Blockade of mineralocorticoid receptor ameliorates oral contraceptive-induced insulin resistance by suppressing elevated uric acid and glycogen synthase kinase-3 instead of circulating mineralocorticoid.

Context: Estrogen-progestin combined oral contraceptive (COC) has been connected to mineralocorticoid receptor (MR) activation and adverse cardiometabolic events. We consequently hypothesised that insulin resistance (IR), hyperuricemia, and elevated circulating GSK-3 induced by COC is through activation of MR via mineralocorticoid and glucocorticoid pathways.

Methods

Female Wistar rats aged 12 weeks received (po) vehicle and COC (1.0 μg ethinylestradiol plus 5.0 μg levonorgestrel) with or without MR blocker (0.25 mg/kg spironolactone; Spl), daily for eight weeks.

Results

Data showed that COC treatment led to increased IR, 1-hour postload glucose level, insulinemia, triglyceride/HDL-cholesterol ratio, total cholesterol/HDL-cholesterol ratio, uric acid, GSK-3, aldosterone, corticosterone values, impaired glucose tolerance and pancreatic β-cell function. However, MR blockade by Spl ameliorated all these alterations except that of aldosterone.

Conclusion

The results demonstrate that COC induces IR, hyperuricemia and high GSK-3 levels through activation of MR via glucocorticoid dependent pathway.