Effect of Plasma Amino Acid Replacement on Glucagon and Substrate Responses to Insulin-Induced Hypoglycemia in Humans

A defective glucagon response impairs glucose recovery from insulin-induced hypoglycemia in some insulin-dependent (type I) diabetic patients. Our objective was to determine whether the glucagon reponse to insulin-induced hypoglycemia could be stimulated in nondiabetic humans. Because insulin reduces plasma amino acid concentrations, and amino acids are known to stimulate glucagon secretion, we investigated the effect of amino acid replacement during insulin infusion on the glucagon response to hypoglycemia in six healthy nondiabetic subjects. In two separate studies, blood glucose was clamped at the postabsorptive level during a constant infusion of insulin (0.05 U · kg⁻¹ · h⁻¹) for 3 h. Blood glucose was then reduced to 45 mg/dl over 20 min. Hormone and substrate concentrations during recovery from hypoglycemia were monitored for 2 h. In the control study, normal saline was infused, and in the other study, an amino acid mixture was infused to prevent the insulin-induced fall in plasma amino acids. Amino acid replacement did not change the basal glucagon levels but resulted in a more robust glucagon response to hypoglycemia (from 184 ± 24 to 292 ± 36 pg/ml) than in the control study (from 176 ± 30 to an average 229 ± 32 pg/ml, P < 0.01). Plasma concentrations of epinephrine, norepinephrine, cortisol, and growth hormones increased during hypoglycemia, but the magnitude of the response was not different between the control and amino acid-replacement studies. Amino acid replacement did not affect glucose recovery but inhibited the recovery of plasma concentrations of free fatty acids, glycerol, and β-hydroxybutyrate. We conclude that the glucagon response to insulin-induced hypoglycemia is enhanced by amino acid replacement in humans and that changes in plasma amino acid concentrations modulate the effect of stress hormones on lipid metabolism during hypoglycemia.