A Study to Evaluate the Effect of Lipid Infusion on Toll Like Receptor 4 (TLR4) Signaling

The investigators plan to examine the effect of a lipid infusion on TLR4 expression and
insulin sensitivity. A group of 30 subjects aged 18-60 years old, lean (BMI < 26 kg/m2)
normal glucose tolerant subjects without a family history of type 2 diabetes will receive a
lipid or saline infusion. The subjects will be randomly assigned to first receive either a
48 hour long lipid or saline infusion. Approximately 4-6 weeks later subjects will return to
undergo another study (if, in the first study they received lipid, on the second study they
will receive saline, and vice versa). A near-equal number of women and men will be included
in each group.

Inclusion Criteria:

1. Subjects must have the following laboratory values: Hematocrit ≥ 35%, serum
creatinine ≤ 1.5 mg/dl, aspartate aminotransferase (AST) < 2 X upper limit of normal,
Alanine aminotransferase (ALT) < 2 X upper limit of normal, alkaline phosphatase < 2
X upper limit of normal, normal urinalysis [no glucose, trace protein, trace ketones,
lipase < 50 IU/L, no bacteria, up to 1-3 white blood cells (WBC) and red blood cells
(RBC) per hpf], and normal platelets, prothrombin time (PT) and partial
thromboplastin time (PTT).

2. Female subjects must be non-lactating. Female patients are eligible only if they have
a negative pregnancy test throughout the study period (or postmenopausal).
Postmenopausal women taking hormone replacement will be included if they have been on
a stable dose for ≥6 months.

3. Subjects whose body weight has been stable (within 2%) for at least three months.

Exclusion Criteria:

1. Subjects with impaired glucose tolerance based on American Diabetes Association
criteria.

2. Subjects taking drugs known to affect glucose and lipid homeostasis will be excluded.
Statins will be permitted if the subject has been on a stable dose for at least three
months. Subjects who have taken for more than a week non-steroidal anti inflammatory
drugs (NSAIDS) within two months or systemic steroids, anabolic steroids, growth
hormone or immunosuppressants within 12 months will be excluded. Subjects taking
low-dose (81 mg/day or less) aspirin will be allowed.

3. Patients with a history of clinically significant heart disease (New York Heart
Classification greater than grade II; more than non-specific ST-T wave changes on the
EKG), peripheral vascular disease (history of claudication), or pulmonary disease
(dyspnea on exertion of one flight or less; abnormal breath sounds on auscultation)
will not be studied.

4. Recent systemic or pulmonary embolus, impaired renal function, poorly controlled
blood pressure (systolic BP>170, diastolic BP>95), resting heart rate >100,
electrolyte abnormalities, neuromuscular or musculoskeletal disease.

5. Subjects who smoke.

6. Subjects who engage in a regular exercise program (zero or one exercise sessions per
week are allowed).

7. Any subject who has donated blood in the previous two months.

8. Any subject with a hematocrit of less than 35.

9. Subjects who are claustrophobic.

10. Women taking oral contraceptives.

11. alcohol consumption greater than 30 grams daily.

12. baseline plasma triglyceride levels over 200 mg/dl