ROLES OF GTP AND PHOSPHOLIPASE-C IN THE POTENTIATION OF CA2-INDUCED INSULIN-SECRETION BY GLUCOSE IN RAT PANCREATIC-ISLETS()

Glucose can augment insulin secretion independently of K+ channel clos ure, provided cytoplasmic free Ca2+ concentration is elevated. A role for phospholipase C (PLC) in this phenomenon has been both claimed and refuted. Recently, we have shown a role for GTP in the secretory effe ct of glucose as well as in glucose-induced PLC activation, using isle ts pre-treated with GTP synthesis inhibitors such as mycophenolic acid (MPA). Therefore, in the current studies, we examined first, whether glucose augments Ca2+-induced PLC activation and second, whether GTP i s required for this effect, when K+(ATP) channels are kept open using diazoxide. Isolated rat islets pre-labeled with [H-3]myo-inositol were studied with or without first priming with glucose. There was a 98% g reater augmentation of insulin secretion by 16.7 mM glucose (in the pr esence of diazoxide and 40 mM K+) in primed islets; however, the abili ty of high glucose to augment PLC activity bore no relationship to the secretory response. MPA markedly inhibited PLC in both conditions; ho wever, insulin secretion was only inhibited (by 46%) in primed islets. None of these differences were attributable to alterations in labelin g of phosphoinositides or levels of GTP or ATP. These data indicate th at an adequate level of GTP is critical for glucose's potentiation of Ca2+-induced insulin secretion in primed islets but that PLC activatio n can clearly be dissociated from insulin secretion and therefore cann ot be the major cause of glucose's augmentation of Ca2+-induced insuli n secretion.