The Autonomic Nervous System and the Metabolic Syndrome

• Sponsor: Vanderbilt University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00580957
• Collaborator: (none)
• Enrollment: 56
• Location: 1
• Arms: 2
• Duration (Months): 81
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Obesity	Drug: Blocked; Drug: Intact	N/A

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 Design

• Study Type: Interventional
• Actual Enrollment: 56 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Official Title: The Autonomic Nervous System and the Metabolic Syndrome
• Study Start Date: Aug 1, 2008
• Actual Primary Completion Date: May 1, 2015
• Actual Study Completion Date: May 1, 2015

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Insulin Resistance [Last 30 minutes of a two hour insulin clamp]

   Glucose infusion rate in mg/kg/min

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232

Sponsors and Collaborators

• Vanderbilt University

Investigators

• Principal Investigator: Italo Biaggioni, M.D., Vanderbilt University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Italo Biaggioni, Professor of Medicine and Pharmacology, Vanderbilt University
• ClinicalTrials.gov Identifier: NCT00580957
• Other Study ID Numbers: 060085; CRC-1522
• First Posted: Dec 27, 2007
• Last Update Posted: Aug 5, 2016
• Last Verified: Jul 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Italo Biaggioni, Professor of Medicine and Pharmacology, Vanderbilt University: Obesity; Hypertension; Autonomic Nervous System
• Additional relevant MeSH terms: Metabolic Syndrome; Trimethaphan

Study Results

Participant Flow

Arm/Group Title	Blocked	Intact
Arm/Group Description	Active treatment arm. Transient autonomic blockade with Trimethaphan and blood pressure restoration with L-NMMA will be used during insulin clamp 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	Saline will be used instead of trimethaphan during insulin clamp Intact: Saline IV infusion to simulate trimethaphan infusion in active arm Insulin clamp will be done to determine insulin resistance
Period Title: Overall Study
STARTED	28	28
COMPLETED	21	21
NOT COMPLETED	7	7

Baseline Characteristics

Arm/Group Title	Blocked Then Intact	Intact Then Blocked	Total
Arm/Group Description	Active treatment arm. Transient autonomic blockade with Trimethaphan and blood pressure restoration with L-NMMA will be used during insulin clamp 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	Saline will be used instead of trimethaphan during insulin clamp Intact: Saline IV infusion to simulate trimethaphan infusion in active arm Insulin clamp will be done to determine insulin resistance	Total of all reporting groups
Overall Participants	21	21	42
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	21 100%	21 100%	42 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44 (6)	43 (5)	43 (5.5)
Sex: Female, Male (Count of Participants)
Female	12 57.1%	12 57.1%	24 57.1%
Male	9 42.9%	9 42.9%	18 42.9%
Region of Enrollment (participants) [Number]
United States	21 100%	21 100%	42 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Blocked	Intact
Arm/Group Description	Active treatment arm. Transient autonomic blockade with Trimethaphan and blood pressure restoration with L-NMMA will be used during insulin clamp 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	Saline will be used instead of trimethaphan during insulin clamp Intact: Saline IV infusion to simulate trimethaphan infusion in active arm Insulin clamp will be done to determine insulin resistance
Measure Participants	21	21
Mean (Standard Error) [mg/kg/min]	3.8 (0.3)	3.1 (0.3)

Adverse Events

Time Frame	During and up to 1 hour after finishing the 2 hour insulin clamp.
Arm/Group Title	Blocked		Intact
Arm/Group Description	Active treatment arm. Transient autonomic blockade with Trimethaphan and blood pressure restoration with L-NMMA will be used during insulin clamp 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		Saline will be used instead of trimethaphan during insulin clamp Intact: Saline IV infusion to simulate trimethaphan infusion in active arm Insulin clamp will be done to determine insulin resistance
All Cause Mortality
	Blocked		Intact
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Blocked		Intact
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		0/27 (0%)
Other (Not Including Serious) Adverse Events
	Blocked		Intact
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		0/27 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.