Introduction It is widely accepted that insulin resistance in MetSyn increases the risk of cerebrovascular disease (CVD) and stroke. Additionally, MetSyn is associated with cognitive impairments and increased risk of neurodegenerative diseases. Despite strong association of poor cerebrovascular health in MetSyn, the cerebral blood flow (CBF) response to acute insulin surges in humans remains largely unexplored. Cerebrovascular dysfunction in response to insulin and potential mechanism(s) that attenuate CBF may not only highlight the central underpinnings of the pathophysiology of stroke and CVD, it may provide key insights to understanding cognitive decline strongly linked to older individuals with MetSyn. Therefore, establishing the mechanisms of insulin-mediated cerebrovascular control are not only important for decreasing mortality in MetSyn, it may be profoundly important to maintaining brain health. Insulin-meditated vasodilation is largely a vascular endothelium-dependent process. Elegant experiments using animal models suggests insulin resistance disrupts six endothelial signaling pathways, with the strongest evidence implicating a loss of nitric oxide (NO) vasodilation, and exaggerated endothelin (ET-1) constriction. The literature indicates that in MetSyn, a spike in insulin leads to vasoconstriction and cerebral hypoperfusion. These findings are directionally opposite from no change or insulin-mediated vasodilation and increase in CBF reported in the literature. Evidence suggests that uncoupled function of nitric oxide synthase (NOS) leads to unfavorable balance between NO, reactive oxygen species, and ET-1. Normally, stimulation of insulin receptor on the vascular endothelium should provide an environment in which NOS manufactures NO leading to vasodilation and inhibition of ET-1. Instead, in MetSyn insulin stimulates the vasoconstrictor ET-1 to a greater extent while, NOS is uncoupled generating more reactive oxygen species that scavenges the NO that is generated leading to a greater vasoconstrictor signal rather than vasodilation.