Soluble Epoxide Hydrolase Inhibition and Insulin Resistance

Obesity Clinical Trial

Official title:

Effect of Inhibition Soluble Epoxide Hydrolase on Insulin Sensitivity in Humans

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03486223
• Other study ID #: 170468
• Secondary ID: 5R01DK117875
• Status: Completed
• Phase: Phase 2
• Start date: May 17, 2018
• Est. completion date: November 18, 2021

Study information

• Verified date: March 2023
• Source: Vanderbilt University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 16
• Est. completion date: November 18, 2021
• Est. primary completion date: November 18, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 21 Years to 50 Years

Eligibility

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 ß-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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Endocrine System Diseases
• Glucose Metabolism Disorders
• Metabolic Diseases
• Obesity
• PreDiabetes

Intervention

Drug:
• GSK2256294
Drug will be taken daily by mouth for 7 days.
• Placebo oral capsule
Placebo will be taken daily by mouth for 7 days.

Locations

Country	Name	City	State
United States	Vanderbilt University Medical Center	Nashville	Tennessee

Sponsors (3)

Lead Sponsor	Collaborator
Vanderbilt University Medical Center	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

References & Publications (4)

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. — View Citation

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. — View Citation

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-Isoprostane — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Soluble Epoxide Hydrolase Activity	soluble epoxide hydrolase (sEH) activity measured by 14,15-DHET conversion rate in plasma	Day 7
Other	Plasma Total Epoxyeicosatrienoic Acids (EETs)	total Epoxyeicosatrienoic acids in plasma	Day 7
Other	Plasma IL-6	Plasma cytokine interleukin-6 (IL-6)	Day 7
Other	Plasma VEGF	Plasma vascular endothelial growth factor (VEGF)	Day 7
Other	Adipose Tissue Total Epoxyeicosatrienoic Acids (EETs)	total Epoxyeicosatrienoic acids in adipose tissue (pmol per mg tissue)	Day 7
Other	Soluble Epoxide Hydrolase Activity in Tissue	soluble epoxide hydrolase (sEH) activity measured by 14,15-DHET conversion rate in adipose and muscle, per mg tissue	Day 7
Primary	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	Forearm Blood Flow (FBF)	Insulin stimulated forearm blood flow determined by strain-gauge plethysmography	Day 7
Secondary	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
Secondary	Blood Pressure	determined by non-invasive brachial blood pressure measurement (systolic blood pressure, SBP; diastolic blood pressure, DBP)	Day 7
Secondary	Renal Plasma Flow (RPF)	Renal plasma flow determined by PAH infusion, ml/min/per 1.73 m^2 body surface area	Day 7