Lowering insulin mitigates female reproductive aging and diet-induced ovarian dysfunction

Abstract Hyperinsulinemia has consequences beyond metabolic dysfunction, including reproductive system effects. We found that hyperinsulinemia at age 46-47 was predictive of earlier menopause in the Study of Women’s Health Across the Nation. To test causality between insulin levels and reproductive aging, we longitudinally evaluated chow- or high-fat, high-sucrose (HFHS)-fed Ins1 -null female mice with full or partial Ins2 insulin gene expression. Ins1 -/- ;Ins2 +/- mice had lower HFHS-induced hyperinsulinemia and less weight gain than their full- Ins2 littermates, despite comparable HFHS-induced glucose intolerance up to 9 months. By 15 months, Ins1 -/- ;Ins2 +/+ ovaries showed multinucleated giant cell accumulation with HFHS, while Ins1 -/- ;Ins2 +/- mice were protected against this response and maintained a higher reserve of follicles. Moreover, aged Ins1 -/- ;Ins2 +/- mice were 9-fold more likely to conceive on HFHS than hyperinsulinemic Ins1 -/- ;Ins2 +/+ mice. Elevated insulin is therefore a critical mechanistic link between metabolic dysfunction and reproductive aging, and curtailing insulin levels protects against subfertility and HFHS-induced ovarian decline.