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

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.