Soluble Epoxide Hydrolase Inhibition and Insulin Resistance

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) 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