The Autonomic Nervous System and the Metabolic Syndrome

The overall goal of this proposal is to determine the role of the autonomic nervous system in the insulin resistant state associated with obesity and the metabolic syndrome. Obesity results from an accumulation of excessive fat deposit due to increase caloric intake or decrease energy expenditure, this condition is usually associated with diseases such as hypertension or diabetes, a cluster known as the metabolic syndrome. The first step in the development of the metabolic syndrome is a resistance to the action of insulin. The mechanism underlying insulin resistance in obesity is still unknown, however some investigators have proposed that the autonomic nervous system, particularly the increase sympathetic activation in obesity may play an important role. We have extensive experience studying the role of the autonomic nervous system in the cardiovascular alterations associated with obesity by producing complete autonomic withdrawal with a drug named trimethaphan. We propose to use the same approach to study the role of the autonomic nervous system in the development of insulin resistance in obesity.

Study Overview

• Status: Completed
• Conditions: Obesity
• Intervention / Treatment: Drug: Blocked; Drug: Intact

Detailed Description

The purpose of this study is to look at the role of the autonomic nervous system, an involuntary nervous system that controls your blood pressure, in insulin resistance and the metabolic syndrome. Insulin is a substance that helps your body use the sugar in the food that you eat. Some people's tissues stop reacting in a normal way to insulin, a condition known as insulin resistance. A person with insulin resistance can have other health problems, such as obesity, high cholesterol, and high blood pressure. These problems together are called the metabolic syndrome. We think that the autonomic or involuntary nervous system controls the way your body responds to insulin. This system is changed in obese people, and we think that it may cause the insulin resistance. We plan to study this with two drugs -trimethaphan and L-NMMA. Neither of these drugs are approved by the Food and Drug Administration (FDA), and they will be used for research purposes only.

Fifty people will take part in this study.

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• For lean subjects:
• 21 subjects aged 18-60 yr.
• All potential volunteers will have routine blood test to screen for hepatic, renal, and hematological abnormalities.
• Body mass index < 25Kg/m^2 .
• Female volunteers of childbearing potential will undergo HCG pregnancy test at screening and again on the study day.
• For Obese subjects with metabolic syndrome:
• 21 subjects aged 18-60 yr.
• All potential volunteers will have routine blood test to screen for hepatic, renal, and hematological abnormalities.
• Body mass index > 30Kg/m^2.

• Participants will be enrolled if they met at least three of the following criteria for metabolic syndrome (Expert panel, Jama 2001):

  1. Waist circumference >102 cm in men and >88 cm in women
  2. High fasting blood sugar (>110 mg%)
  3. Triglyceride levels >150 mg%
  4. Low HDL cholesterol (<40 mg% for men; <50 mg% for women)
  5. High blood pressure (systolic=130 and diastolic = 85 mmHg) • Female volunteers of childbearing potential will undergo serum HCG pregnancy test at screening and urine HCG pregnancy test again on the study day.

Exclusion Criteria:

• Pregnant females
• Subjects unable to give voluntary informed consent
• Subjects on anticoagulant drugs or anemic (anemia defined as Hcto less than 35%)
• Subjects with a recent medical illness documented by physicians's visit or detected during the screening visit.
• Subjects with a history of coronary heart disease.
• Subjects with known kidney or liver disease.
• Subjects with recent weight loss or consuming low carbohydrate diet.

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Blocked; Active treatment arm. Transient autonomic blockade with Trimethaphan and blood pressure restoration with L-NMMA will be used during insulin clamp	Drug: Blocked; Trimethaphan 4 mg/min IV will be infused for the duration of the study. L-NMMA 125-500 mcg/k/min IV will be titrated to restore blood pressure to pre-trimethaphan levels Insulin clamp will be used to determine insulin resistance; Other Names: Trimethaphan
Placebo Comparator: Intact; Saline will be used instead of trimethaphan during insulin clamp	Drug: Intact; Saline IV infusion to simulate trimethaphan infusion in active arm Insulin clamp will be done to determine insulin resistance; Other Names: Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin Resistance	Glucose infusion rate in mg/kg/min	Last 30 minutes of a two hour insulin clamp

Collaborators and Investigators

• Sponsor: Vanderbilt University

Study record dates

Study Major Dates

• Study Start: August 1, 2008
• Primary Completion (Actual): May 1, 2015
• Study Completion (Actual): May 1, 2015

Study Registration Dates

• First Submitted: December 20, 2007
• First Submitted That Met QC Criteria: December 20, 2007
• First Posted (Estimate): December 27, 2007

Study Record Updates

• Last Update Posted (Estimate): August 5, 2016
• Last Update Submitted That Met QC Criteria: July 6, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: Obesity; Hypertension; Autonomic Nervous System
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Insulin Resistance; Hyperinsulinism; Metabolic Syndrome; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Adjuvants, Anesthesia; Ganglionic Blockers; Nicotinic Antagonists; Trimethaphan
• Other Study ID Numbers: 060085; CRC-1522 (Other Identifier: Vanderbilt University)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED