Opioid Receptor Blockade Improves Hypoglycemia-Associated Autonomic Failure in Type 1 Diabetes Mellitus

Abstract

Recurrent hypoglycemia induces hypoglycemia-associated autonomic failure (HAAF), characterized by deterioration in counterregulatory responses. Endogenous opioids may mediate the development of HAAF, and blockade of opioid receptors with naloxone prevented HAAF in nondiabetic subjects. We hypothesized that opioid receptor blockade with naloxone during antecedent hypoglycemia in patients with type 1 diabetes mellitus (T1DM) would prevent the development of HAAF. Eight subjects with T1DM (three women, aged 34 ± 7.4 yr, hemoglobin A1c 7.3 ± 1.1%) were studied on 2 consecutive days on three separate occasions. Day 1 consisted of: 1) two 90-min hypoglycemic clamps (60 mg/dl, N-); 2) two 90-min hypoglycemic clamps (60 mg/dl) with concomitant naloxone infusion (N+); or 3) two 90-min euglycemic clamps (90 mg/dl) with concomitant naloxone infusion (control). Day 2 consisted of hyperinsulinemic stepped hypoglycemic clamps (90, 80, 70, and 60 mg/dl plasma glucose steps). Day 2 hypoglycemia counterregulatory hormonal response and glucose turnover [(3-(3)H)-glucose] as indicators of recovery from hypoglycemia. Antecedent hypoglycemia in N- group resulted in a markedly decreased epinephrine response and a lower rate of endogenous glucose production (EGP) during subsequent hypoglycemia compared with control (75 ± 17 vs. 187 ± 21 pg/ml, P < 0.05 and 0.8 ± 0.1 vs. 1.4 ± 0.2 mg/kg · min, P < 0.05, respectively). In contrast, in the N+ studies, plasma epinephrine was 164 ± 18 pg/ml and EGP was 1.3 ± 0.2 mg/kg · min during subsequent hypoglycemia, both levels similar to those seen in control studies (P = NS vs. control). Plasma glucagon did not increase with hypoglycemia. Blockade of endogenous opioids with naloxone during antecedent hypoglycemia improves HAAF in patients with T1DM by ameliorating the epinephrine response and restoring EGP.