Role of Sympathetic Vasoconstriction on Insulin-Mediated Microvascular Recruitment and Glucose Uptake in Obesity

Sponsor
Vanderbilt University Medical Center (Other)
Overall Status
Recruiting
CT.gov ID
NCT03318094
Collaborator
(none)
36
1
3
97.2
0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to better understand the contribution of sympathetic vasoconstriction to impaired insulin-mediated vasodilation and subsequently insulin-mediated glucose uptake. The investigators will test the hypothesis that removal of sympathetic vasoconstriction can result in improvement in insulin-mediated vasodilation and subsequently sensitivity to insulin-mediated glucose uptake.

Condition or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

Several studies have shown that obese subjects have impaired Nitric Oxide (NO)-mediated dilation; and those who develop insulin resistance tend to be more obese, have higher insulin levels and greater sympathetic activity. Furthermore, we have made the novel observation that autonomic blockade improves glucose utilization in obese subjects with insulin resistance, providing a causal relation between sympathetic activation and insulin resistance. The autonomic blockade also improved NO-mediated dilation in obese subjects, which may improve glucose uptake by promoting glucose delivery.

The investigators will enroll obese insulin-resistant subjects and in parallel experiments two comparator groups: obese insulin sensitive subjects, and healthy lean control subjects. We will assess the effects of insulin (hyperinsulinemic euglycemic clamp) on microvascular recruitment, and forearm glucose uptake on two separate occasions randomly assigned and at least one month apart, during an intrabrachial infusion of the alpha-adrenergic blocker phentolamine (blocked day) or saline control (Control day).

Study Design

Study Type:
Interventional
Anticipated Enrollment :
36 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
Single (Participant)
Primary Purpose:
Basic Science
Official Title:
Vanderbilt University Medical Center
Actual Study Start Date :
Oct 24, 2017
Anticipated Primary Completion Date :
Nov 30, 2022
Anticipated Study Completion Date :
Nov 30, 2025

Arms and Interventions

Arm Intervention/Treatment
Placebo Comparator: Intact Day

Saline

Other: Saline
Intrabrachial saline will be given this day

Experimental: Blocked Day

Phentolamine

Drug: Phentolamine
Intrabrachial phentolamine will be given on the blocked day
Other Names:
  • alpha-adrenergic blocker
  • Active Comparator: Vasodilator Comparison

    Sodium Nitroprusside

    Drug: Sodium Nitroprusside
    Intrabrachial sodium nitroprusside will be given this day to compare with phentolamine
    Other Names:
  • Active comparison
  • Outcome Measures

    Primary Outcome Measures

    1. Contrast Enhanced-Ultrasonography (CEU) [Before clamp and 15 minutes after clamp]

      The Primary Outcome will be the change in CEU induced by insulin during hyperinsulinemic clamp compared to baseline. To test the null hypothesis that insulin will not produce any changes in microvascular blood volume using CEU in response to α-adrenergic blockade (phentolamine) in the isolated forearm model.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 60 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria:
    • Males and females of all races between 18 and 60 years of age.

    • Obesity defined as body mass index between 30-40 kg/m2

    • Insulin resistance defined as homeostasis model assessment 2 insulin resistance (HOMA2-IR) score >1.6 (never diagnosed or treated type 2 diabetic), or being a well-controlled type 2 diabetic on metformin only.

    • Able and willing to provide informed consent

    Exclusion Criteria:
    • Pregnancy or breastfeeding

    • Current smokers or history of heavy smoking (>2 packs/day)

    • History of alcohol or drug abuse

    • Morbid obesity (BMI > 40 kg/m2)

    • Previous allergic reaction to study medications

    • Evidence of type I diabetes.

    • Cardiovascular disease other than hypertension such as myocardial infarction within 6 months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third-degree heart block, mitral valve stenosis, aortic stenosis, or hypertrophic cardiomyopathy

    • History of serious cerebrovascular disease such as cerebral hemorrhage, stroke, or transient ischemic attack

    • History or presence of immunological or hematological disorders

    • Impaired hepatic function [aspartate amino transaminase (AST) and/or alanine amino transaminase (ALT) > 2.0 x upper limit of normal range]

    • Impaired renal function (serum creatinine >1.5 mg/dl)

    • Moderate to severe anemia (hemoglobin <11 g/dl)

    • Treatment with serotonin-norepinephrine reuptake inhibitors (SNRIs) or norepinephrine transporter (NET) inhibitors

    • Treatment with phosphodiesterase 5 inhibitors

    • Treatment with anticoagulants

    • Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days in 1 month)

    • Treatment with any investigational drug in the 1 month preceding the study

    • Inability to give, or withdraw, informed consent

    • Other factors which in the investigator's opinion would prevent the subject from completing the protocol (i.e., clinically significant abnormalities on clinical, mental examination or laboratory testing or inability to comply with protocol)

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Autonomic Dysfunction Center Nashville Tennessee United States 37232

    Sponsors and Collaborators

    • Vanderbilt University Medical Center

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Italo Biaggioni, Professor Medicine and Pharmacology, Vanderbilt University Medical Center
    ClinicalTrials.gov Identifier:
    NCT03318094
    Other Study ID Numbers:
    • 162097
    First Posted:
    Oct 23, 2017
    Last Update Posted:
    Aug 25, 2022
    Last Verified:
    Aug 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    No
    Keywords provided by Italo Biaggioni, Professor Medicine and Pharmacology, Vanderbilt University Medical Center
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Aug 25, 2022