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

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.

Figure 1.

Endogenous and tracer cortisol measurements. Data are expressed as mean ± SEM for metformin (black squares), gliclazide (open triangles), and placebo (open circles). A and D, Plasma cortisol; B and E, D4-cortisol enrichment; C and F, D4-cortisol/D3-cortisol ratio in OND (n = 8; A–C) and ODM (n = 8; D–F) groups.

Figure 2.

The effect of metformin on 11βHSD1 activity in vivo. Data are expressed as mean ± SEM for the effect of metformin (black columns), gliclazide (bricked columns), and placebo (white columns) on the Ra of cortisol (A) and D3-cortisol (B) during steady state. C, The effect of metformin (black squares), gliclazide (open triangles), and placebo (open circles) on Ra cortisol after 5 mg oral cortisone ingestion in the ODM group. Phases were compared using paired t tests in the OND group and repeated measures ANOVA with post hoc Fisher's LSD testing in the ODM group. Placebo-phase data in OND and ODM groups were compared using the unpaired t test. *, P < .05 vs placebo; $, P < .05 vs metformin; #, P < .05 vs OND group.

Figure 3.

The effect of metformin on 11βHSD1 activity in vitro. Data are expressed as mean ± SEM for the rate of cortisol production in primary human hepatocytes (A) and human Simpson-Golabi-Behmel syndrome adipocytes (B) after incubation with vehicle (white columns) or increasing doses of metformin (black columns) for 24 hours (n = 4 per concentration). Comparisons were performed using repeated measures ANOVA with post hoc Fisher's LSD testing. *, P < .05 vs vehicle.