Affiliation:
1. Albert Einstein College of Medicine , Bronx, NY 10461 , USA
2. New York University Langone Medical Center , New York, NY 10017 , USA
3. Center for Drug Evaluation and Research, U.S. Food and Drug Administration , Silver Spring, MD 20903 , USA
Abstract
Abstract
Context
Hypoglycemia-associated autonomic failure (HAAF), defined as blunting of counterregulatory hormone and symptom responses to recurrent hypoglycemia, remains a therapeutic challenge in diabetes treatment. The opioid system may play a role in HAAF pathogenesis since activation of opioid receptors induces HAAF. Blockade of opioid receptors with intravenous naloxone ameliorates HAAF experimentally yet is not feasible therapeutically.
Objective
To investigate the effects of opioid receptor blockade with intranasal naloxone on experimentally induced HAAF.
Design
Randomized, double-blinded, placebo-controlled crossover study.
Setting
Academic research center.
Participants
Healthy nondiabetic volunteers.
Interventions
Paired 2-day studies, 5 to 10 weeks apart, each consisting of 3 consecutive hypoglycemic episodes (hyperinsulinemic hypoglycemic clamps, glucose nadir: 54 mg/dL): 2 on day 1 with administration of intranasal naloxone vs placebo, followed by the third episode on day 2.
Main Outcome Measures
Differences in counterregulatory hormones responses and hypoglycemia symptoms between first and third hypoglycemic episodes in naloxone vs placebo studies.
Results
Out of 17 participants, 9 developed HAAF, confirming variable interindividual susceptibility. Among participants susceptible to HAAF, naloxone maintained some hormonal and symptomatic responses to hypoglycemia and prevented the associated requirement for increased glucose infusion. Unexpectedly, naloxone reduced plasma epinephrine and GH responses to the first hypoglycemic episode but prevented further reduction with subsequent hypoglycemia.
Conclusion
This is the first study to report that intranasal naloxone, a widely used opioid receptor antagonist, may ameliorate some features of HAAF. Further investigation is warranted into mechanisms of variable interindividual susceptibility to HAAF and the effects of intranasal naloxone in people with diabetes at risk for HAAF.
Funder
National Institute of Diabetes and Digestive and Kidney Diseases
Einstein-Mount Sinai Diabetes Research Center
Albert Einstein College of Medicine
National Center for Advancing Translational Science
National Institutes of Health
American Diabetes Association
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