The silent metabolic burden: hyperglycemia in a VCD-mouse model of menopause

Introduction: Menopause is characterized by ovarian failure, leading to a marked decline in circulating sex hormones and placing middle-aged women at increased risk for developing cardiometabolic diseases. Menopausal women often exhibit impaired glucose metabolism and increased body weight due to excess fat accumulation. However, the onset and trajectory of these alterations remain poorly defined. Hypothesis: We hypothesize that dysregulation of glucose homeostasis occurs prior to weight gain and measurable adiposity during menopause. Methods and Results: To recapitulate human menopause, we employed 4-vinylcyclohexene dioxide (VCD)-induced gradual ovarian failure. Two-month-old female C57BL/6 mice were randomly assigned to Control (n=7) or VCD groups (n=8) and received daily intraperitoneal injections of vehicle (sesame oil) or 160mg/Kg of VCD, respectively, for 15 days. Body weight was monitored longitudinally throughout the study. Menopause was confirmed at week 32 post-VCD injections by elevated serum follicle-stimulating hormone (FSH: 19.83±1.21 ng/mL vs. 2.66±1.073 ng/mL controls, p< 0.0001) and cessation of estrous cycling. No differences in body weight were observed between groups (26.03±0.64g vs. 26.14±0.60g controls). Body composition assessed using Dual-energy X-ray absorptiometry (DEXA) further demonstrated that the VCD group exhibited no changes in fat mass (4.29±0.18g vs. 4.48±0.16g controls) and lean mass (19.26±0.49 vs. 19.10±0.50g controls) relative to controls. However, the VCD group showed significant increases in fasting blood glucose levels (162.3±11.61 mg/dL vs.118.9±14.22 mg/dL controls, p< 0.0329), in the absence of insulin resistance, as indicated by HOMA-IR values between groups (11.96±2.83 vs.12.16± 3.01 controls) Conclusion: These findings reveal that hyperglycemia precedes measurable changes in body composition during menopause, supporting the concept that impaired glucose regulation is an early cardiometabolic risk factor in menopause. This work underscores the need for early glucose metabolic screening and intervention in women undergoing menopausal transition Funding Source: R15HL165328-01A1 to MACS and R03DK138218 to HR This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.