Comparison of Experimentally Induced and Naturally Occurring Sensitivity to Leucine Hypoglycemia1

Abstract

We have previously reported that administration of L-leucine to healthy subjects pretreated with sulfonylurea compounds consistently induces significant hypoglycemia comparable to that induced in infants and children with leucine-sensitive “idiopathic hypoglycemia.” Release of additional insulin is the primary mechanism by which leucine causes a decrease in blood glucose both in experimentally induced and in naturally occurring leucine hypoglycemia. To explore further possible relationships between the 2 types of leucine hypoglycemia, a series of amino acids as well as the first 2 metabolites of leucine, alpha-ketoisocaproate and isovalerate, were administered to sulfonylurea-pretreated healthy subjects. The results indicate that (a) of the amino acids other than leucine, only isoleucine produces hypoglycemia; (b) alpha-ketoisocaproate induces a sharp but lesser hypoglycemic effect than leucine; (c) some of the administered alpha-ketoisocaproate is transaminated to leucine in vivo; and (d) isovalerate has no hypoglycemic effect. It is concluded that 1) sulfonylureainduced sensitivity to leucine hypoglycemia resembles closely that seen in “idiopathic hypoglycemia”; 2) it can be used as a model for further study of leucine hypoglycemia; and 3) leucine itself, rather than one of its metabolites, induces release of insulin.