Back to results

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

Primary Purpose

Insulin Resistance, Healthy, Obesity

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Phentolamine

Saline

Sodium Nitroprusside

About this trial

This is an interventional basic science trial for Insulin Resistance focused on measuring insulin resistance, phentolamine, microvascular recruitment, autonomic nervous system

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesAccepts Healthy Volunteers

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)

Sites / Locations

Autonomic Dysfunction CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Placebo Comparator

Experimental

Active Comparator

Arm Label

Intact Day

Blocked Day

Vasodilator Comparison

Arm Description

Saline

Phentolamine

Sodium Nitroprusside

Outcomes

Primary Outcome Measures

Contrast Enhanced-Ultrasonography (CEU)

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.

Secondary Outcome Measures

Full Information

NCT ID

NCT03318094

First Posted

October 17, 2017

Last Updated

April 27, 2023

Sponsor

Vanderbilt University Medical Center

1. Study Identification

Unique Protocol Identification Number

NCT03318094

Brief Title

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

Official Title

Vanderbilt University Medical Center

Study Type

Interventional

2. Study Status

Record Verification Date

April 2023

Overall Recruitment Status

Recruiting

Study Start Date

October 24, 2017 (Actual)

Primary Completion Date

November 30, 2025 (Anticipated)

Study Completion Date

November 30, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Vanderbilt University Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. 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.

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Insulin Resistance, Healthy, Obesity

Keywords

insulin resistance, phentolamine, microvascular recruitment, autonomic nervous system

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 1

Interventional Study Model

Crossover Assignment

Masking

Participant

Allocation

Randomized

Enrollment

36 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Intact Day

Arm Type

Placebo Comparator

Arm Description

Saline

Arm Title

Blocked Day

Arm Type

Experimental

Arm Description

Phentolamine

Arm Title

Vasodilator Comparison

Arm Type

Active Comparator

Arm Description

Sodium Nitroprusside

Intervention Type

Drug

Intervention Name(s)

Phentolamine

Other Intervention Name(s)

alpha-adrenergic blocker

Intervention Description

Intrabrachial phentolamine will be given on the blocked day

Intervention Type

Other

Intervention Name(s)

Saline

Intervention Description

Intrabrachial saline will be given this day

Intervention Type

Drug

Intervention Name(s)

Sodium Nitroprusside

Other Intervention Name(s)

Active comparison

Intervention Description

Intrabrachial sodium nitroprusside will be given this day to compare with phentolamine

Primary Outcome Measure Information:

Title

Contrast Enhanced-Ultrasonography (CEU)

Description

Time Frame

Before clamp and 15 minutes after clamp

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

60 Years

Accepts Healthy Volunteers

Eligibility Criteria

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)

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Italo Biaggioni, MD

Phone

6159363420

autonomics@vanderbilt.edu

Facility Information:

Facility Name

Autonomic Dysfunction Center

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37232

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Misty D Hale, CCRP

Phone

615-343-8649

autonomics@vanderbilt.edu

First Name & Middle Initial & Last Name & Degree

Jorge E Celedonio

Phone

6153223304

autonomics@vanderbilt.edu

12. IPD Sharing Statement

Learn more about this trial

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

We'll reach out to this number within 24 hrs