Diabetes Mellitus, Endocrine System Diseases, Glucose Metabolism Disorders, Obesity, PreDiabetes
Conditions
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.
Interventions
DRUGGSK2256294
Drug will be taken daily by mouth for 7 days.
DRUGPlacebo oral capsule
Placebo will be taken daily by mouth for 7 days.
Sponsors
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Masking description
Arms 1/2 are placebo controlled and blinded to investigator and participant
Intervention model description
Arm 1 and 2 are crossover arms
Eligibility
Sex/Gender
ALL
Age
21 Years to 50 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Sensitivity | 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
| Measure | Time frame | Description |
|---|---|---|
| Forearm Blood Flow (FBF) | Day 7 | Insulin stimulated forearm blood flow determined by strain-gauge plethysmography |
| Insulin Signaling in Tissue | 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. |
| Blood Pressure | Day 7 | determined by non-invasive brachial blood pressure measurement (systolic blood pressure, SBP; diastolic blood pressure, DBP) |
| Renal Plasma Flow (RPF) | Day 7 | Renal plasma flow determined by PAH infusion, ml/min/per 1.73 m\^2 body surface area |
Other
| Measure | Time frame | Description |
|---|---|---|
| Soluble Epoxide Hydrolase Activity | Day 7 | soluble epoxide hydrolase (sEH) activity measured by 14,15-DHET conversion rate in plasma |
| Soluble Epoxide Hydrolase Activity in Tissue | Day 7 | soluble epoxide hydrolase (sEH) activity measured by 14,15-DHET conversion rate in adipose and muscle, per mg tissue |
| Plasma Total Epoxyeicosatrienoic Acids (EETs) | Day 7 | total Epoxyeicosatrienoic acids in plasma |
| Plasma IL-6 | Day 7 | Plasma cytokine interleukin-6 (IL-6) |
| Plasma VEGF | Day 7 | Plasma vascular endothelial growth factor (VEGF) |
| Adipose Tissue Total Epoxyeicosatrienoic Acids (EETs) | Day 7 | total Epoxyeicosatrienoic acids in adipose tissue (pmol per mg tissue) |
Countries
United States
Participant flow
Recruitment details
35 volunteers were screened for inclusion
Pre-assignment details
16 individuals were randomized. Of those not randomized, 19 did not meet inclusion criteria and were excluded. 1 participant was randomized but was excluded due to illness prior to receiving any study intervention.
Participants by arm
| Arm | Count |
|---|---|
| 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.
GSK2256294: Drug will be taken daily by mouth for 7 days.
Placebo oral capsule: Placebo will be taken daily by mouth for 7 days. | 8 |
| 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.
GSK2256294: Drug will be taken daily by mouth for 7 days.
Placebo oral capsule: Placebo will be taken daily by mouth for 7 days. | 8 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Intervention 1 | received oral steroids for sinus infection; randomized but did not receive intervention | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo Then GSK2256294 | GSK2256294 Then Placebo | Total |
|---|---|---|---|
| Age, Continuous | 45 years STANDARD_DEVIATION 8 | 48 years STANDARD_DEVIATION 10 | 47 years STANDARD_DEVIATION 9 |
| Body mass index | 39 kg/m^2 STANDARD_DEVIATION 7 | 43 kg/m^2 STANDARD_DEVIATION 9 | 41 kg/m^2 STANDARD_DEVIATION 8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 8 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Glucose | 97 mg/dl STANDARD_DEVIATION 8 | 96 mg/dl STANDARD_DEVIATION 8 | 97 mg/dl STANDARD_DEVIATION 8 |
| HDL Cholesterol | 50 mg/dl STANDARD_DEVIATION 11 | 47 mg/dl STANDARD_DEVIATION 7 | 48 mg/dl STANDARD_DEVIATION 9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 6 Participants | 11 Participants |
| Region of Enrollment United States | 8 participants | 8 participants | 16 participants |
| Sex: Female, Male Female | 8 Participants | 6 Participants | 14 Participants |
| Sex: Female, Male Male | 0 Participants | 2 Participants | 2 Participants |
| Triglycerides | 117 mg/dl STANDARD_DEVIATION 48 | 128 mg/dl STANDARD_DEVIATION 65 | 122 mg/dl STANDARD_DEVIATION 55 |
| Waist circumference | 112 cm STANDARD_DEVIATION 14 | 121 cm STANDARD_DEVIATION 24 | 116 cm STANDARD_DEVIATION 20 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 2 / 15 | 2 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 |
Outcome results
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
Time frame: Day 7
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Insulin Sensitivity | 12.0 mg/kg/FFM/min | Standard Deviation 4.3 |
| GSK2256294 | Insulin Sensitivity | 11.6 mg/kg/FFM/min | Standard Deviation 3.7 |
Comparison: A sample size of 16 per group was estimated to have 86% power to detect a within-subject difference of 3.76 (80% of the above difference) or larger (with an SD for the within-subject difference of 4.6) in insulin sensitivity.p-value: 0.71Wilcoxon (Mann-Whitney)
Secondary
Blood Pressure
determined by non-invasive brachial blood pressure measurement (systolic blood pressure, SBP; diastolic blood pressure, DBP)
Time frame: Day 7
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Blood Pressure | SBP | 122.9 mmHg | Standard Deviation 11 |
| Placebo | Blood Pressure | DBP | 77.4 mmHg | Standard Deviation 6.8 |
| GSK2256294 | Blood Pressure | SBP | 124.3 mmHg | Standard Deviation 9.6 |
| GSK2256294 | Blood Pressure | DBP | 78.9 mmHg | Standard Deviation 8.7 |
Secondary
Forearm Blood Flow (FBF)
Insulin stimulated forearm blood flow determined by strain-gauge plethysmography
Time frame: Day 7
Population: Unable to obtain FBF measurement during 2 Placebo study days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Forearm Blood Flow (FBF) | 3.5 ml/min/100ml | Standard Deviation 1.9 |
| GSK2256294 | Forearm Blood Flow (FBF) | 3.1 ml/min/100ml | Standard Deviation 1.2 |
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.
Time frame: Day 7
Population: Unable to obtain adipose sample for pAKT measurement during 2 Placebo study days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Insulin Signaling in Tissue | Adipose Tissue | 0.21 pAKT/pAKT ratio | Standard Deviation 0.14 |
| Placebo | Insulin Signaling in Tissue | Muscle Tissue | 0.74 pAKT/pAKT ratio | Standard Deviation 0.55 |
| GSK2256294 | Insulin Signaling in Tissue | Adipose Tissue | 0.19 pAKT/pAKT ratio | Standard Deviation 0.18 |
| GSK2256294 | Insulin Signaling in Tissue | Muscle Tissue | 0.73 pAKT/pAKT ratio | Standard Deviation 0.58 |
Secondary
Renal Plasma Flow (RPF)
Renal plasma flow determined by PAH infusion, ml/min/per 1.73 m\^2 body surface area
Time frame: Day 7
Population: Unable to obtain RBF measurement in 8 participants due to availability of PAH
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Renal Plasma Flow (RPF) | 648 ml/min/per 1.73 m^2 | Standard Deviation 138 |
| GSK2256294 | Renal Plasma Flow (RPF) | 614 ml/min/per 1.73 m^2 | Standard Deviation 103 |
Other Pre-specified
Adipose Tissue Total Epoxyeicosatrienoic Acids (EETs)
total Epoxyeicosatrienoic acids in adipose tissue (pmol per mg tissue)
Time frame: Day 7
Population: Adequate sample not available in 1 participant during GSK
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adipose Tissue Total Epoxyeicosatrienoic Acids (EETs) | 176 pmol/mg | Standard Deviation 291 |
| GSK2256294 | Adipose Tissue Total Epoxyeicosatrienoic Acids (EETs) | 66 pmol/mg | Standard Deviation 44 |
Other Pre-specified
Plasma IL-6
Plasma cytokine interleukin-6 (IL-6)
Time frame: Day 7
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Plasma IL-6 | 1.48 pmol/ml | Standard Deviation 0.61 |
| GSK2256294 | Plasma IL-6 | 1.48 pmol/ml | Standard Deviation 0.69 |
Other Pre-specified
Plasma Total Epoxyeicosatrienoic Acids (EETs)
total Epoxyeicosatrienoic acids in plasma
Time frame: Day 7
Population: Adequate sample not available in 1 participant during GSK
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Plasma Total Epoxyeicosatrienoic Acids (EETs) | 21.4 pmol/mL | Standard Deviation 8.4 |
| GSK2256294 | Plasma Total Epoxyeicosatrienoic Acids (EETs) | 22.4 pmol/mL | Standard Deviation 9.3 |
Other Pre-specified
Plasma VEGF
Plasma vascular endothelial growth factor (VEGF)
Time frame: Day 7
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Plasma VEGF | 31.9 pg/ml | Standard Deviation 18.6 |
| GSK2256294 | Plasma VEGF | 29.0 pg/ml | Standard Deviation 24.4 |
Other Pre-specified
Soluble Epoxide Hydrolase Activity
soluble epoxide hydrolase (sEH) activity measured by 14,15-DHET conversion rate in plasma
Time frame: Day 7
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Soluble Epoxide Hydrolase Activity | 4.1 pmol 14,15-DHET/ml/hr | Standard Deviation 4.5 |
| GSK2256294 | Soluble Epoxide Hydrolase Activity | 1.9 pmol 14,15-DHET/ml/hr | Standard Deviation 2.6 |
Other Pre-specified
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
Time frame: Day 7
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Soluble Epoxide Hydrolase Activity in Tissue | Adipose | 2176 pmol 14,15-DHET/mg tissue/hr | Standard Deviation 965 |
| Placebo | Soluble Epoxide Hydrolase Activity in Tissue | Muscle | 3.5 pmol 14,15-DHET/mg tissue/hr | Standard Deviation 1.6 |
| GSK2256294 | Soluble Epoxide Hydrolase Activity in Tissue | Adipose | 1280 pmol 14,15-DHET/mg tissue/hr | Standard Deviation 675 |
| GSK2256294 | Soluble Epoxide Hydrolase Activity in Tissue | Muscle | 1.9 pmol 14,15-DHET/mg tissue/hr | Standard Deviation 1.1 |