The Role of TLR4 on Lipid-induced Insulin Resistance

Phase 2

Completed

Brief Summary: The purpose of this study is to determine whether pharmacologic inhibition of Toll-like receptor 4 (TLR4) with eritoran for injection (E5564) prevents lipid-induced insulin resistance in lean, normal glucose tolerant (NGT) subjects.

Recruitment & Eligibility

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.

Arm && Interventions

Group	Intervention	Description
D5W (5% Dextrose in water) + Intralipid	D5W (5% Dextrose in water)	IV Administration of 5% Dextrose in water /D5W (vehicle) 12 mg plus Intralipid infusion at a rate of 30 ml/hour
D5W (5% Dextrose in water) + Saline	D5W (5% Dextrose in water)	IV administration of 5% Dextrose in water/D5W (vehicle) 12 mg every 12 hours plus Saline infusion at a rate of 30 mL/hour
Eritoran + Intralipid	Eritoran	IV administration of Eritoran 12 mg every 12 hours plus Intralipid infusion at a rate of 30 ml/hour

Primary Outcome Measures

Name	Time	Method
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.
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.

Secondary Outcome Measures

Name	Time	Method
Effect of Eritoran on TLR4 Expression on Peripheral Blood Monocytes	72 hours	TLR4 expression on 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 Cytokine Concentration	72 hours	TNF-alpha levels (tumor necrosis factor-alpha) 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.