Human Pancreatic Islets React to Glucolipotoxicity by Secreting Pyruvate and Citrate

Nutrients. 2023 Nov 15;15(22):4791. doi: 10.3390/nu15224791.


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.

Keywords: GSIS; INS-1E; NMR; glucolipotoxicity; human pancreatic islets; insulin content; quantitative metabolomics; type 2 diabetes.

MeSH terms

  • Animals
  • Citric Acid / metabolism
  • Citric Acid / pharmacology
  • Diabetes Mellitus, Type 2* / metabolism
  • Glucose / metabolism
  • Glucose / pharmacology
  • Humans
  • Insulin / metabolism
  • Insulin-Secreting Cells* / metabolism
  • Islets of Langerhans*
  • Pyruvic Acid / metabolism
  • Rats


  • Pyruvic Acid
  • Citric Acid
  • Glucose
  • Insulin

Grants and funding

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.).