Effects of antecedent hypoglycemia on subsequent counterregulatory responses to exercise.

Abstract

Antecedent hypoglycemia can blunt counterregulatory responses to subsequent hypoglycemia. It is uncertain, however, if prior hypoglycemia can blunt counterregulatory responses to other physiologic stresses. The aim of this study, therefore, was to determine whether antecedent hypoglycemia attenuates subsequent neuroendocrine and metabolic responses to exercise. Sixteen lean, healthy adults (eight men and eight women, ages 28+/-2 years, BMI 22+/-1 kg/m2, VO2max 43+/-3 ml x kg(-1) x min(-1)) were studied during 2-day protocols on two randomized occasions separated by 2 months. On day 1, subjects underwent morning and afternoon 2-h hyperinsulinemic (528+/-30 pmol/l) glucose clamp studies of 5.3+/-0.1 mmol/l (euglycemic control) or 2.9+/-0.1 mmol/l (hypoglycemic study). On day 2, subjects underwent 90 min of exercise on a static cycle ergometer at 80% of their anaerobic threshold (approximately 50% VO2max). Glycemia was equated during day 2 exercise studies via an exogenous glucose infusion. Day 1 hypoglycemia had significant effects on neuroendocrine and metabolic responses during day 2 exercise. The usual exercise-induced reduction in insulin, together with elevations of plasma epinephrine, norepinephrine, glucagon, growth hormone, pancreatic polypeptide, and cortisol levels, was significantly blunted after day 1 hypoglycemia (P<0.01). Commensurate with reduced neuroendocrine responses, key metabolic counterregulatory mechanisms of endogenous glucose production (EGP), lipolytic responses, and ketogenesis were also significantly attenuated (P<0.01) after day 1 hypoglycemia. Significantly greater rates of glucose infusion were required to maintain euglycemia during exercise after day 1 hypoglycemia compared with day 1 euglycemia (8.8+/-2.2 vs. 0.6+/-0.6 micromol x kg(-1) x min(-1); P<0.01). During the first 30 min of exercise, day 1 hypoglycemia had little effect on EGP, but during the latter 60 min of exercise, day 1 hypoglycemia was associated with a progressively smaller increase in EGP compared with day 1 euglycemia. Thus, by 90 min, the entire exercise-induced increment in EGP (8.8+/-1.1 micromol x kg(-1) x min(-1)) was abolished by day 1 hypoglycemia. We conclude that 1) antecedent hypoglycemia results in significant blunting of essential neuroendocrine (glucagon, insulin, catecholamines) and metabolic (endogenous glucose production, lipolysis, ketogenesis) responses to exercise; 2) antecedent hypoglycemia may play a role in the pathogenesis of exercise-related hypoglycemia in type 1 diabetic patients; and 3) antecedent hypoglycemia can blunt counterregulatory responses to other physiologic stresses in addition to hypoglycemia.