Soluble Epoxide Hydrolase Inhibition and Insulin Resistance

• ClinicalTrials.gov Identifier: NCT03486223
• Recruitment Status: Completed
• First Posted: April 3, 2018
• Results First Posted: March 23, 2023
• Last Update Posted: March 23, 2023
• Sponsor: Vanderbilt University Medical Center
• Collaborators: National Institutes of Health (NIH); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Information provided by (Responsible Party): James Matt Luther, Vanderbilt University Medical Center

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus; Endocrine System Diseases; Glucose Metabolism Disorders; PreDiabetes; Obesity	Drug: GSK2256294; Drug: Placebo oral capsule	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 16 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Arm 1 and 2 are crossover arms
• Masking: Double (Participant, Investigator)
• Masking Description: Arms 1/2 are placebo controlled and blinded to investigator and participant
• Primary Purpose: Prevention
• Official Title: Effect of Inhibition Soluble Epoxide Hydrolase on Insulin Sensitivity in Humans
• Actual Study Start Date: May 17, 2018
• Actual Primary Completion Date: November 18, 2021
• Actual Study Completion Date: November 18, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Placebo then GSK2256294; 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; Drug will be taken daily by mouth for 7 days.; Other Name: GSK2256294 10mg oral capsule; Drug: Placebo oral capsule; Placebo will be taken daily by mouth for 7 days.; Other Name: Placebo
Experimental: GSK2256294 then Placebo; 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; Drug will be taken daily by mouth for 7 days.; Other Name: GSK2256294 10mg oral capsule; Drug: Placebo oral capsule; Placebo will be taken daily by mouth for 7 days.; Other Name: Placebo

Outcome Measures

Primary Outcome Measures :

1. Insulin Sensitivity [ Time Frame: Day 7 ]
   Insulin sensitivity determined by Hyperinsulinemic-Euglycemic Clamp as the glucose infusion rate (GIR) per fat-free-mass (FFM) during high dose insulin infusion

Secondary Outcome Measures :

1. Forearm Blood Flow (FBF) [ Time Frame: Day 7 ]
   Insulin stimulated forearm blood flow determined by strain-gauge plethysmography
2. Insulin Signaling in Tissue [ Time Frame: Day 7 ]
   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.
3. Blood Pressure [ Time Frame: Day 7 ]
   determined by non-invasive brachial blood pressure measurement (systolic blood pressure, SBP; diastolic blood pressure, DBP)
4. Renal Plasma Flow (RPF) [ Time Frame: Day 7 ]
   Renal plasma flow determined by PAH infusion, ml/min/per 1.73 m^2 body surface area

Other Outcome Measures:

1. Soluble Epoxide Hydrolase Activity [ Time Frame: Day 7 ]
   soluble epoxide hydrolase (sEH) activity measured by 14,15-DHET conversion rate in plasma
2. Plasma Total Epoxyeicosatrienoic Acids (EETs) [ Time Frame: Day 7 ]
   total Epoxyeicosatrienoic acids in plasma
3. Plasma IL-6 [ Time Frame: Day 7 ]
   Plasma cytokine interleukin-6 (IL-6)
4. Plasma VEGF [ Time Frame: Day 7 ]
   Plasma vascular endothelial growth factor (VEGF)
5. Adipose Tissue Total Epoxyeicosatrienoic Acids (EETs) [ Time Frame: Day 7 ]
   total Epoxyeicosatrienoic acids in adipose tissue (pmol per mg tissue)
6. Soluble Epoxide Hydrolase Activity in Tissue [ Time Frame: Day 7 ]
   soluble epoxide hydrolase (sEH) activity measured by 14,15-DHET conversion rate in adipose and muscle, per mg tissue

Eligibility Criteria

• Ages Eligible for Study: 21 Years to 50 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

1. Men and women,
2. Age 21 to 50 years, and

3. Pre-diabetes as defined by

   1. Fasting plasma glucose 100-125 mg/dL, or
   2. Two-hour plasma glucose 140-199 mg/dL, or
   3. HbA1c 5.7-6.4%
4. BMI ≥ 30 kg/m2, inclusive

5. For female subjects, the following conditions must be met:

   1. Postmenopausal status for at least one year, or
   2. Status-post surgical sterilization, or
   3. 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:

1. 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
2. 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
3. Resistant hypertension, defined as hypertension requiring the administration of more than three anti-hypertensive agents including a diuretic to achieve control
4. Use of spironolactone
5. Pregnancy or breast-feeding
6. Any history of smoking
7. 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
8. 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
9. Abnormal corrected QT interval on screening ECG (QTc).
10. Treatment with anticoagulants
11. History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack
12. History or presence of immunological or hematological disorders
13. Diagnosis of asthma requiring regular inhaler use
14. Clinically significant gastrointestinal impairment that could interfere with drug absorption
15. Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino transaminase [ALT] >3.0 x upper limit of normal range)
16. History of gastrointestinal bleed
17. 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)
18. Hematocrit <35%
19. 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
20. Treatment with chronic systemic glucocorticoid therapy
21. Treatment with lithium salts
22. History of alcohol or drug abuse
23. Treatment with any investigational drug in the month preceding the study
24. Mental conditions rendering a subject unable to understand the nature, scope, and possible consequences of the study
25. Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study

Contacts and Locations

Locations

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232

Sponsors and Collaborators

Vanderbilt University Medical Center

National Institutes of Health (NIH)

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: James M Luther, MD; Vanderbilt University Medical Center
• Principal Investigator: Nancy J Brown, MD; Vanderbilt University Medical Center

  Study Documents (Full-Text)

Documents provided by James Matt Luther, Vanderbilt University Medical Center:

Study Protocol  [PDF] August 11, 2021

Statistical Analysis Plan  [PDF] August 11, 2021

Informed Consent Form  [PDF] August 11, 2021

More Information

Publications of Results:

Luther JM, Ray J, Wei D, Koethe JR, Hannah L, DeMatteo A, Manning R, Terker AS, Peng D, Nian H, Yu C, Mashayekhi M, Gamboa J, Brown NJ. GSK2256294 Decreases sEH (Soluble Epoxide Hydrolase) Activity in Plasma, Muscle, and Adipose and Reduces F2-Isoprostanes but Does Not Alter Insulin Sensitivity in Humans. Hypertension. 2021 Sep;78(4):1092-1102. doi: 10.1161/HYPERTENSIONAHA.121.17659. Epub 2021 Aug 30.

Other Publications:

Luther JM, Brown NJ. Epoxyeicosatrienoic acids and glucose homeostasis in mice and men. Prostaglandins Other Lipid Mediat. 2016 Sep;125:2-7. doi: 10.1016/j.prostaglandins.2016.07.010. Epub 2016 Jul 19.

Gangadhariah MH, Dieckmann BW, Lantier L, Kang L, Wasserman DH, Chiusa M, Caskey CF, Dickerson J, Luo P, Gamboa JL, Capdevila JH, Imig JD, Yu C, Pozzi A, Luther JM. Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to insulin sensitivity in mice and in humans. Diabetologia. 2017 Jun;60(6):1066-1075. doi: 10.1007/s00125-017-4260-0. Epub 2017 Mar 28.

Ramirez CE, Shuey MM, Milne GL, Gilbert K, Hui N, Yu C, Luther JM, Brown NJ. Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans. Prostaglandins Other Lipid Mediat. 2014 Oct;113-115:38-44. doi: 10.1016/j.prostaglandins.2014.08.001. Epub 2014 Aug 28.

• Responsible Party: James Matt Luther, Associate Professor of Medicine, Vanderbilt University Medical Center
• ClinicalTrials.gov Identifier: NCT03486223
• Other Study ID Numbers: 170468; 5R01DK117875 ( U.S. NIH Grant/Contract )
• First Posted: April 3, 2018
• Results First Posted: March 23, 2023
• Last Update Posted: March 23, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Available upon request.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Metabolic Diseases; Glucose Metabolism Disorders; Endocrine System Diseases