Time-dependent potentiation of insulin release induced by alpha-ketoisocaproate and leucine in rats: possible involvement of phosphoinositide hydrolysis

• Published in: Diabetologia Vol. 31; no. 7; p. 435
• Main Author: Zawalich, W S
• Format: Journal Article
• Language: English
• Published: Germany 01.07.1988
• Subjects: Animals; Caproates - pharmacology; Hydrolysis; In Vitro Techniques; Inositol - metabolism; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Keto Acids - pharmacology; Leucine - pharmacology; Male; Phosphatidylinositols - physiology; Rats; Rats, Inbred Strains; Reference Values; Tritium
• ISSN: 0012-186X
• DOI: 10.1007/bf00271588

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.