Magnitude of Exercise-Induced β-Endorphin Response Is Associated with Subsequent Development of Altered Hypoglycemia Counterregulation

Context: beta-Endorphin release in response to recurrent hypoglycemia is implicated in the pathogenesis of hypoglycemia-associated autonomic failure. Objective: We hypothesized that exercise-induced beta-endorphin release will also result in the deterioration of subsequent hypoglycemia counterregulation and that the counterregulatory response will negatively correlate with the degree of antecedent beta-endorphin elevation. Design, Setting, Participants, and Interventions: Sixteen healthy subjects (six females, aged 26 +/- 4.3 yr, body mass index 26.1 +/- 5.6 kg/m(2)) were studied with three experimental paradigms on 2 consecutive days. Day 1 consisted of one of the following: 1) two 90-min hyperinsulinemic hypoglycemic clamps (3.3 mmol/liter); 2) two 90-min hyperinsulinemic euglycemic clamps while subjects exercised at 60% maximal oxygen uptake; or 3) two 90-min hyperinsulinemic euglycemic clamps (control). Day 2 followed with hyperinsulinemic (396 +/- 7 pmol/liter) stepped hypoglycemic clamps (5.0, 4.4, 3.9, and 3.3 mmol/liter plasma glucose steps). Main Outcome Measures: Day 2 hypoglycemia counterregulatory hormonal response and glucose turnover ([3-H-3]-glucose) as indicators of recovery from hypoglycemia. Results: There was a significant inverse correlation between plasma beta-endorphin levels during exercise and catecholamine release during subsequent hypoglycemia. Subjects with an exercise- induced rise in beta-endorphin levels to above 25 pg/ml (n = 7) exhibited markedly reduced levels of plasma epinephrine and norepinephrine compared with control (2495 +/- 306 vs. 4810 +/- 617 pmol/liter and 1.9 +/- 0.3 vs. 2.9 +/- 0.4 nmol/liter, respectively, P < 0.01 for both). The rate of endogenous glucose production recovery in this group was also much lower than in controls (42 vs. 89%, P < 0.01). Conclusions: The physiological increase in beta-endorphin levels during exercise is associated with the attenuation of counterregulation during subsequent hypoglycemia. (J Clin Endocrinol Metab 97: 623-631, 2012)