期刊
ENDOCRINOLOGY
卷 150, 期 2, 页码 580-591出版社
ENDOCRINE SOC
DOI: 10.1210/en.2008-0726
关键词
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资金
- Canadian Diabetes Association [2374]
- National Science and Engineering Research Canada Graduate Scholarship
- Banting and Best Diabetes Centre (BBDC) Novo Nordisk Studentship (University of Toronto)
- Canadian Institutes of Health Research (CIHR) Frederick Banting and Charles Best Canada Graduate Scholarship
- Crohn's and Colitis Foundation of Canada
- Canadian Association of Gastroenterology
- CIHR Summer Studentship
- BBDC Charles Hollenberg Summer Studentship
- Canada Research Chairs Program
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 NCl-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-myristate13-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. (Endocrinology 150: 580-591, 2009)
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