title: Glucotoxicity inhibits cAMP-protein kinase A-potentiated glucose-stimulated insulin secretion in pancreatic β-cells.
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.
authors: Diabetes Center of Shenzhen University and School of Medicine, Shenzhen University, Shenzhen, China.
authors: Xiangchen
authors: X
authors: Kong
authors: Dan
authors: D
authors: Yan
authors: Xuerui
authors: X
authors: Wu
authors: Youfei
authors: Y
authors: Guan
authors: Xiaosong
authors: X
authors: Ma
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000633:toxicity*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D013549:Sweetening Agents / Q000633:toxicity*
chemical_list: D007328:Insulin; D013549:Sweetening Agents; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose
keywords: cAMP; glucagon-like peptide-1; glucotoxicity; insulin secretion; protein kinase A; 关键词：cAMP，胰高血糖素样肽-1，葡萄糖毒性，胰岛素分泌，PKA。