Endocrine Abstracts

Background: Glucocorticoids are powerful anti-infla mmatory drugs. However, metabolic side effects are common and limit their long-term use. Furthermore, the underlying mechanisms of adverSemetabolic effects are not well known, and this lack of knowledge results in poor treatment. We have previously shown that the antidiabetic drug metformin prevents glucocorticoid-induced metabolic effects in older, sick patients. Here, we investigate metformin in a young and healthy population on high-dose glucocorticoids to establish the role of metformin and identify potential mechanisms counteracting glucocorticoid-induced side effects.

Methods: In a randomized, placebo-controlled, cross-over trial, we compared metformin to placebo during high-dose glucocorticoid treatment in 18 lean, healthy males. All participants received prednisone 30 mg/d for two 8-day periods separated by a 28-day washout period. During one period, participants additionally had metformin; during the other, they received a placebo. Metabolic assessments were performed before and after each study period, including a mixed meal tolerance test (MMTT) and blood metabolomics.

Results: 18 male subjects (mean age 27 standard deviation [SD] ±5.2 years, BMI 22.9 ±1.8 kg/m²) completed the study. Glucose levels during the MMTT increased with placebo (glucose change in incremental area under the concentration-time curve [AUC] 1.18 ±1.12 mmol/l) but remained stable with metformin (0.02 ±1.25 mmol/l, P=0.01). Insulin AUC increased with placebo (94 ±183 pmol/l) but not with metformin (-182 ±168 pmol/l, P<0.001). Accordingly, whole-body insulin sensitivity improved with metformin (6.4 ±11.8) compared to placebo (-8.2 ±10.65, P<0.001). Pathway enrichment analysis of metabolites revealed that metformin impacts free fatty acid and bile acid synthesis in the postprandial state.

Conclusion: Metformin prevents the detrimental effects of glucocorticoids on glucose homeostasis by improving insulin sensitivity. Our findings confirm metformin’s role in preventing and treating glucocorticoid-induced side effects. Furthermore, the impact of metformin on free fatty acid flux and bile acid synthesis supports that adipose tissue and the gut are sites of metformin action.