Protective effect of insulin against hypoglycemia-associated counterregulatory failure

Antecedent hypoglycemic episodes reduce the counterregulatory neuroendocrin e response to hypoglycemia. The role of insulin in the mechanism responsibl e for the antecedent hypoglycemia causing subsequent counterregulatory fail ure has not been elucidated. We performed antecedent hypoglycemic clamps (5 6 mg/dL) lasting 2 h with differing degrees of hyperinsulinemia, which were followed by 6-h stepwise hypoglycemic clamps (76-66-56-46 mg/dL) on the ne xt day. Experiments were carried out in 30 young, healthy men. Fifteen of t hese subjects were tested on 2 occasions. On 1 occasion the antecedent hypo glycemia was induced by insulin infusion at a rate of 1.5 mU/min.kg (low in sulin-ante-hypo); on the other occasion the insulin infusion rate was 15.0 mU/min.kg (high insulin-ante-hypo). Both sessions were separated by at leas t 4 weeks, and their order was balanced across subjects. The remaining 15 s ubjects (control group) received the same stepwise hypoglycemic clamp as th e other subjects, but without antecedent hypoglycemia. During the stepwise hypoglycemic clamp, the counterregulatory increases in ACTH, cortisol, and norepinephrine were significantly blunted after the low insulin-ante-hypo ( P < 0.01, P < 0.05, and P < 0.05, respectively) but not after the high insu lin-ante-hypo (P = 0.12, P = 0.92, and P = 0.19, respectively) compared to that in the control group. The cortisol, norepinephrine, and glucagon respo nses were greater after the high than after the low insulin-ante-hypo (all P < 0.05). In conclusion, the present study clearly demonstrates that even a single episode of mild hypoglycemia reduces neuroendocrine counterregulat ion 18-24 h later. Insulin has a moderate protective effect on subsequent c ounterregulation.