Metformin Increases Cortisol Regeneration by 11?HSD1 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.

Abstract

CONTEXT:
The mechanism of action of metformin remains unclear. Given the regulation of the cortisol-regenerating enzyme 11?hydroxysteroid dehydrogenase 1 (11?HSD1) by insulin and the limited efficacy of selective 11?HSD1 inhibitors to lower blood glucose when co-prescribed with metformin, we hypothesized that metformin reduces 11?HSD1 activity.

OBJECTIVE:
To determine whether metformin regulates 11?HSD1 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 11?HSD1. Oral cortisone was given to measure hepatic 11?HSD1 activity in the ODM group. The effect of metformin on 11?HSD1 was also assessed in human hepatocytes and Simpson-Golabi-Behmel syndrome adipocytes.

MAIN OUTCOME MEASURES:
The effect of metformin on whole-body and hepatic 11?HSD1 activity.

RESULTS:
Whole-body 11?HSD1 activity was approximately 25% higher in the ODM group than the OND group. Metformin increased whole-body cortisol regeneration by 11?HSD1 in both groups compared with placebo and gliclazide and tended to increase hepatic 11?HSD1 activity. In vitro, metformin did not increase 11?HSD1 activity in hepatocytes or adipocytes.

CONCLUSIONS:
Metformin increases whole-body cortisol generation by 11?HSD1 probably through an indirect mechanism, potentially offsetting other metabolic benefits of metformin. Co-prescription with metformin should provide a greater target for selective 11?HSD1 inhibitors.

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

• Journal Article Type: Article
• Acceptance Date: Jul 20, 2016
• Online Publication Date: Jul 26, 2016
• Publication Date: Oct 1, 2016
• Deposit Date: Feb 17, 2020
• 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
• DOI: https://doi.org/10.1210/jc.2016-2069
• Public URL: https://nottingham-repository.worktribe.com/output/1463479
• Publisher URL: https://academic.oup.com/jcem/article/101/10/3787/2764942