Despite a nearly equal prevalence of type 2 diabetes (T2D), women with T2D have a greater excess risk for vascular complications, such as cardiovascular disease (CVD), diabetic kidney disease (DKD), and dementia. Our studies and others have shown several candidate mechanisms underlying the sex disparities in diabetic vascular complications. These include women’s exhibition of more severe cardiometabolic phenotype than men in the latent period of T2D (i.e., metabolic syndrome, insulin resistance [IR], or intermediate diabetes), the synergistic adverse effects of female sex hormone deficiency and hyperglycemia/IR during midlife, women’s poorer glycemic control versus men resulting from psychosocial and economic stressors, and sex differences in medication access, use, and effects. Recent multi-omics analyses, including ours, have also shown cardiometabolic traits, such as dyslipoproteinmia and perturbations of amino acids and lipids, represent potentially novel sex-specific mechanisms for vascular complications. Further, several large-scale GWAS have demonstrated sex-specific genetic susceptibility to multiple clinical and subclinical macrovascular complications, such as carotid atherosclerosis, coronary heart disease, and strokes. All this evidence indicates the need to understand sex differences in diabetic vascular disease from multiple domains of risk factors across life-course, including genetic predisposition, intermediate cardiometabolic traits, lifestyles, treatments, psychosocial stress, and broad environmental influence. The objective of this study is to systematically investigate the associations of genetic, metabolic, proteomic profiles, health history, treatments, lifestyles, and external environmental exposures with women’s excess risk of vascular complications in T2D. We will include a broad spectrum of health status (i.e., euglycemia, latent T2D, undiagnosed, and diagnosed T2D) to elucidate early prevention targets for diabetic vascular complications.
