Type 1 diabetes impaired endothelium-dependent relaxation similarly in both male and female mice, but through distinct mechanisms involving mitochondrial ROS in males and glycolysis in females.
Does targeted metabolic or hormonal modulation improve endothelium-dependent relaxation in a sex-specific manner in mice with Type 1 diabetes?
Endothelial dysfunction in Type 1 diabetes is driven by distinct, sex-specific metabolic and hormonal pathways, highlighting the potential need for sex-tailored vascular therapies.
Type 1 diabetes (T1D) is a major cardiovascular risk factor, notably in women, through its ability to abolish the vascular protection usually conferred by female sex. Women with T1D exhibit more severe cardiovascular alterations than men, yet the sex-specific mechanisms whereby T1D disrupts vascular function remain incompletely understood. Herein, we hypothesised that T1D impairs vascular function through sex-specific mechanisms involving alterations in endothelial cell metabolism. Streptozotocin (STZ) was employed to induce T1D, which developed equally in male and female mice. T1D markedly reduced body weight, while elevating circulating triglycerides and cholesterol and reducing estradiol and testosterone levels in females and males, respectively. T1D increased systolic blood pressure in males but lowered it in females who also exhibited reduced measures of arterial stiffness, including intima–media thickness and pulse wave velocity. T1D impaired endothelium-dependent relaxation (EDR) to a similar extent in both sexes, despite females exhibiting greater baseline EDR. Given the central role of endothelial metabolism in T1D-associated endothelial dysfunction, we assessed EC bioenergetics. T1D induced selective upregulations of glycolytic (PFKFB1,3) and β-oxidation (ACADL, EHHADH, ECHS1, HADHB) enzymes in the vasculature. However, Seahorse analysis revealed higher baseline endothelial ECAR and OCR in males, which were reduced with T1D. T1D elicited no alterations in endothelial cell metabolism in females. Due to sex-specific changes in metabolic profile, we further investigated the contribution of glycolysis and β-oxidation to the control of vascular function. In T1D, blocking β-oxidation with ETO1 did not improve vascular dysfunction, but selective inhibition of PFKFB3 with PFK158 restored EDR exclusively in females. The limited contribution of glycolytic and β-oxidation pathways to male EDR prompted investigation of potential links with the pentose phosphate pathway (PPP). In T1D, blocking PPP with G6PDi restored EDR specifically in males. To further examine ROS contribution to endothelial dysfunction in T1D, ROS scavengers were used. T1D unmasked distinct ROS-dependent mechanisms, with Tempol improving vascular function in both sexes and mitotempo revealing a dominant role of mitochondrial ROS in males. Because STZ reduced sex hormone levels, we supplemented male T1D mice with DHT and female mice with E2 either in vivo or ex vivo. DHT restored EDR in males despite persistent glycolytic defects, whereas E2 normalised reproductive organ weights in females, with a trend towards an improved EDR observed ex vivo only. T1D induced an immunosuppressed phenotype, as revealed by cytokine profiling, which was reversed by DHT/E2 supplementation. In summary, T1D induces sex-specific disturbances in vascular function, metabolism, redox balance, and hormone signalling. Although T1D impairs EDR similarly in both sexes, males show reduced glycolytic and mitochondrial capacity, greater PPP reliance, and mitochondrial ROS–driven dysfunction partly restored by DHT. Females maintain endothelial metabolism but develop compensatory mitochondrial shifts, and a glycolysis-dependent EDR impairment rescued by PFKFB3 inhibition and influenced by E2. Thus, vascular dysfunction in T1D arises through distinct metabolic and hormone-sensitive pathways in each sex. 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.
Saloň et al. (Fri,) conducted a other in Type 1 diabetes. Streptozotocin (STZ), metabolic inhibitors, and sex hormones vs. Non-diabetic controls and opposite sex was evaluated on Endothelium-dependent relaxation and endothelial cell metabolism. Type 1 diabetes impaired endothelium-dependent relaxation similarly in both male and female mice, but through distinct mechanisms involving mitochondrial ROS in males and glycolysis in females.