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

Phase 2

Terminated

Brief 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.

Recruitment & Eligibility

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.

Arm && Interventions

Group	Intervention	Description
Diabetes (T2DM) Group - D5W	D5W	T2DM subjects receive IV administration of 5% Dextrose in water/D5W (vehicle) 12 mg every 12 hours
Obese Group-D5W	D5W	Obese subjects receive IV administration of 5% Dextrose in water/D5W (vehicle) 12 mg every 12 hours
Diabetes (T2DM) Group - Eritoran	Eritoran	T2DM subjects receive IV administration of Eritoran 12 mg every 12 hours
Obese Group - Eritoran	Eritoran	Obese subjects receive IV administration of Eritoran 12 mg every 12 hours

Primary Outcome Measures

Name	Time	Method
Effect of Eritoran on Hepatic Insulin Sensitivity	72 hours	Hepatic insulin sensitivity = is determined by euglycemic hyperinsulinemic clamp procedure. Endogenous glucose production or EGP (mg/kg/min) calculated from the clamp is measured. Lower EGP indicates better hepatic insulin sensitivity. There is no established reference range.
Effect of Eritoran on Muscle Insulin Sensitivity	72 hours	Muscle insulin sensitivity = muscle insulin sensitivity is determined by euglycemic hyperinsulinemic clamp procedure. M value (mg glucose / kg of body weight / minute) calculated from the clamp is measured. Higher M value indicates better insulin sensitivity. There is no established reference range.

Secondary Outcome Measures

Name	Time	Method
Effect of Eritoran on TLR4 Expression in Muscle Tissue	72 hours	TLR4 expression in muscle tissue is determined by RNAseq using arbitrary units. Higher TLR4 expression indicates higher inflammatory response. There is no reference range.
Effect of Eritoran on TLR4 Expresison in Adipose Tissue	72 hours	TLR4 expression in the adipose tissue is determined by RNAseq using arbitrary units. Higher TLR4 expression indicates higher inflammatory response. There is no reference range.
Effect of Eritoran on TLR4 Expression in Peripheral Blood Monocytes	72 hours	TLR4 expression in the peripheral blood monocytes is determined by flow cytometry using arbitrary units. Higher TLR4 expression indicates higher inflammatory response. There is no reference range.
Effect of Eritoran on Plasma TNF-alpha (Tumor Necrosis Factor-alpha) Concentration	72 hours	TNF-alpha levels are determined by ELISA. Higher level indicates higher inflammatory response. There is no established reference range.
Effect of Eritoran on Intramyocellular Diacylglycerol and Ceramide Content	72 hours	Intramyocellular diacylglycerol and ceramide content are determined by mass spectrometry. Higher levels have been associated with diabetes.