Effect of Amino Acids and Proteins on Insulin Secretion in Man

Following the demonstration that administration of leucine accentuates the hypoglycemia of some patients with “idiopathic hypoglycaemia of childhood” (1956) and of some patients with pancreatic islet cell tumours (1959) we initiated studies to explore the mechanism of leucine-induced hypoglycaemia. Sensitivity to leucine-hypoglycaemia can be induced consistently in healthy subjects after administration of sulfonylurea compounds. Increased release of pancreatic insulin is the primary mechanism by which leucine causes a fall in blood glucose in sulfonylurea-induced as well as in naturally occurring leucine hypoglycaemia. Experimentally-induced sensitivity to leucine hypoglycaemia can be used as a model for the further study of leucine hypoglycaemia. Potentiation of insulin activity has not been demonstrated to play a role in the production of leucine-induced hypoglycaemia in man. Leucine induces release of insulin and lowers blood glucose in healthy subjects without prior administration of hypoglycaemic agents, but to a quantitatively lesser extent than in sulfonylurea-induced leucine hypoglycaemia. The more pronounced sensitivity to leucine hypoglycaemia produced experimentally by administration of sulfonylureas and that observed in some patients with “idiopathic hypoglycaemia” or functioning islet cell tumours represents a great exaggeration of what appears to be a normal physiological phenomenon. To determine the effect of leucine on insulin release under physiologic circumstances, protein meals (cooked beef or chicken liver) rich in leucine were fed to healthy subjects. The increases in plasma insulin which resulted from the ingestion of the protein meals were considerably greater than those which would have been expected to have resulted from the modest increases in plasma leucine which occurred. These findings suggested that amino acids other than leucine or amino acids in combination with leucine stimulated the release of insulin. Essential 1-amino acids, either as mixtures or individually, were administered intravenously to healthy subjects. The various mixtures — whether they contained leucine or not — and most, but not all, of the individual amino acids stimulated the release of insulin. The most effective stimulus for insulin release was either a mixture of 10 essential amino acids or arginine given alone. Histidine was ineffective. Thus, the phenomenon of amino-acid-induced release of insulin does not depend on the presence of leucine in the infusion mixture. A variety of individual amino acids, induce the release of insulin, but there are large differences among these amino acids in their capacities to stimulate its secretion. Increases in blood glucose observed during some of the amino-acid infusions cannot be the major cause of the increases in plasma insulin. Rising plasma levels of certain amino acids after protein feeding can be considered to be physiologic stimuli for the secretion of insulin. It is speculated that the purpose of the insulinogenic response to protein ingestion is to aid in the utilization of absorbed amino acids and in their synthesis to protein. Leucine and arginine themselves, rather than one of their metabolites, are the potens stimuli to insulin release when these amino acids are administered. The mechanism by which leucine induces insulin release differs from that by which the other essential amino acids induce release of insulin. The magnitude of insulin secretion induced by the administration of mixtures of amino acids or ingested proteins depends not only upon the amount administered but also on the synergism between particular amino acids and in the case of mixed meals of protein and carbohydrate upon synergism between amino acids and glucose as well. Administration of human growth hormone and adrenalcortical steroids increases the sensitivity of the pancreatic islet cells to the insulin-releasing stimulus of amino acids. In non-obese, mildly diabetic subjects, increases in plasma insulin after administration of the 10-amino-acid mixture and of arginine were smaller than in healthy subjects. The history of the study of “leucine hypoglycaemia” and related phenomena is an example of how the exploration of a seemingly uncommon metabolic aberration observed in pathologic states and its experimental reproduction may lead to the recognition of what appear to be important physiologic relationships. In this instance the participation of amino acids in control of secretion of insulin (and also of growth hormone and glucagon) have evolved.