University of Wisconsin–Madison

Mechanisms of Cerebrovascular Control: Acute Insulin Surges Lead to Brain Hypoperfusion in Human Metabolic Syndrome

January 1970 to January 1970

Our central hypothesis is that vasodilator actions of insulin are already impaired in metabolic
syndrome (MetSyn) due to loss of dilator and gain of constrictor signals. This proposal focuses
on two that most likely reduce cerebral blood flow (CBF) in MetSyn: 1) Loss of nitric oxide (NO)
vasodilation, and 2) Exaggerated endothelin (ET-1) constriction. This study will
address three specific aims:
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 reactive versus anterior cerebral or basilar artery), and the negative effects of
insulin resistance (IR) are similarly regionally specific.
Study design: Following initial screening and a screening visit, participation in this study will
involve two separate MRI study visits (Saline infusion as placebo on one visit and either LNMMA
infusion to inhibit NOS OR BQ 123 infusion to inhibit ET-1 on the other visit). Subjects
will be directed into an experimental condition (placebo/L-NMMA or placebo/BQ 123). Once
assigned an experimental condition group, the drug order (placebo/drug) will be performed in a
randomly assigned, counter-balanced single blind fashion. The experimental procedures will be
identical on all testing days with the exception of which drug will be infused. Throughout each
visit, subjects will be monitored for heart rate, blood pressure, end-tidal carbon dioxide, and
verbal communication of adverse symptoms (how is the subject feeling) while in the MRI
scanner.

This project led by: