Insulin Resistance, Diabetes, Obesity
Conditions
Keywords
obesity, insulin resistance, type II diabetes
Brief summary
Normally, the hormone insulin works to help keep blood sugar normal. However, as a person gains weight, insulin does not work as well and blood sugar tends to be a little higher than normal. This is called insulin resistance. Two investigational drugs (not approved by the Food and Drug Administration) for the treatment of high lipid levels or insulin resistance are being examined in this study: one drug is called tauroursodeoxycholic acid (TUDCA), the other is called sodium phenylbutyrate (PBA). This study is designed to test if TUDCA and/or PBA is effective in people who are obese with insulin resistance and high lipids. We hypothesize that pharmacologically-induced decreases in ER stress will improve insulin action and hepatic lipid metabolism in obese subjects.
Detailed description
A 4-week randomized, controlled trial will be conducted to evaluate the following specific aims in obese subjects: Determine the effect of treatment with TUDCA or PBA on: 1. Body fat distribution: a) intrahepatic triglyceride (IHTG) content, b) intramyocellular triglyceride (IMTG) content, and c) intra-abdominal fat content, assessed by using magnetic resonance spectroscopy and magnetic resonance imaging. 2. In vivo insulin sensitivity in adipose tissue (suppression of lipolysis), liver (suppression of glucose production), and skeletal muscle (stimulation of glucose uptake), assessed by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotope tracer infusion. 3. VLDL-triglyceride (TG) and VLDL-apolipoprotein-B100 (apoB-100) secretion rates, assessed by stable isotopically labeled tracer infusion methods. 4. Skeletal muscle intracellular insulin signaling, fatty acid oxidation, and markers of inflammation, assessed by evaluating skeletal muscle biopsies ex vivo. 5. Adipose tissue insulin signaling, ER stress, and inflammation, assessed by evaluating adipose tissue biopsies ex vivo.
Interventions
1750 mg/day for four weeks. Seven pills daily, 2 with breakfast, 2 with lunch, and 3 with dinner.
OTHERplacebo
7 pills daily for 4 weeks
DRUGsodium phenylbutyrate
20g/day for four weeks.
Sponsors
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* BMI range 30 to 45 * sedentary (defined as regular exercise \< 1 h per week or \< 2 x/week for the last 6 months)
Exclusion criteria
* active or previous infection with hepatitis B or C * liver diseases * history of alcohol abuse * current alcohol consumption \> 20 g/day * severe hypertriglyceridemia ( \> 400 mg/dL) * active peptic ulcer disease * taking cholestyramine or oral contraceptives * women who are pregnant or lactating
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Body Composition | Baseline and four weeks | Fat mass (%) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Sensitivity in the Liver | Baseline and four weeks | HISI (hepatic insulin sensitivity index). HISI is the inverse of the product of endogenous glucose production and plasma insulin concentration and provides an index of how well circulating insulin controls the amount of glucose supplied by the liver. A higher number is indicative of greater insulin sensitivity. |
| VLDL-triglyceride (TG) Concentration | Baseline and four weeks | — |
Countries
United States
Participant flow
Recruitment details
Participants will be recruited by reviewing the VFH database pf research subjects and by local postings. Potential subjects will be contacted by telephone for an initial pre-screen, at which time the study is discussed and a brief medical history and concomitant medication list is obtained. ICF will be sent to interested subjects.
Pre-assignment details
Screening tests to determine eligibility included: medical hx & PE, blood tests, resting ECG, OGTT, MRI/MRS/MRE of abdomen/liver, and DEXA scan. Two baseline metabolism studies prior to study drug intervention. There were 67 screen fails, 4 subjects withdrew consent before beginning study intervention.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Subjects will be given a placebo rather than tauroursodeoxycholic acid.
placebo: 7 pills daily for 4 weeks | 10 |
| Tauroursodeoxycholic Acid Subjects will receive tauroursodeoxycholic acid for four weeks.
tauroursodeoxycholic acid: 1750 mg/day for four weeks. Seven pills daily, 2 with breakfast, 2 with lunch, and 3 with dinner. | 10 |
| Sodium Phenylbutyrate Subjects will receive sodium phenylbutyrate for four weeks.
sodium phenylbutyrate: 20g/day for four weeks. | 6 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Dissat w/# of study medication (40/day) | 0 | 0 | 4 |
Baseline characteristics
| Characteristic | Tauroursodeoxycholic Acid | Sodium Phenylbutyrate | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 6 Participants | 10 Participants | 26 Participants |
| Age, Continuous | 47 years STANDARD_DEVIATION 9 | 49 years STANDARD_DEVIATION 8 | 49 years STANDARD_DEVIATION 14 | 47 years STANDARD_DEVIATION 10.6 |
| Region of Enrollment United States | 10 participants | 6 participants | 10 participants | 26 participants |
| Sex: Female, Male Female | 6 Participants | 2 Participants | 6 Participants | 14 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 4 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 6 |
| other Total, other adverse events | 0 / 10 | 0 / 10 | 0 / 6 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 6 |
Outcome results
Primary
Body Composition
Fat mass (%)
Time frame: Baseline and four weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Body Composition | Before Intervention | 39 percentage | Standard Deviation 7 |
| Placebo | Body Composition | After Intervention | 39 percentage | Standard Deviation 7 |
| Tauroursodeoxycholic Acid | Body Composition | After Intervention | 39 percentage | Standard Deviation 8 |
| Tauroursodeoxycholic Acid | Body Composition | Before Intervention | 39 percentage | Standard Deviation 8 |
| Sodium Phenylbutyrate | Body Composition | Before Intervention | 37 percentage | Standard Deviation 6 |
| Sodium Phenylbutyrate | Body Composition | After Intervention | 39 percentage | Standard Deviation 7 |
Secondary
Insulin Sensitivity in the Liver
HISI (hepatic insulin sensitivity index). HISI is the inverse of the product of endogenous glucose production and plasma insulin concentration and provides an index of how well circulating insulin controls the amount of glucose supplied by the liver. A higher number is indicative of greater insulin sensitivity.
Time frame: Baseline and four weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Insulin Sensitivity in the Liver | Before Intervention | 0.010 100/ (µmol/min * uIU/mL) | Standard Deviation 0.007 |
| Placebo | Insulin Sensitivity in the Liver | After Intervention | 0.008 100/ (µmol/min * uIU/mL) | Standard Deviation 0.004 |
| Tauroursodeoxycholic Acid | Insulin Sensitivity in the Liver | After Intervention | 0.012 100/ (µmol/min * uIU/mL) | Standard Deviation 0.006 |
| Tauroursodeoxycholic Acid | Insulin Sensitivity in the Liver | Before Intervention | 0.009 100/ (µmol/min * uIU/mL) | Standard Deviation 0.004 |
| Sodium Phenylbutyrate | Insulin Sensitivity in the Liver | After Intervention | 0.009 100/ (µmol/min * uIU/mL) | Standard Deviation 0.003 |
| Sodium Phenylbutyrate | Insulin Sensitivity in the Liver | Before Intervention | 0.008 100/ (µmol/min * uIU/mL) | Standard Deviation 0.003 |
Secondary
VLDL-triglyceride (TG) Concentration
Time frame: Baseline and four weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | VLDL-triglyceride (TG) Concentration | Before Intervention | 0.57 mmol/l | Standard Deviation 0.33 |
| Placebo | VLDL-triglyceride (TG) Concentration | After Intervention | 0.58 mmol/l | Standard Deviation 0.33 |
| Tauroursodeoxycholic Acid | VLDL-triglyceride (TG) Concentration | Before Intervention | 0.74 mmol/l | Standard Deviation 0.5 |
| Tauroursodeoxycholic Acid | VLDL-triglyceride (TG) Concentration | After Intervention | 0.75 mmol/l | Standard Deviation 0.56 |
| Sodium Phenylbutyrate | VLDL-triglyceride (TG) Concentration | Before Intervention | 0.89 mmol/l | Standard Deviation 0.25 |
| Sodium Phenylbutyrate | VLDL-triglyceride (TG) Concentration | After Intervention | 0.97 mmol/l | Standard Deviation 0.18 |