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Hypoglycemia-Associated Autonomic Failure Is Prevented by Opioid Receptor Blockade

The Department of Medicine, Division of Endocrinology and Metabolism (J.L., M.-H.C., I.G.), Diabetes Research Center (I.G., H.S.), and the Institute for Clinical and Translational Research (H.S.), Albert Einstein College of Medicine, Bronx, New York 10461

Address all correspondence and requests for reprints to: Ilan Gabriely, M.D., Department of Medicine (Division of Endocrinology and Metabolism), Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461. E-mail: gabriely{at}aecom.yu.edu.

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, 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 (24 vs. 163%; P < 0.01). In contrast, naloxone on d 1 completely prevented the defective counterregulatory responses; epinephrine, norepinephrine, and glucagon (852 ± 82, 769 ± 77, and 98 ± 7 pg/ml) and endogenous glucose production recovery (167%) were identical to those after d 1 euglycemia (P < NS for all). Infusion of naloxone alone during euglycemia on d 1 (C+) had no effect on d 2 responses.

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