Summary: Neurodegenerative disease (e.g. Alzheimer’s disease, dementia, stroke) affects 1 in 6 people worldwide, leads to chronic disability and a loss of quality-of-life, and costs hundreds of billions of healthcare dollars in the US alone. Reduced cerebral blood flow (CBF) is associated with cognitive impairment, many neurodegenerative disorders, and is observed in the early stages of neurodegenerative disease development. Insulin resistance (IR) is an independent risk factor for neurodegenerative disease and early changes in resting CBF in adults with IR may contribute to neurodegenerative disease development and worse disease outcomes. Despite the link between IR, neurodegenerative disease, and altered CBF, we do not know enough about how vascular dysfunction manifests or the role of IR in neurodegenerative disease development. Thus, it is essential that we identify key vascular signaling pathways involved in maintenance of resting CBF in healthy adults as a fundamental understanding of healthy physiology of the cerebral circulation will help us understand how this physiology is altered during IR. Given that the role of NOS signaling in control of resting CBF remains controversial, Aim 1 of this dissertation will determine the contribution of NOS signaling to control of resting CBF in healthy adults. Next, animal data indicate insulin triggers a robust NOS-mediated dilation in cerebral arteries, and is dysfunctional in animals with IR. An oral glucose tolerance test (OGTT) induces a physiologic insulin surge, which may produce vasodilation in human cerebrovasculature. Furthermore, an OGTT may provide a new challenge for assessing cerebrovascular function in adults with IR. Aim 2 of this dissertation will evaluate CBF responses to an OGTT and the contribution of NOS to changes in CBF during OGTT to characterize the role of insulin signaling in regulation of CBF. Finally, studies in older adults with type 2 diabetes reveal lower resting global and regional CBF, yet younger adults with less severe IR remain largely understudied and early changes in CBF may contribute to worse disease outcomes. Aim 3 of this dissertation will determine if adults with IR exhibit diminished resting CBF compared to healthy counterparts to identify if vascular dysfunction is already present in adults with IR.