Type 1 Diabetes Alters Endothelium-Dependent Relaxation and Endothelial Cell Bioenergetics More Severally in Young Female than aged-match Male mice

Objective: Type 1 Diabetes (T1D), whose prevalence is dramatically increasing in the United States, is a significant risk factor for cardiovascular disease (CVD). Recent evidence indicates that T1D abolishes the protective effects of female sex hormones. However, the underlying mechanisms of endothelial dysfunction remain unclear in females. Recent findings support a role for endothelial cell (EC) bioenergetics, namely glycolysis, in controlling endothelial function and indicates that T1D-associated hyperglycolysis impairs endothelial function in males. Our study sought to explore the sex specific role of EC bioenergetics in controlling endothelial function under physiological conditions and in the context of T1D. Methods: T1D was induced in male and female Balb/C mice using Streptozotocin (STZ), and cardiometabolic function was assessed in both control and T1D animals after 28 days. Vasomotor studies, bioenergetic assessments and gene expression analysis via qRT-PCR were conducted using thoracic aortas. Results: STZ induced comparable increases in glycemia and HbA1c in males and females and led to a reduction in body weight, fat, lean mass, and fluids. Sex-specific differences were observed in organ weights, with T1D males showing increased adrenal gland and testicular weights, while T1D females exhibited decreased uterus and ovarian weights. These changes suggested the involvement of sex hormones in sex-specific T1D responses, prompting further investigation through wire myography. While females demonstrated better baseline endothelium-dependent relaxation than males, T1D impaired vascular function in both sexes, with a more pronounced effect in females. Assessment of bioenergetics in intact vessels using Seahorse assays revealed higher endothelial-specific glycolytic activity in males compared to females. However, T1D impaired endothelial glycolytic function in males by reducing both glycolytic reserve and capacity, while no significant changes in glycolysis were observed in T1D females. These findings suggest that other metabolic pathways may contribute to T1D-related vascular impairment in females. Interestingly, while oxygen consumption rate (OCR) between males and females did not differ, indicating a higher reliance on beta-oxidation in females, both glycolytic (PFKFB3) and beta-oxidation (ACADL, ECHS1, and HADHB) enzymes were upregulated in female endothelial cells. Despite these metabolic shifts, inhibiting glycolysis or beta-oxidation in vasomotor studies did not restore endothelial function, indicating that additional factors may contribute to vascular dysfunction in T1D. Conclusions: This study underscores the sex-specific differences in vascular function in response to T1D, highlighting the possible role of sex hormones in regulating endothelial bioenergetics. While endothelial bioenergetics are crucial for vascular health, the findings suggest that these bioenergetic pathways may not significantly contribute to vasomotion in the context of acute T1D exposure. Instead, other mechanisms or factors may play a more prominent role in regulating vascular tone in in this context. R01HL147639, R01HL155265, R01AR082307, P01HL1605571, R01HL176323, R01HL175471 This abstract was presented at the American Physiology Summit 2025 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.