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.

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.

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.

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