Clinical trial NCT03486223: Soluble Epoxide Hydrolase Inhibition and Insulin Resistance
Official title: Effect of Inhibition Soluble Epoxide Hydrolase on Insulin Sensitivity in Humans
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes Mellitus
Endocrine System Diseases
Glucose Metabolism Disorders
PreDiabetes
Obesity
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2018-04-03
Enrollment: 16
Sex: ALL
Minimum age (years): 21
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Arm 1 and 2 are crossover arms
Primary purpose: PREVENTION

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.

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.

Eligibility 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

Primary outcomes:
measure: Insulin Sensitivity
timeFrame: Day 7
Secondary outcomes:
measure: Forearm Blood Flow (FBF)
timeFrame: Day 7
measure: Insulin Signaling in Tissue
timeFrame: Day 7
measure: Blood Pressure
timeFrame: Day 7
measure: Renal Plasma Flow (RPF)
timeFrame: Day 7
Other outcomes:
measure: Soluble Epoxide Hydrolase Activity
timeFrame: Day 7
measure: Plasma Total Epoxyeicosatrienoic Acids (EETs)
timeFrame: Day 7
measure: Plasma IL-6
timeFrame: Day 7
measure: Plasma VEGF
timeFrame: Day 7
measure: Adipose Tissue Total Epoxyeicosatrienoic Acids (EETs)
timeFrame: Day 7
measure: Soluble Epoxide Hydrolase Activity in Tissue
timeFrame: Day 7
Locations:
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Vanderbilt University Medical Center
name: James M Luther, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Vanderbilt University Medical Center
name: Nancy J Brown, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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.
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.
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-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.