The Role of TLR4 on Lipid-induced Insulin Resistance

Study Overview
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Brief Summary
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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.

Detailed Description
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E5564 = Eritoran

Official Title
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The Role of TLR4 on Lipid-Induced Insulin Resistance

Conditions
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Insulin Sensitivity

Intervention / Treatment
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* Drug: Eritoran
* Drug: D5W (5% Dextrose in water)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: D5W (5% Dextrose in water) + Saline<br>IV administration of 5% Dextrose in water/D5W (vehicle) 12 mg every 12 hours plus Saline infusion at a rate of 30 mL/hour | Drug: D5W (5% Dextrose in water)<br>* D5W = 5% Dextrose Water Vehicle<br>* Other names: Vehicle;|
| Active Comparator: D5W (5% Dextrose in water) + Intralipid<br>IV Administration of 5% Dextrose in water /D5W (vehicle) 12 mg plus Intralipid infusion at a rate of 30 ml/hour | Drug: D5W (5% Dextrose in water)<br>* D5W = 5% Dextrose Water Vehicle<br>* Other names: Vehicle;|
| Active Comparator: Eritoran + Intralipid<br>IV administration of Eritoran 12 mg every 12 hours plus Intralipid infusion at a rate of 30 ml/hour | Drug: Eritoran<br>* Eritoran = E5564 Eritoran is a pharmacologic inhibitor of TLR4.<br>* Other names: E5564;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of Eritoran on Muscle Insulin Sensitivity | 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. | 72 hours | 
| Effect of Eritoran on Hepatic Insulin Sensitivity | 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. | 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of Eritoran on TLR4 Expression on Peripheral Blood Monocytes | 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. | 72 hours | 
| Effect of Eritoran on Plasma Cytokine Concentration | TNF-alpha levels (tumor necrosis factor-alpha) are determined by ELISA. Higher level indicates higher inflammatory response. There is no established reference range. | 72 hours | 
| Effect of Eritoran on Intramyocellular Diacylglycerol and Ceramide Content | Intramyocellular diacylglycerol and ceramide content are determined by mass spectrometry. Higher levels have been associated with diabetes. | 72 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Insulin signaling and glucose disposal in muscle, Hepatic insulin sensitivity, TLR4 signaling and inflammatory gene expression, Plasma cytokine concentration, Intramyocellular diacylglycerol and ceramide content