Roles of GTP and phospholipase C in the potentiation of Ca(2+)-induced insulin secretion by glucose in rat pancreatic islets.
Glucose can augment insulin secretion independently of K+ channel closure, 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 effect of glucose as well as in glucose-induced PLC activation, using islets pre-treated with GTP synthesis inhibitors such as mycophenolic acid (MPA). Therefore, in the current studies, we examined first, whether glucose augments Ca(2+)-induced PLC activation and second, whether GTP is required for this effect, when K+(ATP) channels are kept open using diazoxide. Isolated rat islets pre-labeled with [3H]myo-inositol were studied with or without first priming with glucose. There was a 98% greater augmentation of insulin secretion by 16.7 mM glucose (in the presence of diazoxide and 40 mM K+) in primed islets; however, the ability of high glucose to augment PLC activity bore no relationship to the secretory response. MPA markedly inhibited PLC in both conditions; however, insulin secretion was only inhibited (by 46%) in primed islets. None of these differences were attributable to alterations in labeling of phosphoinositides or levels of GTP or ATP. These data indicate that an adequate level of GTP is critical for glucose's potentiation of Ca(2+)-induced insulin secretion in primed islets but that PLC activation can clearly be dissociated from insulin secretion and therefore cannot be the major cause of glucose's augmentation of Ca(2+)-induced insulin secretion.
Vadakekalam
J
J
William S Middleton Veterans' Administration Hospital, Department of Medicine, University of Wisconsin-Madison 53792, USA.
Rabaglia
M E
ME
Metz
S A
SA
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D046508:Culture Techniques; D003981:Diazoxide / Q000494:pharmacology; D004357:Drug Synergism; D004789:Enzyme Activation; D005947:Glucose / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010716:Phosphatidylinositols / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D010738:Type C Phospholipases / Q000378:metabolism*
D007328:Insulin; D010716:Phosphatidylinositols; D015221:Potassium Channels; D006160:Guanosine Triphosphate; D010738:Type C Phospholipases; D005947:Glucose; D003981:Diazoxide; D002118:Calcium