Vascular Insulin Resistance and Free Fatty Acids: The Micro-Macro Circulation Nexus

Vascular dysfunction, often leading to cardiovascular disease, is associated with conditions like obesity, hypertension, and type 2 diabetes mellitus. This dysfunction is characterized by impairment in endothelial function, microvascular dysfunction, and large artery changes, such as increased stiffness and sensitivity to vasoconstrictors. Vascular smooth muscle cells (VSMCs) in resistance arteries and arterioles control short-term skeletal muscle blood flow through myogenic control, shear-induced nitric oxide (NO) production, and metabolic regulation (1). Blood flow regulation in the microvascular unit is achieved through arteriolar dilation, a mechanism that plays a crucial role in capillary recruitment. Vasodilation in local arterioles augments microvascular blood flow and extends upstream, causing an increase in macrovascular flow due to flow-induced shear stress. Vascular responses also show axial heterogeneity, with different effects of vasoactive substances across the vascular tree. Insulin's vasodilatory effects occur in stages, initially, causing the dilation of terminal arterioles, enhancing capillary recruitment rapidly without changing overall limb blood flow. This is followed by relaxation of larger resistance vessels, which increases overall limb blood flow (1, 2). Alterations in macrovasculature occur after insulin's effect on enhancing glucose utilization in skeletal muscle, suggesting a temporal separation between increases in overall total limb blood flow and muscle glucose disposal. The vasodilatory action of insulin is partly mediated by NO production in the vascular endothelium (1-3). Insulin-mediated microvascular recruitment precedes glucose uptake in skeletal muscle, and blocking this recruitment with NO synthesis inhibitor or with vasoconstrictors like endothelin-1 induces metabolic insulin resistance. However, infusing vasodilators during hyperinsulinemia does not consistently alleviate microvascular insulin resistance or enhance glucose disposal in muscle, suggesting that macrovascular flow facilitates rather than directly enhances glucose disposal (1-3). Impaired microvascular responses to insulin, “microvascular insulin resistance,” observed before the development of metabolic insulin resistance, plays a significant role in glucose intolerance development (3).