Soluble Epoxide Hydrolase Inhibition and Insulin Resistance

Study Overview
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Brief Summary
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The purpose of this study is to test how soluble epoxide hydrolase (sEH) inhibition with GSK2256294 affects tissue sEH activity and insulin sensitivity.

Detailed Description
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We will test the hypothesis that soluble epoxide hydrolase (sEH) inhibition with GSK2256294 improves insulin sensitivity using the gold-standard, hyperinsulinemic-euglycemic clamps, with stable isotope dilution to assess hepatic gluconeogenesis. We will assess insulin-stimulated vasodilation in the forearm using plethysmography and in the renal vasculature using para-aminohippurate (PAH, IND#133828) clearance. We will obtain adipose and muscle tissue before and after clamp to assess insulin signaling in these tissues. Subjects are randomized to treatment with the sEH inhibitor GSK2256294 (10mg/day) or matching placebo for one week. On the seventh day of drug treatment, subjects will report to the CRC in the morning after an overnight fast to undergo a hyperinsulinemic-euglycemic clamp with adipose tissue biopsies. During the Hyperinsulinemic-euglycemic clamp, insulin will be infused for 2 hours at low dose (20 mU/m2/min) and 2 hours at high dose (80 mU/m2/min) to assess insulin sensitivity. The Glucose Infusion Rate (GIR) will be adjusted to maintain glucose near 95 mg/dL. The average GIR during the final 30 minutes of the high dose period will be used as the measure of insulin sensitivity. After completion of the study day, subjects will undergo a seven-week washout from study drug and then receive the opposite drug for one week. On the seventh day of treatment they will report to the CRC after an overnight fast and repeat the study day protocol.

Official Title
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Effect of Inhibition Soluble Epoxide Hydrolase on Insulin Sensitivity in Humans

Conditions
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Diabetes Mellitus, Endocrine System Diseases, Glucose Metabolism Disorders, PreDiabetes, Obesity

Intervention / Treatment
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* Drug: GSK2256294
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women, Age 21 to 50 years, and Pre-diabetes as defined by Fasting plasma glucose 100-125 mg/dL, or Two-hour plasma glucose 140-199 mg/dL, or HbA1c 5.7-6.4% BMI ≥ 30 kg/m2, inclusive For female subjects, the following conditions must be met: Postmenopausal status for at least one year, or Status-post surgical sterilization, or If of childbearing potential, utilization of adequate birth control and willingness to undergo serum β-hcg testing prior to drug treatment and on every study day. Exclusion Criteria: Diabetes type 1 or type 2, as defined by a fasting plasma glucose of 126 mg/dL or greater, a two-hour plasma glucose of 200 mg/dL or greater, a HbA1c >6.4%, or the use of anti-diabetic medication Subjects who have participated in a weight-reduction program during the last six month or whose weight has increased or decreased more than two kg over the preceding six months Resistant hypertension, defined as hypertension requiring the administration of more than three anti-hypertensive agents including a diuretic to achieve control Use of spironolactone Pregnancy or breast-feeding Any history of smoking Any history of cancer including skin cancer, any history of a precancerous lesion, abnormal PSA, or lack of screening adherent to American Cancer Society Guidelines for the Early Detection of Cancer Cardiovascular disease such as myocardial infarction within six months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (left ventricular hypertrophy acceptable), deep-vein thrombosis, pulmonary embolism, second- or third-degree heart block, mitral valve stenosis, aortic stenosis, or hypertrophic cardiomyopathy Abnormal corrected QT interval on screening ECG (QTc). Treatment with anticoagulants History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack History or presence of immunological or hematological disorders Diagnosis of asthma requiring regular inhaler use Clinically significant gastrointestinal impairment that could interfere with drug absorption Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino transaminase [ALT] >3.0 x upper limit of normal range) History of gastrointestinal bleed Estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m2 or with an albumin-to-creatinine ratio (UACR) >300µg/mg, where eGFR is determined by the four-variable Modification of Diet in Renal Disease (MDRD) equation, where serum creatinine is expressed in mg/dL and age in years: eGFR (mL/min/1.73m2)=186 • Scr-1.154 • age-0.203 • (1.212 if black) • (0.742 if female) Hematocrit <35% Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult Treatment with chronic systemic glucocorticoid therapy Treatment with lithium salts History of alcohol or drug abuse Treatment with any investigational drug in the month preceding the study Mental conditions rendering a subject unable to understand the nature, scope, and possible consequences of the study Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 50 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: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Arm 1 and 2 are crossover arms
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo then GSK2256294<br>Subjects will receive placebo oral capsule daily by mouth for 7 days, then seven week washout and then GSK2256294 daily by mouth for 7 days. | Drug: GSK2256294<br>* Drug will be taken daily by mouth for 7 days.<br>* Other names: GSK2256294 10mg oral capsule;Drug: Placebo oral capsule<br>* Placebo will be taken daily by mouth for 7 days.<br>* Other names: Placebo;|
| Experimental: GSK2256294 then Placebo<br>Subjects will receive GSK2256294 daily by mouth for 7 days, then seven week washout and then placebo oral capsule daily by mouth for 7 days. | Drug: GSK2256294<br>* Drug will be taken daily by mouth for 7 days.<br>* Other names: GSK2256294 10mg oral capsule;Drug: Placebo oral capsule<br>* Placebo will be taken daily by mouth for 7 days.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin Sensitivity | Insulin sensitivity determined by Hyperinsulinemic-Euglycemic Clamp as the glucose infusion rate (GIR) per fat-free-mass (FFM) during high dose insulin infusion | Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forearm Blood Flow (FBF) | Insulin stimulated forearm blood flow determined by strain-gauge plethysmography | Day 7 | 
| Insulin Signaling in Tissue | Insulin stimulated phosphorylated AKT to total AKT ratio (pAKT/AKT) in adipose and muscle tissue sample. AKT is an insulin sensitive serine/threonine kinase also known as protein kinase B. | Day 7 | 
| Blood Pressure | determined by non-invasive brachial blood pressure measurement (systolic blood pressure, SBP; diastolic blood pressure, DBP) | Day 7 | 
| Renal Plasma Flow (RPF) | Renal plasma flow determined by PAH infusion, ml/min/per 1.73 m^2 body surface area | Day 7 |