The Role of TLR4 on Lipid-induced Insulin Resistance

Inclusion Criteria: * Subjects capable of giving informed consent. * lean (BMI \<26 kg/m2) * normal glucose-tolerant subjects (completers) without a family history of Type 2 diabetes mellitus (DM) * Both genders. (50% males) * Age = 18-65 years. Older subjects are excluded because aging is a pro-inflammatory state. * All ethnic groups * Premenopausal women in the follicular phase, non-lactating, and with a negative pregnancy test. Postmenopausal women on stable dose of or not exposed to hormone replacement for \>=6 months. * Lab: Hematocrit \>=34%, serum creatinine \<=1.4 mg/dL, normal electrolytes, urinalysis, and coagulation tests. Liver function tests up to 2x normal range. * Stable body weight (+/-1%) for \>=3 months. * One or less sessions of strenuous exercise/wk for last 6 months. Exclusion Criteria: * Presence of diabetes or impaired glucose tolerance based on ADA criteria; * Current treatment with drugs known to affect glucose and lipid homeostasis. Subjects on a stable dose of statin (\>3months) are eligible. * Non-steroidal anti-inflammatory drugs or systemic steroid use for more than 1 week within 3 months. * Current treatment with anticoagulants (warfarin). Aspirin (up to 325 mg) and clopidogrel will be permitted if these can be held for seven days prior to the biopsies. * History of heart disease (New York Heart Classification greater than class II; more than non-specific ST-T wave changes on the ECG), peripheral vascular disease, pulmonary disease, smokers. * Poorly controlled blood pressure (systolic BP\>160, diastolic BP\>90 mmHg). * Active inflammatory, autoimmune, infectious, hepatic, gastrointestinal, malignant, and psychiatric disease.