Hypoglycemia-Associated Autonomic Failure Is Prevented by Opioid Receptor Blockade

• Published in: The journal of clinical endocrinology and metabolism 2009-09, Vol.94 (9), p.3372-3380
• Main Authors: Leu, James, Cui, Min-Hui, Shamoon, Harry, Gabriely, Ilan
• Format: Article
• Language: English
• Subjects: Adult; Autonomic Nervous System Diseases - etiology; Autonomic Nervous System Diseases - prevention & control; beta-Endorphin - blood; Biological and medical sciences; Blood Glucose - analysis; C-Peptide - analysis; Endocrinopathies; Epinephrine - blood; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Glucagon - blood; Gluconeogenesis; Humans; Hypoglycemia - complications; Hypoglycemia - physiopathology; Insulin - blood; Male; Medical sciences; Naloxone - therapeutic use; Narcotic Antagonists; Norepinephrine - blood; Original; Receptors, Opioid - physiology; Syndrome; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2009-0882

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. Opioid receptor blockade with naloxone during hypoglycemia prevents subsequent hypoglycemia associated autonomic failure in non-diabetic subjects.