Lipotoxicity impairs incretin signalling

Diabetologia. 2013 Feb;56(2):231-3. doi: 10.1007/s00125-012-2788-6. Epub 2012 Nov 28.

Abstract

The incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic peptide are secreted by enteroendocrine cells and augment glucose-induced insulin secretion in response to food ingestion in a glucose-dependent manner. This mechanism forms the basis for incretin-based therapies in type 2 diabetes. However, the insulinotropic effect of incretins is diminished in type 2 diabetic patients, due in part to reduced expression of incretin receptors as a consequence of glucotoxicity. In this issue of Diabetologia, Kang et al (DOI: 10.1007/s00125-012-2776-x ) provide evidence that in addition to glucotoxicity, lipotoxicity also affects incretin receptor expression and signalling in insulin-secreting cells and isolated islets. In animal models of diabetes, the authors show that co-administration of a lipid-lowering drug with a dipeptidyl peptidase-4 inhibitor or a glucagon-like peptide-1 agonist improved glucose tolerance and beta cell mass. These novel findings provide convincing support for the notion that restoring normal circulating lipid levels in type 2 diabetes might help improve the efficacy of incretin-based therapies.

Publication types

  • Comment

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism*
  • Fatty Acids, Nonesterified / metabolism*
  • Glucagon-Like Peptide-1 Receptor
  • Incretins / therapeutic use*
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism*
  • Male
  • Receptors, Glucagon / metabolism*

Substances

  • Fatty Acids, Nonesterified
  • Glucagon-Like Peptide-1 Receptor
  • Incretins
  • Receptors, Glucagon