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J Clin Endocrinol Metab. 2009 Sep;94(9):3372-80. doi: 10.1210/jc.2009-0882. Epub 2009 Jun 30.

Hypoglycemia-associated autonomic failure is prevented by opioid receptor blockade.

Author information

1
Department of Medicine, Division of Endocrinology and Metabolism, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.

Abstract

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 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 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/m(2)). 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.

PMID:
19567512
PMCID:
PMC2741720
DOI:
10.1210/jc.2009-0882
[Indexed for MEDLINE]
Free PMC Article

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