Metformin increases cortisol regeneration by 11βHSD1 in obese men with and without type 2 diabetes mellitus

CONTEXT: The mechanism of action of metformin remains unclear. Given regulation of the cortisol-regenerating enzyme 11βHSD1 by insulin, and 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.

DESIGN: Double blind randomised placebo controlled crossover study Setting: A hospital clinical research facility Participants: Eight obese non-diabeticmen (OND) and eight obesemenwith type 2 diabetes (ODM) Intervention: Participants received 28 days of metformin (1g twice daily), placebo, or (in the ODM group) gliclazide (80mg 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 SGBS adipocytes.

MAIN OUTCOME MEASURES: The effect of metformin on whole body and hepatic 11βHSD1 activity.

RESULTS: Whole body 11βHSD1 activity was ~25% higher in the ODM than 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.