Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration

Diabetologia. 2004 Mar;47(3):463-469. doi: 10.1007/s00125-004-1347-1. Epub 2004 Feb 13.


Aims/hypothesis: Whether excess glucose (glucotoxicity) and excess non-esterified fatty acids (lipotoxicity) act synergistically or separately to alter beta-cell function on Type 2 diabetes remains controversial. We examined the influence of non-esterified fatty acids, with or without concomitant increased glucose concentrations, on human islet function and on the expression of genes involved in lipid metabolism.

Methods: Human islets isolated from non-diabetic and non-obese donors were cultured with 5.5, 16 or 30 mmol/l glucose, and when appropriate with 1 or 2 mmol/l non-esterified fatty acids. After 48 h, glucose-stimulated insulin secretion, insulin content, triglyceride content and expression of different genes were evaluated.

Results: Non-esterified fatty acids decreased glucose-stimulated insulin secretion, insulin content and increased triglyceride content of human isolated islets, independently from the deleterious effect of glucose. Increased glucose concentrations also decreased glucose-stimulated insulin secretion and insulin content, but had no influence on triglyceride content. Glucose-stimulated insulin secretion of islets appeared to be significantly correlated with their triglyceride content. Glucose and non-esterified fatty acids modified the gene expression of carnitine palmitoyltransferase-I, acetyl-CoA carboxylase, acyl-CoA oxidase and uncoupling protein 2.

Conclusion/interpretation: In our model of isolated human islets, increased glucose and non-esterified fatty acids separately reproduced the two major beta-cell alterations observed in vivo, i.e. loss of glucose-stimulated insulin secretion and reduction in islet insulin content. Our results also suggest that this deleterious effect was, at least in part, mediated by modifications in lipid metabolism gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cells, Cultured
  • DNA Primers
  • Fatty Acids, Nonesterified / pharmacology*
  • Fatty Acids, Nonesterified / toxicity
  • Glucose / pharmacology*
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Triglycerides / metabolism


  • DNA Primers
  • Fatty Acids, Nonesterified
  • Insulin
  • Triglycerides
  • Glucose