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Lookup NU author(s): Professor Brian WalkerORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2016 by the Endocrine Society. Context: The mechanism of action of metformin remains unclear. Given the regulation of the cortisol-regenerating enzyme 11βhydroxysteroid dehydrogenase 1 (11βHSD1) by insulin and the limited efficacy of selective 11βHSD1 inhibitors to lower blood glucose when co-prescribed with metformin, we hypothesized that metformin reduces 11βHSD1 activity. Objective: To determine whether metformin regulates 11βHSD1 activity in vivo in obese men with and without type 2 diabetes mellitus. Design: Double-blind, randomized, placebo-controlled, crossover study. Setting: A hospital clinical research facility. Participants: Eight obese nondiabetic (OND) men and eight obese men with type 2 diabetes (ODM). Intervention: Participants received 28 days of metformin (1 g twice daily), placebo, or (in the ODM group) gliclazide (80 mg twice daily) in random order. A deuterated cortisol infusion at the end of each phase measured cortisol regeneration by 11βHSD1. Oral cortisone was given to measure hepatic 11βHSD1 activity in the ODM group. The effect of metformin on 11βHSD1 was also assessed in human hepatocytes and Simpson-Golabi-Behmel syndrome adipocytes. Main Outcome Measures: The effect of metformin on whole-body and hepatic 11βHSD1 activity. Results: Whole-body 11βHSD1 activity was approximately 25% higher in the ODM group than the OND group. Metformin increased whole-body cortisol regeneration by 11βHSD1 in both groups compared with placebo and gliclazide and tended to increase hepatic 11βHSD1 activity. In vitro, metformin did not increase 11βHSD1 activity in hepatocytes or adipocytes. Conclusions: Metformin increases whole-body cortisol generation by 11βHSD1 probably through an indirect mechanism, potentially offsetting other metabolic benefits of metformin. Co-prescription with metformin should provide a greater target for selective 11βHSD1 inhibitors.
Author(s): Anderson AJ, Andrew R, Homer NZ, Jones GC, Smith K, Livingstone DE, Walker BR, Stimson RH
Publication type: Article
Publication status: Published
Journal: Journal of Clinical Endocrinology and Metabolism
Year: 2016
Volume: 101
Issue: 10
Pages: 3787-3793
Print publication date: 01/10/2016
Online publication date: 26/07/2016
Acceptance date: 20/07/2016
Date deposited: 22/12/2017
ISSN (print): 0021-972X
ISSN (electronic): 1945-7197
Publisher: Endocrine Society
URL: https://doi.org/10.1210/jc.2016-2069
DOI: 10.1210/jc.2016-2069
PubMed id: 27459533
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