The Effect of TLR4 Inhibition in Obese and Type 2 Diabetic Subjects

E5564 = Eritoran

Inclusion Criteria:

- Subjects capable of giving informed consent.

- lean (BMI <26 kg/m2) with normal glucose-tolerant subjects without a family history of
type 2 DM

- obese (BMI 30-37 kg/m2) with normal glucose-tolerant subjects

- Type 2 DM subjects base on ADA criteria, who have HbA1c <8.5% and control with diet or
sulfonylureas.

- 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:

- Current treatment with drugs known to affect glucose and lipid homeostasis. Subjects
on a stable dose of statin (>3 months) 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.