COMPARATIVE EFFECTS OF MONOMETHYLSUCCINATE AND GLUCOSE ON INSULIN-SECRETION FROM PERIFUSED RAT ISLETS

In the absence of any other exogenously added fuel, monomethylsuccinat e, the methyl ester of succinic acid, at 10-20 mM stimulates insulin r elease in a biphasic pattern. In quantitative terms, first-phase relea se evoked by 20 mM MMSucc was comparable to that observed with 20 mM g lucose but second-phase release was only 20% of the glucose-induced re sponse. Secretion to both MMSucc and glucose was virtually abolished b y the calcium channel antagonist nitrendipine (0.5 muM). In islets tha t had phosphoinositide pools labeled with [H-3]inositol for 2 h, subse quent stimulation with 20 mM MMSucc results in dramatic and sustained increases in [H-3]inositol efflux rates. Inositol phosphate levels are also increased. In contrast to secretion, the increase in phosphoinos itide hydrolysis caused by MMSucc was largely resistant to nitrendipin e, whereas significant reductions in glucose-induced phosphoinositide hydrolysis were observed in the presence of the calcium channel antago nist. MMSucc (2.75-10 mM) substitutes for glucose in that MMSucc suppo rted the insulinotropic effects of the sulfonylurea tolbutamide (200 m uM) and the gut hormone cholecystokinin (200 nM). A prior 15-min expos ure to 20 mM MMSucc also sensitized islets to the stimulatory effects of 7.5 mM glucose. Finally, a 2-h exposure to 20 mM MMSucc desensitize d the islet, in terms of both phosphoinositide hydrolysis and insulin secretion, to a subsequent exposure to 10 mM glucose. Thus, appropriat e concentrations of MMSucc can cause qualitatively many of the effects induced by glucose. However, striking differences exist in the quanti tative effects that are most simply explained by assuming that MMSucc is able to stimulate phosphoinositide hydrolysis to the same extent as glucose but is less able to enhance Ca2+ influx than glucose. If this view is correct, it leads to the conclusion that an intracellular cal cium-independent signal derived from the metabolism of MMSucc is able to activate phosphoinositide hydrolysis in islets.