title: Time-dependent potentiation of insulin release induced by alpha-ketoisocaproate and leucine in rats: possible involvement of phosphoinositide hydrolysis.
abstract: The ability of the amino acid leucine and its keto acid, alpha-ketoisocaproate, to induce insulin release, to initiate phosphoinositide hydrolysis, and to amplify the subsequent insulin secretory response to glucose was assessed. In islets whose inositol-containing lipids were prelabelled with myo[2-3H]inositol, the addition of either compound resulted in an increase in insulin output, an increase in 3H efflux, rapid and significant increases in labelled inositol phosphate accumulation and a sustained increase in 3H efflux after removal of the stimulant. Direct measurements of labelled inositol phosphate accumulation in islets previously stimulated with alpha-ketoisocaproate demonstrate that this sustained increase in 3H efflux was the result of a persistent increase in phosphoinositide hydrolysis and was not simply a consequence of the hydrolysis of preformed inositol phosphates into more membrane permeable species. Prior exposure of islets to alpha-ketoisocaproate or leucine also resulted in an amplified secretory response to a subsequent glucose (10 mmol/l) stimulus. While peak first phase insulin release averaged 66 +/- 4 (mean +/- SEM, n = 18) pg.islet-1. min-1 from control islets, this value increased to 204 +/- 14 and 246 +/- 11 pg.islet-1.min-1 in the leucine or alpha-keto-isocaproate pretreated islets respectively. The duration of this amplified response paralleled the duration of the persistent increase in 3H efflux. Prior alpha-ketoisocaproate exposure also amplified the subsequent insulin secretory response to tolbutamide and glyceraldehyde.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Yale University School of Nursing, New Haven, Connecticut.
authors.forename: W S
authors.initials: WS
authors.lastname: Zawalich
mesh_terms: D000818:Animals; D002208:Caproates / Q000494:pharmacology*; D006868:Hydrolysis; D066298:In Vitro Techniques; D007294:Inositol / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007651:Keto Acids / Q000494:pharmacology*; D007930:Leucine / Q000494:pharmacology*; D008297:Male; D010716:Phosphatidylinositols / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D014316:Tritium
chemical_list: D002208:Caproates; D007328:Insulin; D007651:Keto Acids; D010716:Phosphatidylinositols; D014316:Tritium; D007294:Inositol; C013082:alpha-ketoisocaproic acid; D007930:Leucine