Opioid Receptor Blockade with Intranasal Naloxone Prevents the Development of Hypoglycemia-Associated Autonomic Failure

Abstract

Attainment of near-normal glycemic goals in type 1 diabetes (T1D) is limited by iatrogenic hypoglycemia. Repeated episodes of hypoglycemia lead to Hypoglycemia-Associated Autonomic Failure (HAAF), with blunted counter-regulatory hormone responses. We previously reported that pharmacologic activation of opioid receptors experimentally recapitulates some features of HAAF (Diabetes 66:2764; 2017), and opioid antagonism with intravenous naloxone prevents experimentally induced HAAF in healthy subjects. We therefore hypothesized that intranasal naloxone would augment central blockade of opioid receptors by bypassing the blood-brain barrier, and would provide a feasible outpatient approach to prevent HAAF. Using a randomized, double-blinded placebo-controlled study design, 7 healthy subjects (7M; age 43±3 year; BMI 25.9±0.9 kg/m2) participated in paired two-day studies, 5 weeks apart. Day 1 consisted of two 120 minute hypoglycemic (∼54 mg/dl) hyperinsulinemic clamps, with hourly intranasal administration of either saline (placebo) or naloxone (4 mg hourly). On day 2, subjects underwent one 120 minute hypoglycemic clamp (∼54 mg/dl). As expected, HAAF was experimentally induced in the placebo studies, based on lower peak epinephrine levels (mean±SEM: first hypoglycemic episode=1375±182 vs. third episode=858±235, pg/ml, p=0.004). With intranasal naloxone, epinephrine levels did not differ from the first to the third hypoglycemic episode (first=942±190 vs. third episode=857±134 pg/ml, p=0.4). Naloxone did not alter the responses of plasma glucagon, cortisol or growth hormone, or hypoglycemic symptoms. These findings suggest that HAAF can be prevented by acute blockade of opioid receptors during hypoglycemia, presumably by inhibiting opioid receptor activation by circulating endorphins. Thus, acute self-administration of intranasal naloxone could be an effective and feasible ’real-world’ approach to ameliorate HAAF in T1D. Disclosure S. Aleksic: None. E. Lontchi-Yimagou: None. R. Hulkower: None. M. Carey: None. M. Ude: None. W.G. Mitchell: None. O. Sandu: None. N. Tomuta: None. H. Shamoon: None. M. Hawkins: None.