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Metformin Increases Cortisol Regeneration by 11βHSD1 in Obese Men With and Without Type 2 Diabetes Mellitus

Anderson, Anna J.; Andrew, Ruth; Homer, Natalie Z.; Jones, Gregory C.; Smith, Kenneth; Livingstone, Dawn E.; Walker, Brian R.; Stimson, Roland H.

Authors

Anna J. Anderson

Ruth Andrew

Natalie Z. Homer

Gregory C. Jones

KENNETH SMITH KEN.SMITH@NOTTINGHAM.AC.UK
Professor of Metabolic Mass Spectrometry

Dawn E. Livingstone

Brian R. Walker

Roland H. Stimson



Abstract

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.

Journal Article Type Article
Publication Date Oct 1, 2016
Journal The Journal of Clinical Endocrinology & Metabolism
Print ISSN 0021-972X
Electronic ISSN 1945-7197
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Volume 101
Issue 10
Pages 3787-3793
APA6 Citation Anderson, A. J., Andrew, R., Homer, N. Z., Jones, G. C., Smith, K., Livingstone, D. E., …Stimson, R. H. (2016). Metformin Increases Cortisol Regeneration by 11βHSD1 in Obese Men With and Without Type 2 Diabetes Mellitus. Journal of Clinical Endocrinology and Metabolism, 101(10), 3787-3793. https://doi.org/10.1210/jc.2016-2069
DOI https://doi.org/10.1210/jc.2016-2069
Publisher URL https://academic.oup.com/jcem/article/101/10/3787/2764942

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