Hypoglycemia-Associated Autonomic Failure Is Prevented by Opioid Receptor Blockade

Context: Repeated hypoglycemia is associated with hypoglycemia-associated autonomic failure (HAAF), a syndrome of defective counterregulation. Objective: HAAF increases the risk of severe hypoglycemia in diabetes, although its mechanism remains unresolved. Because β-endorphin influences the autonomic response to hypoglycemia via opioid receptor activation, we hypothesized that it is also involved in the pathogenesis of HAAF. Research Design and Methods: We asked whether opioid receptor blockade during antecedent hypoglycemia (60 mg/dl) on d 1 would prevent development of HAAF on d 2 in eight nondiabetic subjects (five males, 3 females; age, 28 ± 3.5 yr; body mass index, 24.2 ± 2.1 kg/m2). On four occasions, d 1 was: 1) two 90-min hypoglycemic clamps (N−); 2) two 90-min hypoglycemic clamps plus naloxone (N+); 3) two euglycemic 90-min clamps (C); or 4) two euglycemic 90-min clamps plus naloxone (C+). Results: Day 1 hypoglycemia caused marked deterioration of d 2 hormonal responses to hypoglycemia, consisten...