The Autonomic Nervous System and the Metabolic Syndrome

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.

• Blocked (Drug), also known as Trimethaphan: 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
• Intact (Drug), also known as Saline: Saline IV infusion to simulate trimethaphan infusion in active arm Insulin clamp will be done to determine insulin resistance

Primary outcomes

• Insulin Resistance [Last 30 minutes of a two hour insulin clamp]: Glucose infusion rate in mg/kg/min

Sex: All, ages: 18 Years to 60 Years, accepts healthy volunteers

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.

Participant flow

Outcome results

• Insulin Resistance (Primary), Mean, mg/kg/min: Blocked 3.8 +/- 0.3; Intact 3.1 +/- 0.3

Adverse events

Time frame: During and up to 1 hour after finishing the 2 hour insulin clamp.

• Italo Biaggioni, M.D., Principal investigator, Vanderbilt University