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

April 27, 2023 updated by: Italo Biaggioni, Vanderbilt University Medical Center

Vanderbilt University Medical Center

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Anticipated)

36

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 60 years (Adult)

Accepts Healthy Volunteers

Yes

Description

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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Single

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Contrast Enhanced-Ultrasonography (CEU)
Time Frame: 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.
Before clamp and 15 minutes after clamp

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Vanderbilt University Medical Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 24, 2017

Primary Completion (Anticipated)

November 30, 2025

Study Completion (Anticipated)

November 30, 2025

Study Registration Dates

First Submitted

October 17, 2017

First Submitted That Met QC Criteria

October 20, 2017

First Posted (Actual)

October 23, 2017

Study Record Updates

Last Update Posted (Actual)

May 1, 2023

Last Update Submitted That Met QC Criteria

April 27, 2023

Last Verified

April 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 162097

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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