Autonomic Blockade and Endogenous Glucose Production

NCT ID: NCT03028571

Last Updated: 2021-06-08

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE1
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-04-17
• Study Completion Date: 2024-12-31

Brief Summary

The investigators will test the null hypothesis that there will be no changes in the insulin-mediated suppression of endogenous glucose production (EGP) in response to autonomic blockade. To test this hypothesis, the investigators propose to determine the role of the autonomic nervous system in hepatic insulin resistance.

Detailed Description

In this study, the investigators will test the null hypothesis that there will be no changes in the insulin-mediated suppression of endogenous glucose production (EGP) in response to autonomic blockade. The investigators will measure EGP at baseline (EGPBsl) and during the last 30 minutes of a hyperinsulinemic euglycemic clamp (EGPClamp) on two different occasions (intact and Blocked study days). A double blinded randomize cross-over design will be used. Subjects will be randomized to either the intact or blocked days and a month later will be crossed-over to the other arm. The investigator performing the analysis will also be blinded to the treatments received. At baseline in both study days it is expected to see any differences since the same subject will serve as his own control. During the clamp, insulin suppresses EGP. In obese insulin resistant subjects this suppression should be blunted. If the hypothesis is correct, it is expected an improvement in the suppression by insulin of EGP during autonomic blockade only. For this study, the primary endpoint therefore, will be the EGP during the clamp between the intact and blocked days.

H0= {(EGPClamp)Blocked - (EGPClamp)Intact}=0]

Conditions

Insulin Resistance

Study Design

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

Study Groups

Intact Day

The rates of endogenous glucose appearance (Ra) and peripheral glucose uptake (Rd) will be measured during a regular insulin clamp with concomitant infusion of saline at 48 ml/hr IV

Group Type: PLACEBO_COMPARATOR

Saline

Intervention Type: OTHER

IV saline at a rate of 48 mL/hr, will be given during the insulin clamp to resemble the volume infused in the intact day

Blocked Day

The rates of endogenous glucose appearance (Ra) and peripheral glucose uptake (Rd) will be measured during a regular insulin clamp with concomitant infusion of trimethaphan (4mg/min) IV.

Group Type: EXPERIMENTAL

Trimethaphan

Intervention Type: DRUG

Trimethaphan 4 mg/min IV will be given as a pharmacological tool to study the role of the autonomic nervous system on the regulation of endogenous glucose production by the liver.

Interventions

Trimethaphan

Trimethaphan 4 mg/min IV will be given as a pharmacological tool to study the role of the autonomic nervous system on the regulation of endogenous glucose production by the liver.

Intervention Type: DRUG

Saline

IV saline at a rate of 48 mL/hr, will be given during the insulin clamp to resemble the volume infused in the intact day

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Males and females of all races between 18 and 60 years of age
• Hypertension defined by two or more properly measured seated blood pressure readings >130/85 mmHg or currently on antihypertensive medication. This will allow us to include subjects with "pre-hypertension."
• Obesity will be defined as having a body mass index (BMI) ≥ 30 kg/m2.
• Insulin resistance will be defined as a HOMA2 IR index ≥1.6
• Able and willing to provide informed consent

Exclusion Criteria

• Pregnancy or breast feeding
• Current smokers or history of heavy smoking (>2 packs/day)
• History of alcohol or drug abuse
• Previous allergic reaction to study medications
• Evidence of type I or type II diabetes (i.e. fasting glucose >126 mg/dl, use of anti-diabetic medications)
• 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 renal function
• Anemia
• 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, inability to find IV access)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Vanderbilt University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Italo Biaggioni

Professor of Medicine and Pharmacology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Countries

United States

Other Identifiers

150466

Identifier Type: -

Identifier Source: org_study_id