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

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 Womens 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.