SYNERGISTIC INTERACTION OF GLUCOSE AND NEUROHUMORAL AGONISTS TO STIMULATE ISLET PHOSPHOINOSITIDE HYDROLYSIS

The interaction between neurohumoral agonists and glucose to stimulate phosphoinositide (PI)-specific phospholipase C (PLC) and insulin rele ase was examined. In freshly isolated rat islets, maximal glucose (40 mM), cholecystokinin (CCK; 300 nM), or carbachol (CCh; 1 mM) stimulate d PI hydrolysis 6.5-, 9.8-, and 5.7-fold, respectively, above basal. T he combination of glucose and CCK or of glucose and CCh, but not of CC K and CCh, synergistically increased PI hydrolysis 23.2- and 21.6-fold , respectively, indicating that these secretagogues activate PLC by di stinct pathways and that there is an interaction between them. This sy nergy was maximal at physiological concentrations of stimulatory gluco se (8-10 mM) and was paralleled by a marked synergistic stimulation of insulin secretion. The enhanced PI response was partially Ca2+ depend ent and may involve the activation of distinct isozymes of PLC, which we identify in islets. These studies demonstrate for the first time a unique and highly sensitive synergistic interaction between glucose an d neurohumoral agonists to stimulate PI hydrolysis, and they suggest t hat enhanced PI hydrolysis is important in the potentiation of glucose - and neurohumoral-stimulated insulin secretion.