The objective of this study is to identify insulin-specific cerebral blood flow (CBF) control
mechanisms, and establish cerebrovascular responsive baseline in younger (18-45 yrs)
metabolic syndrome adults (MetSyn) who are at substantial risk of stroke and other types of
cardiovascular mortality even if they never develop diabetes. The central hypothesis is that
vasodilator actions of insulin are impaired in MetSyn due to loss of dilator and gain of
constrictor signals. This study will focus on 2 mechanisms that likely limit CBF in MetSyn:
1) Disruption of nitric oxide (NO) vasodilation, and 2) Exaggerated endothelin (ET-1)
constriction. Three specific aims will be addressed: Aim 1: To test the hypothesis that
physiologic surges of insulin acutely increase CBF in young adults, but adults with MetSyn
exhibit paradoxical insulin-mediated vasoconstriction. Aim 2: To test the hypotheses that key
mechanisms responsible for poor CBF in MetSyn are shifts in NO and ET-1 signaling.
Specifically, in healthy controls, NO mediates robust dilation, with little to no ET-1
constriction. In contrast, adults with MetSyn exhibit uncoupled NO synthase (NOS) and
exaggerated ET-1 constriction. Aim 3: To test the hypothesis that insulin regulation of CBF
is regionally distinct (e.g. Middle Cerebral Artery (MCA) reactive than Anterior Cerebral
Artery (ACA) or basilar), and the negative effects of insulin resistance (IR) are similarly
regionally specific.
Phase:
Phase 1
Details
Lead Sponsor:
University of Wisconsin, Madison
Collaborators:
American Diabetes Association American Heart Association