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, though its mechanism remains unresolved. Since beta-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 Day1 would prevent development of HAAF on Day 2 in 8 non-diabetic subjects (5M/3F, age 28±3.5 yr, BMI 24.2±2.1 kg/m²). On four occasions, Day 1 was either A) two 90-min hypoglycemic clamps (N-); B) two 90-min hypoglycemic clamps plus naloxone (N+); C) two euglycemic 90-min clamps (C); or D) two euglycemic 90-min clamps plus naloxone (C+).

RESULTS - Day 1 hypoglycemia caused marked deterioration of Day 2 hormonal responses to hypoglycemia consistent with HAAF – i.e., decreased plasma epinephrine, norepinephrine and glucagon compared to Control [C] (374±71 vs. 810±94, 307±65 vs. 686±98 and 71±9 vs. 93±4 pg/ml, respectively, p<0.01), as well as in endogenous glucose production ([EGP], 24% vs. 163%, p<0.01). In contrast, naloxone on Day 1 completely prevented the defective counterregulatory responses; epinephrine, norepinephrine, and glucagon (852±82, 769±77, and 98±7 pg/ml) and EGP recovery (167%) were identical to those following Day 1 euglycemia (p<NS for all). Infusion of naloxone alone during euglycemia on Day 1 (C+) had no effect on day 2 responses.

CONCLUSIONS: These data suggest that the opioid signaling system is a promising target for further studies to prevent HAAF.