Effect of diacylglycerol lipase inhibitor RHC 80267 on pancreatic mouse islet metabolism and insulin secretion

Summary The effect of interference with diacylglycerol metabolism was investigated in pancreatic mouse islets. In the presence of the diacylglycerol lipase inhibitor RHC 80267, glucose-induced insulin secretion was reduced 50–60%; whereas carbacholin-induced insulin secretion was unaffected. Addition of the diacylglycerol kinase inhibitor R 59022 did not change glucose-stimulated insulin secretion but abolished the inhibition seen in the presence of RHC 80267. RHC 80267 increased islet glucose utilisation, measured as formation of tritiated water from 5-[³H]-glucose, 3-fold but did not affect glucose oxidation to CO₂, lactate production or islet ATP levels. Glucose utilisation in leucocytes and hepatocytes was not increased by addition of RHC 80267. Islet lipid production from glucose was augmented 4-fold in the presence of RHC 80267 but only accounted for about 5% of the increase in glucose utilisation. The activity of adenylate cyclase and phosphoinositide-specific phospholipase C was unaffected by RHC 80267. Concentrations of RHC 80267 below 35 mol/l did not alter the activity of phospholipase A₂; whereas higher concentrations of the drug inhibited phospholipase A₂ activity approx 25%. The data support the hypothesis that production of arachidonic acid from diacylglycerol may be involved in regulation of insulin secretion.Abbreviations RHC 80267 (1,6-di(O-(carbamoyl)cyclohexanone oxime)hexane) - R 59022 6-[2-[4-[(4-fluorophenyl)phenylmethylene]-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo[3,2-]pyrimidin-5-one