HIV Related Insulin Resistance, Protease Inhibitor Related Insulin Resistance, Endoplasmic Reticulum Stress
Conditions
Keywords
HIV, Protease inhibitor, insulin resistance, Tauroursodeoxycholic acid
Brief summary
Rates of cardiovascular disease and diabetes are more than 2-fold greater in HIV infected people than the general population. Protease inhibitor booster antiretroviral therapy (PI-ART) which is used by \ 50% of HIV infected people in the USA is an established risk factor for diabetes. Tauroursodeoxycholic acid (TUDCA), a naturally occurring bile salt, improves insulin sensitivity in HIV uninfected subjects, although the mechanisms for these benefits are unclear. This study will explore the hypothesis that TUDCA will improve insulin action in people with HIV who are receiving PI-ART. Further, this project will clarify the molecular mechanisms responsible for these improvements potentially benefiting society, irrespective of HIV status.
Detailed description
The purpose of this study is to determine if, and through which mechanisms, tauroursodeoxycholic acid improves insulin sensitivity in subjects with protease-inhibitor associated insulin resistance. The investigators will perform body composition analysis by using a DEXA machine, liver fat measurement by using an MRI, and hyperinsulinemic euglycemic clamp procedures in 48 HIV infected, insulin-resistant/prediabetic subjects before and after 30 days of treatment with tauroursodeoxycholic acid or matching placebo. Biopsies of adipose tissue and skeletal muscle will be taken during fasting conditions and during insulin infusion, before and after treatment to measure markers of endoplasmic reticulum stress and thyroid hormone deiodinase. Outcome measures: The primary outcome measures will be change in glucose clearance during insulin infusion, change in markers of endoplasmic reticulum stress and change in content of D2 in muscle.
Interventions
The intervention group will receive 1.75 grams of tauroursodeoxycholic acid daily for 30 days.
OTHERPlacebo tablet
The placebo group will receive a placebo tablet that is identical to the treatment group except that it does not contain tauroursodeoxycholic acid. The pills will be taken once daily for 30 days.
Sponsors
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* HIV+ * receiving protease inhibitor containing antiretroviral therapy for \>6 months * Undetectable viral load * insulin resistant 1. impaired fasting glucose (fasting blood glucose\>100mg/dl) 2. impaired glucose tolerance (blood glucose \>140mg/dl at 2 hours during oral glucose tolerance testing). * abstained from medications that affect glucose (e.g. prednisone, growth hormone) * stable medications for \>3 months
Exclusion criteria
* weight loss of \>5% of body weight in prior 6 months * active gastrointestinal disease (gallstones, pancreatitis, hepatitis, diarrhea) * use of anti-diabetic medications * cardiovascular disease (uncontrolled hypertension, heart attack, heart failure, prior endocarditis) * history of or active substance abuse * blood clotting disorder or taking medications that affect blood clotting (e.g. coumadin, warfarin) * pregnant, planning to become pregnant or lactating * unable to give informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Glucose Uptake | Glucose uptake is measured at baseline and 30 days after study intervention | We will examine the ability of insulin to cause muscle to take up insulin. Each subject will receive intravenous insulin for 6 hours to see how much sugar needs to be given intravenously to keep the blood sugar normal, a measure called glucose uptake. We will compare glucose uptake measured as the amount of 20% dextrose that is needed to keep the blood sugar at \ 100mg/dl during insulin infusion before and after 30 days of treatment with drug or placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Body Composition | Pre-Treatment and Post 30 day-Treatment | We will measure how much fat is present in each subject before and after treatment with TUDCA or placebo. |
| Liver Fat | Pre-Treatment and Post 30 day-Treatment | We will use MRI to measure the relative (%) amount of fat in each subject's liver before and after 30 days of treatment. This will allow us to determine if the drug reduces liver fat. This is calculated by subtracting the amount of fat in the liver at the beginning of the study from the amount of fat in the liver after 30 days of treatment. Subjects who have claustrophobia or are unable to undergo MRI will not have this measure performed. Due to these reasons liver MRS was only performed in 10 patients in the tauroursodeoxycholic acid group and 9 subjects in the placebo group |
| Liver Function Tests | Pre-Treatment and Post 30 day-Treatment | We will measure liver function tests before and after the study drug to ensure that no abnormalities in liver function occurs with the drug. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tauroursodeoxycholic Acid This group will receive 1.75 grams per day of tauroursodeoxycholic acid given once daily for 30 days.
Tauroursodeoxycholic acid: The intervention group will receive 1.75 grams of tauroursodeoxycholic acid daily for 30 days. | 13 |
| Placebo This group will receive a placebo tablet that is identical to the treatment group except that it does not contain tauroursodeoxycholic acid. The pills will be taken once daily for 30 days.
Placebo tablet: The placebo group will receive a placebo tablet that is identical to the treatment group except that it does not contain tauroursodeoxycholic acid. The pills will be taken once daily for 30 days. | 14 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Tauroursodeoxycholic Acid | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 14 Participants | 27 Participants |
| Age, Continuous | 43 years STANDARD_DEVIATION 11 | 51 years STANDARD_DEVIATION 10 | 48 years STANDARD_DEVIATION 11 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 12 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| 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 | 7 Participants | 10 Participants | 17 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 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 | 6 Participants | 4 Participants | 10 Participants |
| Region of Enrollment United States | 13 participants | 14 participants | 27 participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 9 Participants | 12 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 14 |
| other Total, other adverse events | 1 / 13 | 0 / 14 |
| serious Total, serious adverse events | 0 / 13 | 0 / 14 |
Outcome results
Primary
Glucose Uptake
We will examine the ability of insulin to cause muscle to take up insulin. Each subject will receive intravenous insulin for 6 hours to see how much sugar needs to be given intravenously to keep the blood sugar normal, a measure called glucose uptake. We will compare glucose uptake measured as the amount of 20% dextrose that is needed to keep the blood sugar at \ 100mg/dl during insulin infusion before and after 30 days of treatment with drug or placebo.
Time frame: Glucose uptake is measured at baseline and 30 days after study intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tauroursodeoxycholic Acid | Glucose Uptake | 0 change in glucose infusion rate (ml/hr) | Standard Error 11 |
| Placebo | Glucose Uptake | 8 change in glucose infusion rate (ml/hr) | Standard Error 7 |
Secondary
Body Composition
We will measure how much fat is present in each subject before and after treatment with TUDCA or placebo.
Time frame: Pre-Treatment and Post 30 day-Treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tauroursodeoxycholic Acid | Body Composition | Pre | 35.7 percentage of body fat | Standard Error 2.3 |
| Tauroursodeoxycholic Acid | Body Composition | Post | 35.7 percentage of body fat | Standard Error 2.3 |
| Placebo | Body Composition | Pre | 32.6 percentage of body fat | Standard Error 2.8 |
| Placebo | Body Composition | Post | 31.7 percentage of body fat | Standard Error 2.8 |
Secondary
Liver Fat
We will use MRI to measure the relative (%) amount of fat in each subject's liver before and after 30 days of treatment. This will allow us to determine if the drug reduces liver fat. This is calculated by subtracting the amount of fat in the liver at the beginning of the study from the amount of fat in the liver after 30 days of treatment. Subjects who have claustrophobia or are unable to undergo MRI will not have this measure performed. Due to these reasons liver MRS was only performed in 10 patients in the tauroursodeoxycholic acid group and 9 subjects in the placebo group
Time frame: Pre-Treatment and Post 30 day-Treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tauroursodeoxycholic Acid | Liver Fat | -0.3 Change in Percent liver fat | Standard Error 0.2 |
| Placebo | Liver Fat | 1.2 Change in Percent liver fat | Standard Error 0.6 |
Secondary
Liver Function Tests
We will measure liver function tests before and after the study drug to ensure that no abnormalities in liver function occurs with the drug.
Time frame: Pre-Treatment and Post 30 day-Treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tauroursodeoxycholic Acid | Liver Function Tests | ALT-PRE | 25 ALT (IU/ml) | Standard Error 4 |
| Tauroursodeoxycholic Acid | Liver Function Tests | ALT-Post | 19 ALT (IU/ml) | Standard Error 3 |
| Placebo | Liver Function Tests | ALT-PRE | 21 ALT (IU/ml) | Standard Error 2 |
| Placebo | Liver Function Tests | ALT-Post | 23 ALT (IU/ml) | Standard Error 4 |