Nutrient control of insulin secretion in perifused adult pig islets.

OBJECTIVES: Xenotransplantation of pig islets is a potential solution to the shortage of human islets, but our knowledge of how these islets secrete insulin in response to nutrients is still fragmentary. This was the question addressed in the present study. METHODS: After 24 h culture adult pig islets were perifused to characterize the dynamics of insulin secretion. Some responses were compared to those in human islets. RESULTS: Increasing glucose from 1 to 15 mM weakly (approximately 2x) stimulated insulin secretion, which was potentiated (approximately 12x) by the cAMP-producing agent, forskolin. The effect of glucose was concentration-dependent (threshold at 3-5 mM and maximum at approximately 10 mM). The pattern of secretion was biphasic with a small first phase and an ascending second phase, and a paradoxical increase when the glucose concentration was abruptly lowered. Diazoxide abolished glucose-induced insulin secretion and tolbutamide reversed the inhibition. Glucose also increased secretion when islets were depolarized with tolbutamide or KCl. Insulin secretion was increased by leucine+glutamine, arginine, alanine or a mixture of amino acids, but their effect was significant only in the presence of forskolin. Upon stimulation by glucose alone, human islets secreted approximately 10x more insulin than pig islets, and the kinetics was characterized by a large first phase, a flat second phase, and rapid reversibility. CONCLUSIONS: Compared with human islets, in vitro insulin secretion by adult pig islets is characterized by a different kinetics and a major quantitative deficiency that can be corrected by cAMP.