The Effect of TLR4 Inhibition in Obese and Type 2 Diabetic Subjects
Condition: Insulin Sensitivity
MeSH terms: Insulin Resistance; Hypersensitivity
Intervention: Eritoran; D5W
Intervention description: Pharmacologic inhibitor of TLR4 receptors.; 5% Dextrose Water = Vehicle
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Participant, Care Provider, Investigator, Outcomes Assessor
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Insulin signaling and glucose disposal in muscle; Hepatic insulin sensitivity; TLR4 signaling and inflammatory gene expression; Plasma cytokine concentration; Intramyocellular diacylglycerol and ceramide content

Summary:

      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.
    

Eligibility criteria:

        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.