Naloxone decreases insulin secretion in hyperinsulinemic postmenopausal women and may positively affect hormone replacement therapy

Abstract

Objective: To evaluate the influence of the opioid system on glyco-regulation in postmenopausal women before and after hormone replacement therapy (HRT). Design: Prospective nonrandomized clinical study. Setting: Academic research environment. Patient(s): Twenty-one healthy normo- or hyperinsulinemic postmenopausal women. Intervention(s): Oral glucose tolerance test (OGTT) (saline study), OGTT with IV injection of naloxone (naloxone study), and hyperinsulinemic euglycemic clamp performed before treatment, after 12 weeks of estrogen replacement therapy (ERT), and after 12 additional weeks of estro-progestin combined therapy (i.e., HRT). Main Outcome Measure(s): Glucose, insulin, and c-peptide plasma levels assessed in fasting condition and during the two OGTTs (area under the curve [AUC]). Evaluation of fractional hepatic insulin extraction (FHIE) and peripheral sensitivity to insulin. Result(s): At baseline, there is a greater increase of the FHIE and a more significant reduction of the insulin AUC in the hyperinsulinemic patients during the naloxone study compared with the saline study. In these women, ERT enhanced the c-peptide AUC and improved the FHIE; naloxone infusion mainly increased these two parameters. HRT did not induce any further change. Conclusion(s): Endogenous opioid peptides are involved in the modulation of carbohydrate metabolism in menopause in hyperinsulinemic patients more than in other patients. The favorable changes of the glyco-insulinemic metabolism induced by HRT may be partially due to the induction of the opioidergic activity.