REGULATION OF INSULIN-SECRETION BY PHOSPHOLIPASE-C

Regulation of insulin secretion by phospholipase C. Am. J. Physiol. 27 1 (Endocrinol. Metab. 34): E409-E416, 1996.-Biphasic insulin secretion in response to a sustained glucose stimulus occurs when rat or human islets are exposed to high levels of the hexose. A transient burst of hormone secretion is followed by a rising and sustained secretory resp onse that, in the perfused rat pancreas, is 25- to 75-fold greater tha n prestimulatory insulin release rates. This insulin secretory respons e is paralleled by a significant five- to sixfold increase in the phos pholipase C (PLC)-mediated hydrolysis of islet phosphoinositide (PI) p ools by high glucose. In contrast, mouse islets, when stimulated under comparable conditions with high glucose, display a second-phase respo nse that is flat and only slightly (two- to threefold) greater than pr estimulatory release rates. The minimal second-phase insulin secretory response to high glucose is accompanied by the minimal activation of PLC in mouse islets as well. However, stimulation of mouse islets with the protein kinase C (PKC) activator tetradecanoyl phorbol acetate (T PA) or the muscarinic agonist carbachol, which significantly activates an isozyme of PLC distinct from that activated by high glucose, induc es a rising and sustained second-phase insulin secretory response. Whe n previously exposed to high glucose, both rat and human islets respon d to subsequent restimulation with an amplified insulin secretory resp onse. They display priming, sensitization, or time-dependent potentiat ion. In contrast, mouse islets primed under similar conditions with hi gh glucose fail to display this amplified insulin secretory response o n restimulation. Mouse islets can, however, be primed by brief exposur e to either TPA or carbachol. Finally, whereas rat islets are desensit ized by chronic exposure to high glucose, mouse islet insulin secretor y responses are relatively immune to this adverse effect of the hexose . These and other findings are discussed in relationship to the role b eing played by agonist-induced increases in the PLC-mediated hydrolysi s of islet phosphoinositide pools and the activation of PKC in these s pecies-specific insulin secretory response patterns.