Evidence for paracrine/autocrine regulation of GLP-1-producing cells

Am J Physiol Cell Physiol. 2013 Nov 15;305(10):C1041-9. doi: 10.1152/ajpcell.00227.2013. Epub 2013 Aug 28.


Glucagon-like peptide-1 (GLP-1), secreted from gut L cells upon nutrient intake, forms the basis for novel drugs against type 2 diabetes (T2D). Secretion of GLP-1 has been suggested to be impaired in T2D and in conditions associated with hyperlipidemia and insulin resistance. Further, recent studies support lipotoxicity of GLP-1-producing cells in vitro. However, little is known about the regulation of L-cell viability/function, the effects of insulin signaling, or the potential effects of stable GLP-1 analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors. We determined effects of insulin as well as possible autocrine action of GLP-1 on viability/apoptosis of GLP-1-secreting cells in the presence/absence of palmitate, while also assessing direct effects on function. The studies were performed using the GLP-1-secreting cell line GLUTag, and palmitate was used to simulate hyperlipidemia. Our results show that palmitate induced production of reactive oxygen species and caspase-3 activity and reduced cell viability are significantly attenuated by preincubation with insulin/exendin-4. The indicated lipoprotective effect of insulin/exendin-4 was not detectable in the presence of the GLP-1 receptor (GLP-1R) antagonist exendin (9-39) and attenuated in response to pharmacological inhibition of exchange protein activated by cAMP (Epac) signaling, while protein kinase A inhibition had no significant effect. Insulin/exendin-4 also significantly stimulate acute and long-term GLP-1 secretion in the presence of glucose, suggesting novel beneficial effects of insulin signaling and GLP-1R activation on glycemia through enhanced mass of GLP-1-producing cells and enhanced GLP-1 secretion. In addition, the effects of insulin indicate that not only is GLP-1 important for insulin secretion but altered insulin signaling may contribute to an altered GLP-1 secretion.

Keywords: L cell; exendin-4; glucagon-like peptide-1; insulinotropic; lipotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Proliferation
  • Cell Survival
  • Enteroendocrine Cells / cytology
  • Enteroendocrine Cells / drug effects
  • Enteroendocrine Cells / metabolism*
  • Exenatide
  • Gene Expression Regulation / physiology*
  • Glucagon-Like Peptide 1 / genetics
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucagon-Like Peptide-1 Receptor
  • Insulin / administration & dosage
  • Insulin / pharmacology*
  • Mice
  • Peptides / administration & dosage
  • Peptides / pharmacology*
  • Reactive Oxygen Species
  • Receptors, Glucagon / genetics
  • Receptors, Glucagon / metabolism
  • Time Factors
  • Venoms / administration & dosage
  • Venoms / pharmacology*


  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Insulin
  • Peptides
  • Reactive Oxygen Species
  • Receptors, Glucagon
  • Venoms
  • Glucagon-Like Peptide 1
  • Exenatide