A Comparison of Leucine- and Acetoacetate-induced Hypoglycemia in Man.

In previous studies we have reported that a) marked sensitivity to leucine hypoglycemia can be induced consistently in healthy subjects after the oral administration of sulfonylureas, compounds that are known to stimulate islet cell activity (1), b) a modest but significant hypoglycemic effect can be produced by administering leucine to healthy subjects without sulfonylurea pretreatment (1, 2), c) release of additional insulin is the primary mechanism by which leucine causes hypoglycemia in healthy subjects either with or without sensitization by sulfonylureas (1, 3), and d) leucine itself, rather than one of its metabolites, induces insulin release and hypoglycemia (4). The last conclusion was reached from a comparison of the effects of leucine, alpha-ketoisocaproate, and isovalerate administered in equimolar amounts to the same chlorpropamide-pretreated healthy subjects. Alpha-ketoisocaproate, the first metabolite of leucine, had a lesser effect on increasing plasma levels of insulin and on decreasing blood levels of glucose than did leucine. Isovalerate, the second metabolite in the degradation of leucine, had no hypoglycemic effect (4). Thus neither isovalerate, nor subsequent metabolites derived from its catabolism, were deemed to be likely causes for the hypoglycemia observed after administration of leucine. Mebane and Madison (5) and Madison, Mebane, Unger, and Lochner (6) have reported that administration of ketone bodies to dogs is capable of inducing hypoglycemia and release of pancre-