Insulin regulates glucagon-like peptide-1 secretion from the enteroendocrine L cell

Endocrinology. 2009 Feb;150(2):580-91. doi: 10.1210/en.2008-0726. Epub 2008 Sep 25.


Insulin resistance and type 2 diabetes mellitus are associated with impaired postprandial secretion of glucagon-like peptide-1 (GLP-1), a potent insulinotropic hormone. The direct effects of insulin and insulin resistance on the L cell are unknown. We therefore hypothesized that the L cell is responsive to insulin and that insulin resistance impairs GLP-1 secretion. The effects of insulin and insulin resistance were examined in well-characterized L cell models: murine GLUTag, human NCI-H716, and fetal rat intestinal cells. MKR mice, a model of chronic hyperinsulinemia, were used to assess the function of the L cell in vivo. In all cells, insulin activated the phosphatidylinositol 3 kinase-Akt and MAPK kinase (MEK)-ERK1/2 pathways and stimulated GLP-1 secretion by up to 275 +/- 58%. Insulin resistance was induced by 24 h pretreatment with 10(-7) m insulin, causing a marked reduction in activation of Akt and ERK1/2. Furthermore, both insulin-induced GLP-1 release and secretion in response to glucose-dependent insulinotropic peptide and phorbol-12-myristate-13-acetate were significantly attenuated. Whereas inhibition of phosphatidylinositol 3 kinase with LY294002 potentiated insulin-induced GLP-1 release, secretion was abrogated by inhibiting the MEK-ERK1/2 pathway with PD98059 or by overexpression of a kinase-dead MEK1-ERK2 fusion protein. Compared with controls, MKR mice were insulin resistant and displayed significantly higher fasting plasma insulin levels. Furthermore, they had significantly higher basal GLP-1 levels but displayed impaired GLP-1 secretion after an oral glucose challenge. These findings indicate that the intestinal L cell is responsive to insulin and that insulin resistance in vitro and in vivo is associated with impaired GLP-1 secretion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Enteroendocrine Cells / drug effects*
  • Enteroendocrine Cells / metabolism*
  • Female
  • Glucagon-Like Peptide 1 / metabolism*
  • Humans
  • Insulin / pharmacology*
  • Insulin Resistance / physiology
  • Insulin-Like Growth Factor I / pharmacology
  • Male
  • Mice
  • Mice, Knockout
  • Pregnancy
  • Rats
  • Rats, Wistar
  • Receptor, IGF Type 1 / agonists
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism
  • Signal Transduction / drug effects


  • Insulin
  • Insulin-Like Growth Factor I
  • Glucagon-Like Peptide 1
  • Receptor, IGF Type 1
  • Receptor, Insulin