Inflammation and the Metabolic Syndrome in Humans

This study is a single site, open-label, "baseline-controlled" (pre LPS saline period) study
examining the pro-atherosclerotic metabolic responses and safety responses to a single
administration low-dose (3 ng/kg) endotoxin (LPS) in 20 additional non-metabolic syndrome
participants: 10 healthy overweight and 10 healthy lean counterparts (20 non-metabolic
syndrome participants were studies in first phase), and 40 subjects with the metabolic
syndrome. We are continuing to use an approach whereby "metabolic syndrome" subjects will be
recruited to have key metabolic syndrome abnormalities that are sensitive to insulin
resistance compared to the non-metabolic syndrome groups, although all of these "metabolic
syndrome" subjects may not fulfill traditional NCEP criteria for the syndrome.

Inclusion Criteria:

1. Men and non-pregnant/lactating women between the ages of 18 and 40

2. Subjects must be able to give written informed consent and willing to comply with all
study-related procedures.

3. BMI >18 and < 24 and BIA < 15% fat for men, < 25% fat for women, and do not have
diagnosis of NCEP metabolic syndrome as defined below, OR

4. BMI > 26 but < 30 and BIA > 15% fat for men, > 25% fat for women, do not have
diagnosis of NCEP metabolic syndrome, OR

5. BMI >18 and < 30 and have metabolic syndrome abnormalities as defined below. The
modified NCEP Metabolic Syndrome criteria are as follows

- abdominal obesity, waist circumference: men >= 37 in (94 cm), women >= 31 in (80
cm)

- fasting triglycerides > 150 mg/dL

- HDL cholesterol < 40 mg/dL for men; HDL cholesterol < 50 mg/dL for women

- Blood pressure > 130/ >85 mmHg in untreated patients

- Fasting glucose > 100 mg/dL, but less than 126 mg/dL

6. For inclusion in "metabolic syndrome" group, the following additional criteria must
be fulfilled:

- Three or more of the NCEP criteria defined above. OR

- Two or more of the NCEP criteria AND TG/HDL ratio > 3.0.

Exclusion Criteria:

1. Known atherosclerotic cardiovascular disease, including coronary disease,
cerebrovascular disease, or peripheral vascular disease.

2. History of diabetes mellitus.

3. A plasma glucose greater than 200 mg/dL at the 2 hour blood draw of the oral glucose
tolerance test.

4. History of a non-skin malignancy within the previous 5 years.

5. Renal insufficiency as defined by creatinine >= 1.5 mg/dl at visit 1 (grade 1 of
NIH's Common Toxicity Criteria (CTC), version 2.0, 4/30/99).

6. History of liver disease or ALT, AST, ALK Phosphatase or Gamma GT above normal limits
as defined by HUP William Pepper Clinical Laboratory at visit 1.

7. Elevated (> 1.5x ULN; grade 1, CTC, 4/30/99) Total Bilirubin or LDH at visit 1.

8. Men who consume > 14 alcoholic drinks per week or > 4 alcoholic drinks per occasion
(AMA/NIAAA criteria for "at risk" usage levels).

9. Women who consume > 7 alcoholic drinks per week or > 3 alcoholic drinks per occasion
(AMA/NIAAA criteria for "at risk" usage levels).

10. Total white blood cell count below normal limits as defined at HUP William Pepper
Clinical Laboratory prior to the baseline visit.

11. Hemoglobin below normal limits (gender specific) as defined at HUP William Pepper
Clinical Laboratory prior to the baseline visit.

12. Any medical condition or abnormal laboratory value that is judged clinically
significant by an investigator.

13. Any major active rheumatologic, pulmonary, or dermatologic disease or inflammatory
condition or minor active infection.

14. History of HIV positive.

15. First degree family history of premature cardiovascular disease event (father or
brother if diagnosed at before 55 years of age; mother or sister if diagnosed before
65 years of age).

16. Patients who have undergone any organ transplant.

17. Individuals who currently use tobacco products or have done so in the previous 30
days.

18. Treatment with aspirin, NSAIDs, COX-2 inhibitors, steroids or other immunomodulatory
therapy 2 weeks prior to the screening visit

19. Treatment with statins, fibrates or niacin 4 weeks prior to the screening visit.

20. Current daily use of Vitamin C > 1000 mg, Beta carotene > 1000 IU, vitamin A > 5000
IU, vitamin E > 400 IU, and selenium > 200 mcg.

21. Positive urine pregnancy at the screening visit.

22. Participation in another clinical trial within the previous 6 weeks prior to the
screening visit.

23. Poorly controlled blood pressure (BP > 160/100) or on any anti-hypertensive
medications.

24. For subjects in non-metabolic syndrome groups; a diagnosis of metabolic syndrome
using NCEP ATPIII criteria.

25. For subjects in "metabolic syndrome" group; an abnormal Bruce protocol cardiac
exercise stress test.