The role of cyclic AMP in the pathogenesis of glucose desensitization in rat pancreatic islets

Adenosine-3',5' -cyclic monophosphate (cyclic AMP) promotes exocytosis of i nsulin in pancreatic beta cells. This study was performed to investigate th e role of cyclic AMP in the pathogenesis of glucose desensitization in rat pancreatic islets. In islets cultured with high glucose for 48 hours, 27 mm ol/L glucose-induced insulin release was markedly impaired, while 3.3 mmol/ L glucose-or arginine-induced insulin release was enhanced, indicating gluc ose desensitization. Islet cyclic AMP content was 190% enhanced in high glu cose-culture islets for 48 hours. In islets cultured with dibutyrylcyclic A MP (dbcAMP) or 3-isobutyl methy-xanthine (IBMX), islet insulin content or 2 7 mmol/L glucose-induced insulin release was deteriorated. In contrast, 3.3 mmol/L glucose- or arginine-induced insulin release was increased, which w as similar to glucose-desensitized islets. Wash-out of dbc AMP for the last 24 hours of the 48-hour culture period restored impaired high glucose-indu ced insulin release in the same manner as wash- out of high glucose. Diazox ide, the KATP channel opener, also restored impaired high glucose-induced i nsulin release from dbcAMP-cultured islets. The data suggest that enhanceme nt of cyclic AMP in high glucose-culture islets may be one of the pathogene sis of glucose desensitization.