high level. This finding indicate the importance of WC management across prolong lifespan by assessing the prognosis and prevention strategies of high-risk populations for T2DM in middle-aged adults.
Collapse
Affiliation(s)
- Jooeun Jeon
- Department of Public Health, Graduate School, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.,Department of Epidemiology and Health Promotion, Institute for Health Promotion, Graduate School of Public Health, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Keum Ji Jung
- Department of Epidemiology and Health Promotion, Institute for Health Promotion, Graduate School of Public Health, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
| | - Sun Ha Jee
- Department of Epidemiology and Health Promotion, Institute for Health Promotion, Graduate School of Public Health, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| |
Collapse
|
|
27
|
Ye R, Onodera T, Scherer PE. Lipotoxicity and β Cell Maintenance in Obesity and Type 2 Diabetes. J Endocr Soc 2019; 3:617-631. [PMID: 30834357 PMCID: PMC6391718 DOI: 10.1210/js.2018-00372] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Accepted: 01/30/2019] [Indexed: 12/11/2022] Open
Abstract
Obesity and diabetes are often associated with lipotoxic conditions in multiple tissues. The insulin-producing β cells are susceptible to elevated lipid levels and the ensuing lipotoxicity. The preservation of β cell mass and function is one of the main goals of diabetes management under these metabolically stressful conditions. However, the adverse effects from the adaptive signaling pathways that β cells use to counteract lipotoxic stress have secondary negative effects in their own right. Antilipotoxic signaling cascades in β cells can contribute to their eventual failure. Such dual roles are seen for many other biological adaptive processes as well.
Collapse
Affiliation(s)
- Risheng Ye
- Department of Medical Education, Texas Tech University Health Sciences Center Paul L. Foster School of Medicine, El Paso, Texas
- Touchstone Diabetes Center, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, Texas
| | - Toshiharu Onodera
- Touchstone Diabetes Center, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, Texas
| | - Philipp E Scherer
- Touchstone Diabetes Center, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, Texas
| |
Collapse
|
|
28
|
Jurczak MJ, Saini S, Ioja S, Costa DK, Udeh N, Zhao X, Whaley JM, Kibbey RG. SGLT2 knockout prevents hyperglycemia and is associated with reduced pancreatic β-cell death in genetically obese mice. Islets 2018; 10:181-189. [PMID: 30118626 PMCID: PMC6284495 DOI: 10.1080/19382014.2018.1503027] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Inhibition of the sodium-glucose co-transporter type 2 (SGLT2) has received growing acceptance as a novel, safe and effective means to improve glycemic control in patients with type 2 diabetes. Inhibition of SGLT2 lowers the renal glucose threshold and reduces plasma glucose by promoting glucose excretion in urine. Both animal studies and clinical trials in man suggest that SGLT2 inhibition has the potential to improve pancreatic β-cell function by reducing glucose toxicity. However, there is limited data exploring how reducing glucotoxicity via SGLT2 inhibition affects rates of β-cell proliferation and death throughout life in the context of insulin resistance and type 2 diabetes. SGLT2-/- mice were backcrossed to the db/db strain to produce littermate control db/db-SGLT2+/+ and experimental db/db-SGLT2-/- mice. Mice were euthanized at 5, 12 and 20 weeks of age to collect plasma for glucose, insulin, lipid and cytokine measures, and pancreata for histological analysis including determination of β-cell mass and rates of proliferation and death. SGLT2 deletion in db/db mice reduced plasma glucose as early as 5 weeks of age and continued throughout life without changes in plasma lipids or cytokines. Reduced plasma glucose levels occurred in parallel with an increase in the relative β-cell volume and reduced frequency of β-cell death, and no apparent change in rates of β-cell proliferation. These data add to a growing body of evidence demonstrating that improved glycemic control achieved through SGLT2 inhibition can preserve β-cell function and endogenous insulin secretion by reducing glucose toxicity and rates of β-cell death.
Collapse
Affiliation(s)
- Michael J. Jurczak
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Saumya Saini
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Simona Ioja
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Diana K. Costa
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Nnamdi Udeh
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Xiaojian Zhao
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Jean M. Whaley
- Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ, USA
| | - Richard G. Kibbey
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
- Departments of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
- CONTACT Richard G. Kibbey Internal Medicine-Endocrinology, Yale University School of Medicine, TAC S269, P.O. Box 9812, New Haven, CT 06536-8012; Michael J. Jurczak Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, 200 Lothrop Street, BST W1060, Pittsburgh, PA 15261
| |
Collapse
|
|
29
|
Saha SK, Lee SB, Won J, Choi HY, Kim K, Yang GM, Dayem AA, Cho SG. Correlation between Oxidative Stress, Nutrition, and Cancer Initiation. Int J Mol Sci 2017; 18:E1544. [PMID: 28714931 PMCID: PMC5536032 DOI: 10.3390/ijms18071544] [Citation(s) in RCA: 236] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 07/12/2017] [Accepted: 07/13/2017] [Indexed: 02/07/2023] Open
Abstract
Inadequate or excessive nutrient consumption leads to oxidative stress, which may disrupt oxidative homeostasis, activate a cascade of molecular pathways, and alter the metabolic status of various tissues. Several foods and consumption patterns have been associated with various cancers and approximately 30-35% of the cancer cases are correlated with overnutrition or malnutrition. However, several contradictory studies are available regarding the association between diet and cancer risk, which remains to be elucidated. Concurrently, oxidative stress is a crucial factor for cancer progression and therapy. Nutritional oxidative stress may be induced by an imbalance between antioxidant defense and pro-oxidant load due to inadequate or excess nutrient supply. Oxidative stress is a physiological state where high levels of reactive oxygen species (ROS) and free radicals are generated. Several signaling pathways associated with carcinogenesis can additionally control ROS generation and regulate ROS downstream mechanisms, which could have potential implications in anticancer research. Cancer initiation may be modulated by the nutrition-mediated elevation in ROS levels, which can stimulate cancer initiation by triggering DNA mutations, damage, and pro-oncogenic signaling. Therefore, in this review, we have provided an overview of the relationship between nutrition, oxidative stress, and cancer initiation, and evaluated the impact of nutrient-mediated regulation of antioxidant capability against cancer therapy.
Collapse
Affiliation(s)
- Subbroto Kumar Saha
- Department of Stem Cell and Regenerative Biotechnology, Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, Seoul 05029, Korea.
| | - Soo Bin Lee
- Department of Stem Cell and Regenerative Biotechnology, Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, Seoul 05029, Korea.
| | - Jihye Won
- Department of Stem Cell and Regenerative Biotechnology, Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, Seoul 05029, Korea.
| | - Hye Yeon Choi
- Department of Stem Cell and Regenerative Biotechnology, Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, Seoul 05029, Korea.
| | - Kyeongseok Kim
- Department of Stem Cell and Regenerative Biotechnology, Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, Seoul 05029, Korea.
| | - Gwang-Mo Yang
- Department of Stem Cell and Regenerative Biotechnology, Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, Seoul 05029, Korea.
| | - Ahmed Abdal Dayem
- Department of Stem Cell and Regenerative Biotechnology, Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, Seoul 05029, Korea.
| | - Ssang-Goo Cho
- Department of Stem Cell and Regenerative Biotechnology, Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, Seoul 05029, Korea.
| |
Collapse
|
|
30
|
Rehman K, Akash MSH. Mechanism of Generation of Oxidative Stress and Pathophysiology of Type 2 Diabetes Mellitus: How Are They Interlinked? J Cell Biochem 2017; 118:3577-3585. [PMID: 28460155 DOI: 10.1002/jcb.26097] [Citation(s) in RCA: 321] [Impact Index Per Article: 40.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 04/26/2017] [Indexed: 12/14/2022]
Abstract
Oxidative stress has been considered as a major hallmark for the pathogenesis and development of type 2 diabetes mellitus (T2DM), but still it is debatable whether it is a mere aggregation of inflammatory-induced responses or clinical entity that underlies with various pathophysiological factors. In this regard, the latest studies have shown the increasing trends for the involvement of reactive oxygen species (ROS) and oxidative stress in the pathogenesis and development of T2DM. ROS are highly reactive species and almost all cellular components are chemically changed due to the influence of ROS that ultimately results in the production of lipid peroxidation. Lipid peroxidation is a major causative factor for the development of oxidative stress that leads to overt T2DM and its associated micro- and macro-vascular complications. In this article, we have briefly described the role of various causative factors, transcriptional and metabolic pathways which are responsible to increase the production of oxidative stress, a most pivotal factor for the pathogenesis and development of T2DM. Therefore, we conclude that measurement of oxidative stress biomarkers may be one of the optional tool for the diagnosis and prediction of T2DM. Moreover, the key findings described in this article also provides a new conceptual framework for forthcoming investigations on the role of oxidative stress in pathogenesis of T2DM and drug discovery. J. Cell. Biochem. 118: 3577-3585, 2017. © 2017 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Kanwal Rehman
- Institute of Pharmacy, Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan
| | | |
Collapse
|
|
31
|
Moullé VS, Vivot K, Tremblay C, Zarrouki B, Ghislain J, Poitout V. Glucose and fatty acids synergistically and reversibly promote beta cell proliferation in rats. Diabetologia 2017; 60:879-888. [PMID: 28078385 PMCID: PMC5376373 DOI: 10.1007/s00125-016-4197-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 12/08/2016] [Indexed: 12/31/2022]
Abstract
AIMS/HYPOTHESIS The mechanisms underlying pancreatic islet mass expansion have attracted considerable interest as potential therapeutic targets to prevent or delay the onset of type 2 diabetes. While several factors promoting beta cell proliferation have been identified, in the context of nutrient excess the roles of glucose or NEFA in relation to insulin resistance remain unclear. Here we tested the hypothesis that glucose and NEFA synergistically and reversibly promote beta cell proliferation in the context of nutrient-induced insulin resistance. METHODS Using 72 h infusions of glucose (GLU) or the oleate-enriched lipid emulsion ClinOleic (CLI), singly or in combination, we assessed beta cell proliferation, islet mass and insulin sensitivity in male Lewis rats. The effects of nutrients and endogenous circulating factors were examined in isolated and transplanted islets. Reversibility was studied 3 and 6 days after the end of the infusion. RESULTS GLU infusions modestly stimulated beta cell proliferation, CLI alone had no effect and GLU+CLI infusions markedly stimulated beta cell proliferation. Insulin sensitivity was equally decreased in GLU and GLU+CLI infusions. GLU+CLI infusions also stimulated beta cell proliferation in islets transplanted under the kidney capsule, albeit to a lesser extent compared with endogenous islets. Ex vivo, the combination of glucose and NEFA enhanced beta cell proliferation in rat and human islets independently from secreted insulin, and serum from GLU+CLI-infused rats potentiated the effect of glucose. Glucose tolerance, beta cell proliferation and islet mass were all restored to normal levels 6 days after termination of the infusion. CONCLUSIONS/INTERPRETATION Glucose and NEFA synergistically and reversibly promote beta cell proliferation in part via direct action on the beta cell and independently from secreted insulin.
Collapse
Affiliation(s)
- Valentine S Moullé
- Montreal Diabetes Research Center, University of Montreal, Montreal, QC, Canada
- The University of Montreal Hospital Research Centre (CRCHUM), 900 Saint-Denis, Montreal, QC, H2X 0A9, Canada
| | - Kevin Vivot
- Montreal Diabetes Research Center, University of Montreal, Montreal, QC, Canada
- The University of Montreal Hospital Research Centre (CRCHUM), 900 Saint-Denis, Montreal, QC, H2X 0A9, Canada
| | - Caroline Tremblay
- Montreal Diabetes Research Center, University of Montreal, Montreal, QC, Canada
- The University of Montreal Hospital Research Centre (CRCHUM), 900 Saint-Denis, Montreal, QC, H2X 0A9, Canada
| | - Bader Zarrouki
- Montreal Diabetes Research Center, University of Montreal, Montreal, QC, Canada
- The University of Montreal Hospital Research Centre (CRCHUM), 900 Saint-Denis, Montreal, QC, H2X 0A9, Canada
| | - Julien Ghislain
- Montreal Diabetes Research Center, University of Montreal, Montreal, QC, Canada
- The University of Montreal Hospital Research Centre (CRCHUM), 900 Saint-Denis, Montreal, QC, H2X 0A9, Canada
| | - Vincent Poitout
- Montreal Diabetes Research Center, University of Montreal, Montreal, QC, Canada.
- The University of Montreal Hospital Research Centre (CRCHUM), 900 Saint-Denis, Montreal, QC, H2X 0A9, Canada.
- Department of Medicine, University of Montreal, Montreal, QC, Canada.
- Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, QC, Canada.
| |
Collapse
|
|
32
|
Cumulative increased risk of incident type 2 diabetes mellitus with increasing triglyceride glucose index in normal-weight people: The Rural Chinese Cohort Study. Cardiovasc Diabetol 2017; 16:30. [PMID: 28249577 PMCID: PMC5333419 DOI: 10.1186/s12933-017-0514-x] [Citation(s) in RCA: 174] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Accepted: 02/22/2017] [Indexed: 12/15/2022] Open
Abstract
Background Risk of type 2 diabetes mellitus (T2DM) is increased in metabolically obese but normal-weight people. However, we have limited knowledge of how to prevent T2DM in normal-weight people. We aimed to evaluate the association between triglyceride glucose (TyG) index and incident T2DM among normal-weight people in rural China. Methods We included data from 5706 people with normal body mass index (BMI) (18.5–23.9 kg/m2) without baseline T2DM in a rural Chinese cohort followed for a median of 6.0 years. A Cox proportional-hazard model was used to assess the risk of incident T2DM by quartiles of TyG index and difference in TyG index between follow-up and baseline (TyG-D), estimating hazard ratios (HRs) and 95% confidence intervals (CIs). A generalized additive plot was used to show the nonparametric smoothed exposure–response association between risk of T2DM and TyG index as a continuous variable. TyG was calculated as ln [fasting triglyceride level (mg/dl) × fasting plasma glucose level (mg/dl)/2]. Results Risk of incident T2DM was increased with quartiles 2, 3 and 4 versus quartile 1 of TyG index (adjusted HR [aHR] 2.48 [95% CI 1.20–5.11], 3.77 [1.83–7.79], and 5.30 [2.21–12.71], Ptrend < 0.001 across quartiles of TyG index). Risk of incident T2DM was increased with quartile 4 versus quartile 1 of TyG-D (aHR 3.91 [2.22–6.87]). The results were consistent when analyses were restricted to participants without baseline metabolic syndrome and impaired fasting glucose level. The generalized additive plot showed cumulative increased risk of T2DM with increasing TyG index. Conclusions Risk of incident T2DM is increased with increasing TyG index among rural Chinese people, so the index might be an important indicator for identifying people at high risk of T2DM.
Collapse
|
|
33
|
Diamanti-Kandarakis E, Papalou O, Kandaraki EA, Kassi G. MECHANISMS IN ENDOCRINOLOGY: Nutrition as a mediator of oxidative stress in metabolic and reproductive disorders in women. Eur J Endocrinol 2017; 176:R79-R99. [PMID: 27678478 DOI: 10.1530/eje-16-0616] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2016] [Revised: 09/20/2016] [Accepted: 09/27/2016] [Indexed: 12/12/2022]
Abstract
Nutrition can generate oxidative stress and trigger a cascade of molecular events that can disrupt oxidative and hormonal balance. Nutrient ingestion promotes a major inflammatory and oxidative response at the cellular level in the postprandial state, altering the metabolic state of tissues. A domino of unfavorable metabolic changes is orchestrated in the main metabolic organs, including adipose tissue, skeletal muscle, liver and pancreas, where subclinical inflammation, endothelial dysfunction, mitochondrial deregulation and impaired insulin response and secretion take place. Simultaneously, in reproductive tissues, nutrition-induced oxidative stress can potentially violate delicate oxidative balance that is mandatory to secure normal reproductive function. Taken all the above into account, nutrition and its accompanying postprandial oxidative stress, in the unique context of female hormonal background, can potentially compromise normal metabolic and reproductive functions in women and may act as an active mediator of various metabolic and reproductive disorders.
Collapse
Affiliation(s)
| | - Olga Papalou
- Department of Endocrinology and Diabetes Center of ExcellenceEUROCLINIC, Athens, Greece
| | - Eleni A Kandaraki
- Endocrine Unit3rd Department of Internal Medicine, University of Athens Medical School, Athens, Greece
| | - Georgia Kassi
- Endocrine Unit3rd Department of Internal Medicine, University of Athens Medical School, Athens, Greece
| |
Collapse
|
|
34
|
Gómez-Sámano MÁ, Cuevas-Ramos D, Grajales-Gómez M, Escamilla-Márquez M, López-Estrada A, Guillén-Pineda LE, López-Carrasco G, Gómez-Pérez FJ. Reduced first-phase insulin secretion increases postprandial lipidemia in subjects with impaired glucose tolerance. BMJ Open Diabetes Res Care 2017; 5:e000344. [PMID: 28713570 PMCID: PMC5501239 DOI: 10.1136/bmjdrc-2016-000344] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 01/12/2017] [Accepted: 02/05/2017] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVE It is not clear which phase of insulin secretion is more important to regulate lipoprotein lipase (LPL) activity. After a meal, insulin is released and acts as a major regulator of LPL activity. Postprandial hyperlipidemia is a common comorbidity in subjects with insulin resistance (IR). Therefore this study aimed to evaluate the role of the first-phase insulin secretion (FPIS) on postprandial lipidemia in subjects with IR and impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS This is a cross-sectional, observational and comparative study. We included male and female subjects between 40 and 60 years with a body mass index (BMI) between 23 and 30 kg/m2. Then, patients were divided into three groups. Group 1 consisted of control subjects with normal glucose tolerance and preserved FPIS. Group 2 included patients with IGT and a reduced FPIS. Group 3 consisted of subjects with IGT but normal FPIS. Both groups were paired by age and BMI with subjects in the control group. Subjects underwent an intravenous glucose tolerance test to classify each case, and then a load with a mixed meal load to measure postprandial lipidemia. RESULTS A total of 32 subjects were evaluated: 10 were control subjects, 8 subjects with IGT with a reduced FPIS and 14 subjects with IGT and preserved FPIS. After administration of a standardized meal, group 2 showed a greater glucose area under the curve (AUC) at 30 and 120 min (p=0.001, for both). This group also showed a statistically significant increase (p<0.001) in triglyceride AUC. CONCLUSIONS A reduced FPIS is significantly and independently associated with a larger postprandial hyperlipidemia in subjects with IGT.
Collapse
Affiliation(s)
- Miguel Ángel Gómez-Sámano
- Department of Endocrinology and Metabolism, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
| | - Daniel Cuevas-Ramos
- Department of Endocrinology and Metabolism, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
| | - Mariana Grajales-Gómez
- Department of Endocrinology and Metabolism, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
| | - Marco Escamilla-Márquez
- Department of Endocrinology and Metabolism, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
| | - Angelina López-Estrada
- Department of Endocrinology and Metabolism, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
| | - Luz Elizabeth Guillén-Pineda
- Department of Endocrinology and Metabolism, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
| | - Guadalupe López-Carrasco
- Department of Endocrinology and Metabolism, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
| | - Francisco J Gómez-Pérez
- Department of Endocrinology and Metabolism, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
| |
Collapse
|
|
35
|
Yoon JS, Moon JS, Kim YW, Won KC, Lee HW. The Glucotoxicity Protecting Effect of Ezetimibe in Pancreatic Beta Cells via Inhibition of CD36. J Korean Med Sci 2016; 31:547-52. [PMID: 27051238 PMCID: PMC4810337 DOI: 10.3346/jkms.2016.31.4.547] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Accepted: 12/23/2015] [Indexed: 11/20/2022] Open
Abstract
Inhibition of CD36, a fatty acid transporter, has been reported to prevent glucotoxicity and ameliorate high glucose induced beta cell dysfunction. Ezetimibe is a selective cholesterol absorption inhibitor that blocks Niemann Pick C1-like 1 protein, but may exert its effect through suppression of CD36. We attempted to clarify the beneficial effect of ezetimibe on insulin secreting cells and to determine whether this effect is related to change of CD36 expression. mRNA expression of insulin and CD36, intracellular peroxide level and glucose stimulated insulin secretion (GSIS) under normal (5.6 mM) or high glucose (30 mM) condition in INS-1 cells and primary rat islet cells were compared. Changes of the aforementioned factors with treatment with ezetimibe (20 μM) under normal or high glucose condition were also assessed. mRNA expression of insulin was decreased with high glucose, which was reversed by ezetimibe in both INS-1 cells and primary rat islets. CD36 mRNA expression was increased with high glucose, but decreased by ezetimibe in INS-1 cells and primary rat islets. Three-day treatment with high glucose resulted in an increase in intracellular peroxide level; however, it was decreased by treatment with ezetimibe. Decrease in GSIS by three-day treatment with high glucose was reversed by ezetimibe. Palmitate uptake following exposure to high glucose conditions for three days was significantly elevated, which was reversed by ezetimibe in INS-1 cells. Ezetimibe may prevent glucotoxicity in pancreatic β-cells through a decrease in fatty acid influx via inhibition of CD36.
Collapse
Affiliation(s)
- Ji Sung Yoon
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Jun Sung Moon
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Yong-Woon Kim
- Department of Physiology, Yeungnam University College of Medicine, Daegu, Korea
| | - Kyu Chang Won
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Hyoung Woo Lee
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| |
Collapse
|
|
36
|
Metabolomics applied to the pancreatic islet. Arch Biochem Biophys 2015; 589:120-30. [PMID: 26116790 DOI: 10.1016/j.abb.2015.06.013] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Revised: 06/19/2015] [Accepted: 06/21/2015] [Indexed: 01/18/2023]
Abstract
Metabolomics, the characterization of the set of small molecules in a biological system, is advancing research in multiple areas of islet biology. Measuring a breadth of metabolites simultaneously provides a broad perspective on metabolic changes as the islets respond dynamically to metabolic fuels, hormones, or environmental stressors. As a result, metabolomics has the potential to provide new mechanistic insights into islet physiology and pathophysiology. Here we summarize advances in our understanding of islet physiology and the etiologies of type-1 and type-2 diabetes gained from metabolomics studies.
Collapse
|
|
37
|
Tangvarasittichai S. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J Diabetes 2015; 6:456-480. [PMID: 25897356 PMCID: PMC4398902 DOI: 10.4239/wjd.v6.i3.456] [Citation(s) in RCA: 738] [Impact Index Per Article: 73.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Revised: 11/21/2014] [Accepted: 01/12/2015] [Indexed: 02/05/2023] Open
Abstract
Oxidative stress is increased in metabolic syndrome and type 2 diabetes mellitus (T2DM) and this appears to underlie the development of cardiovascular disease, T2DM and diabetic complications. Increased oxidative stress appears to be a deleterious factor leading to insulin resistance, dyslipidemia, β-cell dysfunction, impaired glucose tolerance and ultimately leading to T2DM. Chronic oxidative stress, hyperglycemia and dyslipidemia are particularly dangerous for β-cells from lowest levels of antioxidant, have high oxidative energy requirements, decrease the gene expression of key β-cell genes and induce cell death. If β-cell functioning is impaired, it results in an under production of insulin, impairs glucose stimulated insulin secretion, fasting hyperglycemia and eventually the development of T2DM.
Collapse
|
|
38
|
Sadeghimahalli F, Karbaschi R, Zardooz H, Khodagholi F, Rostamkhani F. Effect of early life stress on pancreatic isolated islets' insulin secretion in young adult male rats subjected to chronic stress. Endocrine 2015; 48:493-503. [PMID: 25030548 DOI: 10.1007/s12020-014-0337-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Accepted: 06/10/2014] [Indexed: 01/12/2023]
Abstract
Early stressful experiences may predispose organisms to certain disorders, including those of metabolic defects. This study aimed to explore the effects of early life stress on pancreatic insulin secretion and glucose transporter 2 (GLUT2) protein levels in stressed young adult male rats. Foot shock stress was induced in early life (at 2 weeks of age) and/or in young adulthood (at 8-10 weeks of age) for five consecutive days. Blood samples were taken before and after stress exposure in young adult rats. At the end of the experiment, glucose tolerance, isolated islets' insulin secretion, and pancreatic amounts of GLUT2 protein were measured. Our results show that early life stress has no effect on basal plasma corticosterone levels and adrenal weight, either alone or combined with young adulthood stress, but that early life + young adulthood stress could prevent weight gain, and cause an increase in basal plasma glucose and insulin. The homeostasis model assessment of insulin resistance index did not increase, when the rats were subjected to early life stress alone, but increased when combined with young adulthood stress. Moreover, glucose tolerance was impaired by the combination of early life + young adult stress. There was a decrease in islet's insulin secretion in rats subjected to early life stress in response to 5.6 mM glucose concentration, but an increase with a concentration of 16.7 mM glucose. However, in rats subjected to early life + young adulthood stress, islet's insulin secretion increased in response to both the levels of glucose concentrations. GLUT2 protein levels decreased in response to early life stress and early life + young adulthood stress, but there was a greater decrease in the early life stress group. In conclusion, perhaps early life stress sensitizes the body to stressors later in life, making it more susceptible to metabolic syndrome only when the two are in combination.
Collapse
Affiliation(s)
- Forouzan Sadeghimahalli
- Department of Physiology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | | | | | | |
Collapse
|
|
39
|
Cadavez L, Montane J, Alcarraz-Vizán G, Visa M, Vidal-Fàbrega L, Servitja JM, Novials A. Chaperones ameliorate beta cell dysfunction associated with human islet amyloid polypeptide overexpression. PLoS One 2014; 9:e101797. [PMID: 25010593 PMCID: PMC4092029 DOI: 10.1371/journal.pone.0101797] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Accepted: 06/10/2014] [Indexed: 12/14/2022] Open
Abstract
In type 2 diabetes, beta-cell dysfunction is thought to be due to several causes, one being the formation of toxic protein aggregates called islet amyloid, formed by accumulations of misfolded human islet amyloid polypeptide (hIAPP). The process of hIAPP misfolding and aggregation is one of the factors that may activate the unfolded protein response (UPR), perturbing endoplasmic reticulum (ER) homeostasis. Molecular chaperones have been described to be important in regulating ER response to ER stress. In the present work, we evaluate the role of chaperones in a stressed cellular model of hIAPP overexpression. A rat pancreatic beta-cell line expressing hIAPP exposed to thapsigargin or treated with high glucose and palmitic acid, both of which are known ER stress inducers, showed an increase in ER stress genes when compared to INS1E cells expressing rat IAPP or INS1E control cells. Treatment with molecular chaperone glucose-regulated protein 78 kDa (GRP78, also known as BiP) or protein disulfite isomerase (PDI), and chemical chaperones taurine-conjugated ursodeoxycholic acid (TUDCA) or 4-phenylbutyrate (PBA), alleviated ER stress and increased insulin secretion in hIAPP-expressing cells. Our results suggest that the overexpression of hIAPP induces a stronger response of ER stress markers. Moreover, endogenous and chemical chaperones are able to ameliorate induced ER stress and increase insulin secretion, suggesting that improving chaperone capacity can play an important role in improving beta-cell function in type 2 diabetes.
Collapse
Affiliation(s)
- Lisa Cadavez
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
| | - Joel Montane
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
| | - Gema Alcarraz-Vizán
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
| | - Montse Visa
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
| | - Laia Vidal-Fàbrega
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Spain
| | - Joan-Marc Servitja
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
| | - Anna Novials
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
- * E-mail:
| |
Collapse
|
|
40
|
Abstract
Over 200 million people worldwide suffer from diabetes, a disorder of glucose homeostasis. The majority of these individuals are diagnosed with type 2 diabetes. It has traditionally been thought that tissue resistance to the action of insulin is the primary defect in type 2 diabetes. However, recent longitudinal and genome‐wide association studies have shown that insulin resistance is more likely to be a precondition, and that the failure of the pancreatic β cell to meet the increased insulin requirements is the triggering factor in the development of type 2 diabetes. A major emphasis in diabetes research has therefore shifted to understanding the causes of β cell failure. Collectively, these studies have implicated a complex network of triggers, which activate intersecting execution pathways leading to β cell dysfunction and death. In the present review, we discuss these triggers (glucotoxicity, lipotoxicity, amyloid and cytokines) with respect to the pathways they activate (oxidative stress, inflammation and endoplasmic reticulum stress) and propose a model for understanding β cell failure in type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00021.x, 2010)
Collapse
Affiliation(s)
- Takeshi Ogihara
- Department of Pediatrics and the Herman B Wells Center for Pediatric Research
| | - Raghavendra G Mirmira
- Department of Pediatrics and the Herman B Wells Center for Pediatric Research ; Departments of Medicine and Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
| |
Collapse
|
|
41
|
Nagao M, Asai A, Inaba W, Kawahara M, Shuto Y, Kobayashi S, Sanoyama D, Sugihara H, Yagihashi S, Oikawa S. Characterization of pancreatic islets in two selectively bred mouse lines with different susceptibilities to high-fat diet-induced glucose intolerance. PLoS One 2014; 9:e84725. [PMID: 24454742 PMCID: PMC3890274 DOI: 10.1371/journal.pone.0084725] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2013] [Accepted: 11/18/2013] [Indexed: 12/26/2022] Open
Abstract
Hereditary predisposition to diet-induced type 2 diabetes has not yet been fully elucidated. We recently established 2 mouse lines with different susceptibilities (resistant and prone) to high-fat diet (HFD)-induced glucose intolerance by selective breeding (designated selectively bred diet-induced glucose intolerance-resistant [SDG-R] and -prone [SDG-P], respectively). To investigate the predisposition to HFD-induced glucose intolerance in pancreatic islets, we examined the islet morphological features and functions in these novel mouse lines. Male SDG-P and SDG-R mice were fed a HFD for 5 weeks. Before and after HFD feeding, glucose tolerance was evaluated by oral glucose tolerance test (OGTT). Morphometry and functional analyses of the pancreatic islets were also performed before and after the feeding period. Before HFD feeding, SDG-P mice showed modestly higher postchallenge blood glucose levels and lower insulin increments in OGTT than SDG-R mice. Although SDG-P mice showed greater β cell proliferation than SDG-R mice under HFD feeding, SDG-P mice developed overt glucose intolerance, whereas SDG-R mice maintained normal glucose tolerance. Regardless of whether it was before or after HFD feeding, the isolated islets from SDG-P mice showed impaired glucose- and KCl-stimulated insulin secretion relative to those from SDG-R mice; accordingly, the expression levels of the insulin secretion-related genes in SDG-P islets were significantly lower than those in SDG-R islets. These findings suggest that the innate predispositions in pancreatic islets may determine the susceptibility to diet-induced diabetes. SDG-R and SDG-P mice may therefore be useful polygenic animal models to study the gene–environment interactions in the development of type 2 diabetes.
Collapse
Affiliation(s)
- Mototsugu Nagao
- Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Akira Asai
- Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Wataru Inaba
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Momoyo Kawahara
- Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Yuki Shuto
- Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Shunsuke Kobayashi
- Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Daisuke Sanoyama
- Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Hitoshi Sugihara
- Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Soroku Yagihashi
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Shinichi Oikawa
- Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
- * E-mail:
| |
Collapse
|
|
42
|
Montane J, Cadavez L, Novials A. Stress and the inflammatory process: a major cause of pancreatic cell death in type 2 diabetes. Diabetes Metab Syndr Obes 2014; 7:25-34. [PMID: 24520198 PMCID: PMC3917922 DOI: 10.2147/dmso.s37649] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Type 2 diabetes (T2D) is a complex metabolic disorder characterized by hyperglycemia in the context of insulin resistance, which precedes insulin deficiency as a result of β-cell failure. Accumulating evidence indicates that β-cell loss in T2D results as a response to the combination of oxidative stress and endoplasmic reticulum (ER) stress. Failure of the ER's adaptive capacity and further activation of the unfolded protein response may trigger macroautophagy (hereafter referred as autophagy) as a process of self-protection and inflammation. Many studies have shown that inflammation plays a very important role in the pathogenesis of T2D. Inflammatory mechanisms and cytokine production activated by stress via the inflammasome may further alter the normal structure of β-cells by inducing pancreatic islet cell apoptosis. Thus, the combination of oxidative and ER stress, together with autophagy insufficiency and inflammation, may contribute to β-cell death or dysfunction in T2D. Therapeutic approaches aimed at ameliorating stress and inflammation may therefore prove to be promising targets for the development of new diabetes treatment methods. Here, we discuss different mechanisms involved in stress and inflammation, and the role of antioxidants, endogenous and chemical chaperones, and autophagic pathways, which may shift the tendency from ER stress and apoptosis toward cell survival. Strategies targeting cell survival can be essential for relieving ER stress and reestablishing homeostasis, which may diminish inflammation and prevent pancreatic β-cell death associated with T2D.
Collapse
Affiliation(s)
- Joel Montane
- Diabetes and Obesity Research Laboratory, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
| | - Lisa Cadavez
- Diabetes and Obesity Research Laboratory, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
| | - Anna Novials
- Diabetes and Obesity Research Laboratory, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
- Correspondence: Anna Novials, Diabetes and Obesity Research Laboratory, Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clínic de Barcelona, c/Rosello, 149-153 08036, Barcelona, Spain, Tel +34 93 227 5400, Fax +34 93 312 9403, Email
| |
Collapse
|
|
43
|
Lee SH, Athavankar S, Cohen T, Piran R, Kiselyuk A, Levine F. Identification of alverine and benfluorex as HNF4α activators. ACS Chem Biol 2013; 8:1730-6. [PMID: 23675775 DOI: 10.1021/cb4000986] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The principal finding of this study is that two drugs, alverine and benfluorex, used in vastly different clinical settings, activated the nuclear receptor transcription factor HNF4α. Both were hits in a high-throughput screen for compounds that reversed the inhibitory effect of the fatty acid palmitate on human insulin promoter activity. Alverine is used in the treatment of irritable bowel syndrome, while benfluorex (Mediator) was used to treat hyperlipidemia and type II diabetes. Benfluorex was withdrawn from the market recently because of serious cardiovascular side effects related to fenfluramine-like activity. Strikingly, alverine and benfluorex have a previously unrecognized structural similarity, consistent with a common mechanism of action. Gene expression and biochemical studies revealed that they both activate HNF4α. This novel mechanism of action should lead to a reinterpretation of previous studies with these drugs and suggests a path toward the development of therapies for diseases such as inflammatory bowel and diabetes that may respond to HNF4α activators.
Collapse
Affiliation(s)
- Seung-Hee Lee
- Sanford Children’s
Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla,
California, 92037, United States
| | - Sonalee Athavankar
- Sanford Children’s
Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla,
California, 92037, United States
| | - Tom Cohen
- Sanford Children’s
Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla,
California, 92037, United States
| | - Ron Piran
- Sanford Children’s
Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla,
California, 92037, United States
| | - Alice Kiselyuk
- Sanford Children’s
Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla,
California, 92037, United States
| | - Fred Levine
- Sanford Children’s
Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla,
California, 92037, United States
| |
Collapse
|
|
44
|
Koulajian K, Ivovic A, Ye K, Desai T, Shah A, Fantus IG, Ran Q, Giacca A. Overexpression of glutathione peroxidase 4 prevents β-cell dysfunction induced by prolonged elevation of lipids in vivo. Am J Physiol Endocrinol Metab 2013; 305:E254-62. [PMID: 23695217 DOI: 10.1152/ajpendo.00481.2012] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
We have shown that oxidative stress is a mechanism of free fatty acid (FFA)-induced β-cell dysfunction. Unsaturated fatty acids in membranes, including plasma and mitochondrial membranes, are substrates for lipid peroxidation, and lipid peroxidation products are known to cause impaired insulin secretion. Therefore, we hypothesized that mice overexpressing glutathione peroxidase-4 (GPx4), an enzyme that specifically reduces lipid peroxides, are protected from fat-induced β-cell dysfunction. GPx4-overexpressing mice and their wild-type littermate controls were infused intravenously with saline or oleate for 48 h, after which reactive oxygen species (ROS) were imaged, using dihydrodichlorofluorescein diacetate in isolated islets, and β-cell function was assessed ex vivo in isolated islets and in vivo during hyperglycemic clamps. Forty-eight-hour FFA elevation in wild-type mice increased ROS and the lipid peroxidation product malondialdehyde and impaired β-cell function ex vivo in isolated islets and in vivo, as assessed by decreased disposition index. Also, islets of wild-type mice exposed to oleate for 48 h had increased ROS and lipid peroxides and decreased β-cell function. In contrast, GPx4-overexpressing mice showed no FFA-induced increase in ROS and lipid peroxidation and were protected from the FFA-induced impairment of β-cell function assessed in vitro, ex vivo and in vivo. These results implicate lipid peroxidation in FFA-induced β-cell dysfunction.
Collapse
Affiliation(s)
- Khajag Koulajian
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Somesh BP, Verma MK, Sadasivuni MK, Mammen-Oommen A, Biswas S, Shilpa PC, Reddy AK, Yateesh AN, Pallavi PM, Nethra S, Smitha R, Neelima K, Narayanan U, Jagannath MR. Chronic glucolipotoxic conditions in pancreatic islets impair insulin secretion due to dysregulated calcium dynamics, glucose responsiveness and mitochondrial activity. BMC Cell Biol 2013; 14:31. [PMID: 23815372 PMCID: PMC3704974 DOI: 10.1186/1471-2121-14-31] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2012] [Accepted: 06/24/2013] [Indexed: 11/10/2022] Open
Abstract
Background In the progression towards diabetes, glucolipotoxicity is one of the main causes of pancreatic beta cell pathology. The aim of this study was to examine the in vitro effects of chronic glucolipotoxic conditions on cellular responses in pancreatic islets, including glucose and fat metabolism, Calcium mobilization, insulin secretion and insulin content. Results Exposure of islets to chronic glucolipotoxic conditions decreased glucose stimulated insulin secretion in vitro. Reduced protein levels of Glut2/slc2a2, and decreased glucokinase and pyruvate carboxylase mRNA levels indicated a significant lowering in glucose sensing. Concomitantly, both fatty acid uptake and triglyceride accumulation increased significantly while fatty acid oxidation decreased. This general suppression in glucose metabolism correlated well with a decrease in mitochondrial number and activity, reduction in cellular ATP content and dampening of the TCA cycle. Further, we also observed a decrease in IP3 levels and lower Calcium mobilization in response to glucose. Importantly, chronic glucolipotoxic conditions in vitro decreased insulin gene expression, insulin content, insulin granule docking (to the plasma membrane) and insulin secretion. Conclusions Our results present an integrated view of the effects of chronic glucolipotoxic conditions on known and novel signaling events, in vitro, that results in reduced glucose responsiveness and insulin secretion.
Collapse
Affiliation(s)
- Baggavalli P Somesh
- Connexios Life Sciences Pvt Ltd., No. 49, First Main road, 3rd phase, JP Nagar, Bangalore 560 078, India
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
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.
Collapse
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:
| |
Collapse
|
|
47
|
Abstract
β-Cell failure coupled with insulin resistance is a key factor in the development of type 2 diabetes. Changes in circulating levels of adipokines, factors released from adipose tissue, form a significant link between excessive adiposity in obesity and both aforementioned factors. In this review, we consider the published evidence for the role of individual adipokines on the function, proliferation, death and failure of β-cells, focusing on those reported to have the most significant effects (leptin, adiponectin, tumour necrosis factor α, resistin, visfatin, dipeptidyl peptidase IV and apelin). It is apparent that some adipokines have beneficial effects whereas others have detrimental properties; the overall contribution to β-cell failure of changed concentrations of adipokines in the blood of obese pre-diabetic subjects will be highly dependent on the balance between these effects and the interactions between the adipokines, which act on the β-cell via a number of intersecting intracellular signalling pathways. We emphasise the importance, and comparative dearth, of studies into the combined effects of adipokines on β-cells.
Collapse
Affiliation(s)
- Simon J Dunmore
- Diabetes and Metabolic Disease Research Group, Research Institute in Healthcare Science, University of Wolverhampton, Wolverhampton WV1 1LY, UK.
| | | |
Collapse
|
|
48
|
Shu L, Zien K, Gutjahr G, Oberholzer J, Pattou F, Kerr-Conte J, Maedler K. TCF7L2 promotes beta cell regeneration in human and mouse pancreas. Diabetologia 2012; 55:3296-307. [PMID: 22945304 DOI: 10.1007/s00125-012-2693-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2012] [Accepted: 07/17/2012] [Indexed: 11/25/2022]
Abstract
AIMS/HYPOTHESIS Diabetes is characterised by loss and dysfunction of the beta cell. A major goal of diabetes therapy is to promote the formation of new beta cells. Polymorphisms of T cell factor 7-like 2 (TCF7L2) are associated with type 2 diabetes, negatively regulating beta cell survival and function. Here, we provide evidence for a role of TCF7L2 in beta cell proliferation and regeneration. METHODS Pancreatic sections from three mouse models (high-fat diet, exendin-4 and streptozotocin-treated mice) and from healthy individuals and patients with type 2 diabetes were used to investigate the association of beta cell regeneration and TCF7L2 levels. To analyse a direct effect of TCF7L2 on duct cell to beta cell conversion, TCF7L2 was overexpressed in isolated exocrine cells. RESULTS TCF7L2 levels correlated with beta cell compensation during high-fat diet feeding. TCF7L2 was increased together with pancreatic duct cell proliferation and differentiation. Small islet-like cell clusters (ICCs) that contained TCF7L2 originated in the vicinity of the ductal epithelium. In human isolated exocrine tissue, TCF7L2 overexpression induced proliferation of pancreatic duct cells and ICC formation next to duct cells, an effect dependent on the JAK2/STAT3 pathway. CONCLUSIONS/INTERPRETATION The present study demonstrates that TCF7L2 overexpression fosters beta cell regeneration. Our findings imply correlation of TCF7L2 levels and new beta cell formation.
Collapse
Affiliation(s)
- L Shu
- Centre for Biomolecular Interactions Bremen, University of Bremen, Leobener Strasse NW2, Bremen, Germany
| | | | | | | | | | | | | |
Collapse
|
|
49
|
|
|
50
|
Abstract
Recent technical advances have re-invigorated the study of sphingolipid metabolism in general, and helped to highlight the varied and important roles that sphingolipids play in pancreatic β-cells. Sphingolipid metabolites such as ceramide, glycosphingolipids, sphingosine 1-phosphate and gangliosides modulate many β-cell signaling pathways and processes implicated in β-cell diabetic disease such as apoptosis, β-cell cytokine secretion, ER-to-golgi vesicular trafficking, islet autoimmunity and insulin gene expression. They are particularly relevant to lipotoxicity. Moreover, the de novo synthesis of sphingolipids occurs on many subcellular membranes, in parallel to secretory vesicle formation, traffic and granule maturation events. Indeed, the composition of the plasma membrane, determined by the activity of neutral sphingomyelinases, affects β-cell excitability and potentially insulin exocytosis while another glycosphingolipid, sulfatide, determines the stability of insulin crystals in granules. Most importantly, sphingolipid metabolism on internal membranes is also strongly implicated in regulating β-cell apoptosis.
Collapse
Affiliation(s)
- Ebru Boslem
- Diabetes and Obesity Program; Garvan Institute of Medical Research; Darlinghurst, NSW Australia
- St Vincent’s Clinical School; Faculty of Medicine; University of New South Wales; Sydney, NSW Australia
| | - Peter J. Meikle
- Baker IDI Heart and Diabetes Institute; Melbourne, VIC Australia
| | - Trevor J. Biden
- Diabetes and Obesity Program; Garvan Institute of Medical Research; Darlinghurst, NSW Australia
- St Vincent’s Clinical School; Faculty of Medicine; University of New South Wales; Sydney, NSW Australia
- Correspondence to: Trevor J. Biden,
| |
Collapse
|