Sex differences in cardiovascular mechanisms underlying exercise intolerance in type 2 diabetes: the role of skeletal muscle microvasculature

Type 2 diabetes (T2D) disproportionately increases cardiovascular disease risk and premature mortality in females compared with males. Exercise intolerance is a hallmark symptom of T2D and an early indicator of cardiovascular dysfunction. Although both central (cardiac) and peripheral (vascular and skeletal muscle) factors contribute to exercise intolerance in T2D, skeletal muscle microvascular dysfunction is increasingly recognized as an early contributor and a key therapeutic target. However, the sex-specific cardiovascular mechanisms underlying exercise intolerance remain poorly understood. Females with T2D have lower exercise capacity and are less physically active than their male counterparts, which likely contributes to their heightened cardiovascular risk and worse clinical outcomes. Emerging evidence suggests that cardiac mechanisms may play a larger role in exercise intolerance in females, although sex differences in skeletal muscle microvascular function and dysfunction are poorly characterized. This narrative review synthesizes current research on the cardiovascular determinants of exercise intolerance in T2D, with a specific focus on the skeletal muscle microvasculature, and examines how sex differences in cardiovascular physiology and pathophysiology may affect exercise capacity. We highlight gaps in sex-specific research in healthy populations and individuals with T2D that limit insight into underlying disease mechanisms and effective therapies. Closing these gaps is essential for accurate risk assessment, timely diagnosis, and designing interventions that better address the cardiovascular needs of females with T2D.