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Objective: The physiology of counterregulatory responses during hypoglycemia in intensively treated type 2 diabetic subjects is largely unknown. Therefore, the specific aims of the study tested the hypothesis that 1) 6 months of intensive therapy to lower A1C <7.0% would blunt autonomic nervous system (ANS) responses to hypoglycemia, and 2) antecedent hypoglycemia will result in counterregulatory failure during subsequent hypoglycemia in patients with suboptimal and good glycemic control., Research Design and Methods: Fifteen type 2 diabetic patients (8 men/7 women) underwent 6-month combination therapy of metformin, glipizide XL, and acarbose to lower A1C to 6.7% and 2-day repeated hypoglycemic clamp studies before and after intensive therapy. A control group of eight nondiabetic subjects participated in a single 2-day repeated hypoglycemic clamp study., Results: Six-month therapy reduced A1C from 10.2 +/- 0.5 to 6.7 +/- 0.3%. Rates of hypoglycemia increased to 3.2 episodes per patient/month by study end. Hypoglycemia (3.3 +/- 0.1 mmol/l) and insulinemia (1,722 +/- 198 pmol/l) were similar during all clamp studies. Intensive therapy reduced (P < 0.05) ANS and metabolic counterregulatory responses during hypoglycemia. Antecedent hypoglycemia produced widespread blunting (P < 0.05) of neuroendocrine, ANS, and metabolic counterregulatory responses during subsequent hypoglycemia before and after intensive therapy in type 2 diabetic patients and in nondiabetic control subjects., Conclusions: Intensive oral combination therapy and antecedent hypoglycemia both blunt physiological defenses against subsequent hypoglycemia in type 2 diabetes. Prior hypoglycemia of only 3.3 +/- 0.1 mmol/l can result in counterregulatory failure in type 2 diabetic patients with suboptimal control and can further impair physiological defenses against hypoglycemia in intensively treated type 2 diabetes.

The effects of oral carbohydrate on modulating counterregulatory responses in humans remain undecided. This study's specific aim was to determine the effects of oral carbohydrate on autonomic nervous system (ANS) and neuroendocrine responses during hyperinsulinemic hypoglycemia and euglycemia. Nineteen healthy volunteers were studied during paired, single blind experiments. Nine subjects underwent two-step glucose clamps consisting of 60 min of euglycemia (5.0 mmol/l) followed by either 15 g of oral carbohydrate (cal) as orange juice or a noncaloric control (nocal) and subsequent 90 min of clamped hypoglycemia (2.9 mmol/l). Ten other subjects underwent two randomized 150-min hyperinsulinemic-euglycemic clamps with cal or nocal control administered at 60 min. Oral carbohydrate initially blunted (P < 0.05) epinephrine, norepinephrine, cortisol, glucagon, pancreatic polypeptide, muscle sympathetic nerve activity (MSNA), symptom, and systolic blood pressure responses during hypoglycemia. However, by the end of 90 min of hypoglycemia, plasma epinephrine and norepinephrine responses had rebounded and were increased (P < 0.05) compared with control. MSNA and cortisol levels remained suppressed during hypoglycemia (P < 0.05) after cal, whereas pancreatic polypeptide, glucagon, symptom, and blood pressure responses increased similar to control following initial suppression. Oral carbohydrate had no effects on neuroendocrine or ANS responses during hyperinsulinemic euglycemia. These results demonstrate that oral carbohydrate can have differential effects on the time course of ANS and neuroendocrine responses during hypoglycemia. We conclude that gastro-splanchnic-portal sensing of an amount of carbohydrate recommended for use in clinical practice for correction of hypoglycemia can have widespread and significant effects on central nervous system mediated counterregulatory responses in healthy humans.