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- Title
Glucotoxicity inhibits cAMP-protein kinase A-potentiated glucose-stimulated insulin secretion in pancreatic β-cells葡萄糖毒性抑制cAMP-PKA通路促进的胰岛 β细胞中血糖刺激的胰岛素分泌
- Authors
Kong, Xiangchen; Yan, Dan; Wu, Xuerui; Guan, Youfei; Ma, Xiaosong
- Abstract
Background The effect of incretin is markedly blunted in patients with type 2 diabetes ( T2D), and this reduced effect of incretin is correlated with a diminished insulintropic potency of glucagon-like peptide-1 ( GLP-1). We reported recently that GLP-1 potentiates glucose-stimulated insulin secretion ( GSIS) mainly via activation of the cAMP-protein kinase A ( PKA) signaling pathway in INS- 1E cells under hyperglycemic conditions. In the present study, we further explored whether glucotoxicity impairs cAMP- PKA-mediated effects and its relevance to the reduced insulinotropic action of GLP-1 in hyperglycemia. Methods Mouse islets and INS- 1E cells were cultured in 30 mmol/L glucose for 72 h. The effects of glucotoxicity on cAMP- PKA-linked pathways and its insulinotropic action were then evaluated. Results Chronic exposure of INS- 1E cells and primary mouse islets to 30 mmol/L glucose almost abolished GSIS. The cAMP-elevating agent forskolin produced an approximate 1.9-fold increase in GSIS, significantly lower than that observed with 5.5 mmol/L glucose (∼3.3-fold). Moreover, 72 h culture in the presence of 30 mmol/L glucose reduced forskolin-stimulated cAMP accumulation in β-cells. Notably, glucotoxicity reduced the expression and activity of PKA, as well as PKA-mediated effects. In contrast, glucotoxicity had no effect on the expression of Epac2, another cAMP effector. Conclusions Glucotoxicity-induced reductions in PKA and its signaling account, at least in part, for the decreased incretin effect under conditions of glucotoxicity.
- Subjects
INCRETINS; TYPE 2 diabetes; GLUCAGON-like peptide 1; PROTEIN kinases; HYPERGLYCEMIA
- Publication
Journal of Diabetes, 2015, Vol 7, Issue 3, p378
- ISSN
1753-0393
- Publication type
Article
- DOI
10.1111/1753-0407.12185