The Experimental Induction in Man of Sensitivity to Leucine Hypoglycemia*

Abstract

In 1956, Cochrane, Payne, Simpkiss, and Woolf (1) reported that oral administration of L-leucine induces a sharp fall in blood glucose levels in some children with idiopathic familial hypoglycemia, but that it has no effect in normal subjects. Flanagan, Schwartz, and Ryan (2) were the first to report that oral administration of L-leucine to patients with functioning islet-cell tumors also produces a hypoglycemic effect. By the immunoassay of Yalow and Berson for measurement of plasma insulin, an increase has been demonstrated in concentration of plasma insulin during leucine-induced hypoglycemia in infants with idiopathic hypoglycemia (3-5) and in patients with islet-cell tumors (3, 6, 7).The studies described below had the following objectives: 1) to see if healthy people could be made sensitive to the hypoglycemic action of leucine, and 2) to study the mechanism by which leucine causes hypoglycemia. The results of this study indicate 1) that sensitivity to leucine hypoglycemia can be induced consistently in healthy subjects after the oral administration of sulfonylurea compounds, and 2) that release of additional insulin is the primary mechanism of action by which leucine causes hypoglycemia in man.' METHODS Leucine tests were performed after an overnight fast 1) by the oral administration of 0.2 g per kg of an *

Benzothiadiazine suppression of insulin release from normal and abnormal islet tissue in man.

“…Administration of leucine to chlorpropamidepretreated subjects is a strong stimulus for insulin release and consequent hypoglycemia, as has been reported previously from this laboratory (14)(15)(16). This is demonstrated again by the data derived from the seven infusions of leucine before administration of benzothiadiazines (Table II, Figure 1).…”

“…We (14,15) have shown that when leucine is given to chlorpropamide 3-pretreated healthy subjects hypoglycemia together with a sharp increase in plasma insulin occurs. We have also shown that increased release of insulin from the pancreatic beta cells is the mechanism by which leucine increases peripheral levels of insulin (16).…”

Insulin secretion in response to protein ingestion.

“…We conclude that 1) ingestion of protein meals results in significant increases in plasma insulin, 2) these increases in plasma insulin cannot be accounted for solely or even largely by the effect of l-leucine contained in the meals, and 3) ingestion of protein and rising plasma levels of certain amino acids appear to be associated with a physiologic stimulus for insulin release.…”

Evidence That Insulin Release Is the Mechanism for Experimentally Induced Leucine Hypoglycemia in Man*

“…On the other hand, after pretreatment with Novo Ultralente insulin, administration of leucine produced decreases in blood glucose levels that, although significant, were small and inconsistent. A modest but significant hypoglycemic effect was also produced in some healthy subjects by administering leucine without prior administration of hypoglycemic agents ( 1,2). The magnitude of these decreases in blood glucose levels was similar to that observed after administration of leucine to subjects pretreated with Ultralente insulin.…”