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

Phase 2 Study of The Role of Pharmacologic Inhibition of TLR4 With E5564 on Glucose Metabolism in Insulin Resistant Subjects.

To determine whether pharmacologic inhibition of Toll-like receptor 4 (TLR4) with eritoran for injection (E5564) will reduce inflammation and improve glucose metabolism in insulin resistant (obese and T2DM) 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.