Mechanisms of Cerebrovascular Control

• Status: Completed
• Trial end date: 2021-09-30
• Target enrollment: 0
• Participant gender: All

Summary

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
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: University of Wisconsin, Madison
• Collaborators: American Diabetes Association; American Heart Association
• Treatments: Ambrisentan; cyclo(Trp-Asp-Pro-Val-Leu); Insulin

Criteria

• Inclusion Criteria (all):

• Sedentary (≤ 90 minutes of vigorous physical activity per week)

• Women must be premenopausal with a regular menstrual cycle

• For the Ambrisentan trial, participants must be male, due to potential harmful effects of drug on fetus

• Inclusion Criteria (Controls):

• Participants will be lean (BMI ≥19 - ≤25 kg/m2)

• Sedentary (≤ 90 minutes of vigorous physical activity per week)

• Without any cardiovascular co-morbidities

• Inclusion Criteria: (Metabolic Syndrome):

• Participants must qualify under the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) definition of metabolic syndrome as modified by the American Heart Association and International Diabetes Federation. Participants must meet 3 or more of the following 5 criteria:

• fasting glucose ≥ 100 mg/dL,

• fasting triglycerides ≥ 150 mg/dL,

• elevated blood pressure (≥ 130 systolic and/or ≥ 85 diastolic mmHg),

• waist circumference at the iliac crest > 102 cm (men) or ≥ 88 cm (women).

• Exclusion Criteria:

• Fasting glucose ≥ 126 mg/dL

• Having ≥1- ≤ 2 of the above criteria for MetSyn.

• Personal medical history of coronary artery disease, stroke, heart attack, heart valve disease, congestive heart failure, previous heart surgery, history of lung disease (Note: asthma that is not currently active and being treated is NOT considered an exclusion criteria) or peripheral artery disease, or history of renal/kidney and liver/hepatic disease.

• Taking metabolic medications (insulin-sensitizing, lipid-lowering medications, etc.) or any medications for cardiovascular-related issues will be excluded.

• Current use of tobacco (i.e. smoke, smokeless, and vapor). If participant has used tobacco products ≤10 in the last year and ≤1 time in the last month, he or she will still be considered eligible.

• Females will be excluded if pregnant, lactating, or postmenopausal.

• Participants having any contraindications of having an MRI (such as claustrophobia, metallic implant, etc.).

• Participant has an abnormality or contraindication to study participation, which is not covered in the eligibility criteria.