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Autonomic Blockade and Endogenous Glucose Production

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ClinicalTrials.gov Identifier: NCT03028571
Recruitment Status : Recruiting
First Posted : January 23, 2017
Last Update Posted : February 28, 2018
Sponsor:
Information provided by (Responsible Party):
Italo Biaggioni, Vanderbilt University Medical Center

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.

Condition or disease Intervention/treatment Phase
Insulin Resistance Drug: Trimethaphan Other: Saline Phase 1

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]


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Subjects will be studied twice, randomly assigned to star on the intact day (saline) or the blocked day (trimethaphan) and after 1 month cross to the other arm
Masking: Single (Participant)
Primary Purpose: Basic Science
Official Title: Acute Sympathetic Blockade and Endogenous Glucose Production
Actual Study Start Date : February 17, 2017
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2024

Arm Intervention/treatment
Placebo Comparator: 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
Other: 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

Experimental: 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.
Drug: 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.




Primary Outcome Measures :
  1. Endogenous Glucose Production [ Time Frame: Duration of the study (4 hours) ]
    Amount of label glucose appearance



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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03028571


Locations
United States, Tennessee
Vanderbilt University Medical Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Misty Hale, BS    615-322-2318    autonomics@vanderbilt.edu   
Sub-Investigator: Italo Biaggioni, MD         
Sponsors and Collaborators
Vanderbilt University Medical Center

Responsible Party: Italo Biaggioni, Professor of Medicine and Pharmacology, Vanderbilt University Medical Center
ClinicalTrials.gov Identifier: NCT03028571     History of Changes
Other Study ID Numbers: 150466
First Posted: January 23, 2017    Key Record Dates
Last Update Posted: February 28, 2018
Last Verified: February 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Insulin
Trimethaphan
Trimethaphan camsylate
Hypoglycemic Agents
Physiological Effects of Drugs
Adjuvants, Anesthesia
Antihypertensive Agents
Ganglionic Blockers
Autonomic Agents
Peripheral Nervous System Agents
Nicotinic Antagonists
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents