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

Abstract

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.

• Authors: Gareth E Lim, Guan J Huang, Nina Flora, Derek LeRoith, Christopher J Rhodes, Patricia L Brubaker
• Journal: Endocrinology (Endocrinology) Vol. 150 Issue 2 Pg. 580-91 (Feb 2009) ISSN: 1945-7170 [Electronic] United States
• PMID: 18818290 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Animals
• Cells, Cultured
• Enteroendocrine Cells (drug effects, 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, metabolism)
• Signal Transduction (drug effects)