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

NCT ID: NCT03318094

Last Updated: 2025-05-13

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 36 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-10-24
• Study Completion Date: 2025-11-30

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).

Conditions

Insulin Resistance; Healthy; Obesity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: SINGLE

Study Groups

Intact Day

Saline

Group Type: PLACEBO_COMPARATOR

Saline

Intervention Type: OTHER

Intrabrachial saline will be given this day

Blocked Day

Phentolamine

Group Type: EXPERIMENTAL

Phentolamine

Intervention Type: DRUG

Intrabrachial phentolamine will be given on the blocked day

Vasodilator Comparison

Sodium Nitroprusside

Group Type: ACTIVE_COMPARATOR

Sodium Nitroprusside

Intervention Type: DRUG

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

Interventions

Phentolamine

Intrabrachial phentolamine will be given on the blocked day

Intervention Type: DRUG

Saline

Intrabrachial saline will be given this day

Intervention Type: OTHER

Sodium Nitroprusside

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

Intervention Type: DRUG

Other Intervention Names

alpha-adrenergic blocker; Active comparison

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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Vanderbilt University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Italo Biaggioni

Professor Medicine and Pharmacology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Autonomic Dysfunction Center

Nashville, Tennessee, United States

Countries

United States

Other Identifiers

162097

Identifier Type: -

Identifier Source: org_study_id