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 release was examined. In freshly isolated rat islets, maximal glucose (40 mM), cholecystokinin (CCK; 300 nM), or carbachol (CCh; 1 mM) stimulated PI hydrolysis 6.5-, 9.8-, and 5.7-fold, respectively, above basal. The combination of glucose and CCK or of glucose and CCh, but not of CCK and CCh, synergistically increased PI hydrolysis 23.2- and 21.6-fold, respectively, indicating that these secretagogues activate PLC by distinct pathways and that there is an interaction between them. This synergy was maximal at physiological concentrations of stimulatory glucose (8-10 mM) and was paralleled by a marked synergistic stimulation of insulin secretion. The enhanced PI response was partially Ca2+ dependent 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 and neurohumoral agonists to stimulate PI hydrolysis, and they suggest that enhanced PI hydrolysis is important in the potentiation of glucose- and neurohumoral-stimulated insulin secretion.
Kelley
G G
GG
Department of Internal Medicine, Yale University School of Medicine, New Haven 06520-8020, USA.
Zawalich
K C
KC
Zawalich
W S
WS
D000818:Animals; D002118:Calcium / Q000502:physiology; D002217:Carbachol / Q000494:pharmacology; D004357:Drug Synergism; D005947:Glucose / Q000494:pharmacology*; D006868:Hydrolysis / Q000187:drug effects; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D018377:Neurotransmitter Agents / Q000819:agonists*; D009994:Osmolar Concentration; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D010738:Type C Phospholipases / Q000378:metabolism
D007328:Insulin; D007527:Isoenzymes; D018377:Neurotransmitter Agents; D010716:Phosphatidylinositols; D002217:Carbachol; D010738:Type C Phospholipases; D005947:Glucose; D002118:Calcium