GSIS; INS-1E; NMR; glucolipotoxicity; human pancreatic islets; insulin content; quantitative metabolomics; type 2 diabetes; Pyruvic Acid; Citric Acid; Glucose; Insulin; Rats; Animals; Humans; Pyruvic Acid/metabolism; Citric Acid/pharmacology; Citric Acid/metabolism; Glucose/pharmacology; Glucose/metabolism; Insulin/metabolism; Diabetes Mellitus, Type 2/metabolism; Islets of Langerhans; Insulin-Secreting Cells/metabolism; Diabetes Mellitus, Type 2; Insulin-Secreting Cells; Food Science; Nutrition and Dietetics
Abstract :
[en] Progressive decline in pancreatic beta-cell function is central to the pathogenesis of type 2 diabetes (T2D). Here, we explore the relationship between the beta cell and its nutritional environment, asking how an excess of energy substrate leads to altered energy production and subsequent insulin secretion. Alterations in intracellular metabolic homeostasis are key markers of islets with T2D, but changes in cellular metabolite exchanges with their environment remain unknown. We answered this question using nuclear magnetic resonance-based quantitative metabolomics and evaluated the consumption or secretion of 31 extracellular metabolites from healthy and T2D human islets. Islets were also cultured under high levels of glucose and/or palmitate to induce gluco-, lipo-, and glucolipotoxicity. Biochemical analyses revealed drastic alterations in the pyruvate and citrate pathways, which appear to be associated with mitochondrial oxoglutarate dehydrogenase (OGDH) downregulation. We repeated these manipulations on the rat insulinoma-derived beta-pancreatic cell line (INS-1E). Our results highlight an OGDH downregulation with a clear effect on the pyruvate and citrate pathways. However, citrate is directed to lipogenesis in the INS-1E cells instead of being secreted as in human islets. Our results demonstrate the ability of metabolomic approaches performed on culture media to easily discriminate T2D from healthy and functional islets.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Perrier, Johan; Laboratoire CarMeN, UMR INSERM U1060/INRAE U1397, University of Lyon, Université Claude Bernard Lyon 1, 69310 Pierre-Bénite, France
Nawrot, Margaux ; Laboratoire CarMeN, UMR INSERM U1060/INRAE U1397, University of Lyon, Université Claude Bernard Lyon 1, 69310 Pierre-Bénite, France
Madec, Anne-Marie; Laboratoire CarMeN, UMR INSERM U1060/INRAE U1397, University of Lyon, Université Claude Bernard Lyon 1, 69310 Pierre-Bénite, France
Chikh, Karim; Laboratoire CarMeN, UMR INSERM U1060/INRAE U1397, University of Lyon, Université Claude Bernard Lyon 1, 69310 Pierre-Bénite, France ; Department of Endocrinology and Diabetes, Hospices Civils de Lyon, Hopital Lyon Sud, 69310 Pierre-Bénite, France
Chauvin, Marie-Agnès; Laboratoire CarMeN, UMR INSERM U1060/INRAE U1397, University of Lyon, Université Claude Bernard Lyon 1, 69310 Pierre-Bénite, France
Damblon, Christian ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie biologique structurale
Sabatier, Julia; Laboratory of Cell Therapy for Diabetes (LTCD), PRIMS Facility, Institute for Regenerative Medicine and Biotherapy (IRMB), University Hospital of Montpellier, 34295 Montpellier, France
Thivolet, Charles H; Laboratoire CarMeN, UMR INSERM U1060/INRAE U1397, University of Lyon, Université Claude Bernard Lyon 1, 69310 Pierre-Bénite, France ; Department of Endocrinology and Diabetes, Hospices Civils de Lyon, Hopital Lyon Sud, 69310 Pierre-Bénite, France
Rieusset, Jennifer ; Laboratoire CarMeN, UMR INSERM U1060/INRAE U1397, University of Lyon, Université Claude Bernard Lyon 1, 69310 Pierre-Bénite, France
Rautureau, Gilles J P ; Centre de Résonance Magnétique Nucléaire à Très Hauts Champs, UMR 5082 CNRS, ENS Lyon, UCBL, Université de Lyon, 69100 Villeurbanne, France
Panthu, Baptiste ; Laboratoire CarMeN, UMR INSERM U1060/INRAE U1397, University of Lyon, Université Claude Bernard Lyon 1, 69310 Pierre-Bénite, France
Language :
English
Title :
Human Pancreatic Islets React to Glucolipotoxicity by Secreting Pyruvate and Citrate.
Publication date :
15 November 2023
Journal title :
Nutrients
ISSN :
2072-6643
Publisher :
Multidisciplinary Digital Publishing Institute (MDPI), Switzerland
CNRS - Centre National de la Recherche Scientifique SFD - Société Francophone du Diabète SFN - Société Française de Nutrition
Funding text :
Financial support from the IR-RMN-THC Fr3050 CNRS for conducting the research is gratefully acknowledged. This research was funded by the Price of the Francophone Diabetes Society (SFD) and the French Society of Nutrition (SFN) (B.P.).
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