Tauroursodeoxycholic Acid for Protease-inhibitor Associated Insulin Resistance

Study Overview
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Brief Summary
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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
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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.

Official Title
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Tauroursodeoxycholic Acid for Protease-inhibitor Associated Insulin Resistance

Conditions
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HIV Related Insulin Resistance, Protease Inhibitor Related Insulin Resistance, Endoplasmic Reticulum Stress

Intervention / Treatment
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* Drug: Tauroursodeoxycholic acid
* Other: Placebo tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV+ receiving protease inhibitor containing antiretroviral therapy for >6 months Undetectable viral load insulin resistant impaired fasting glucose (fasting blood glucose>100mg/dl) 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: tauroursodeoxycholic acid<br>This group will receive 1.75 grams per day of tauroursodeoxycholic acid given once daily for 30 days. | Drug: Tauroursodeoxycholic acid<br>* The intervention group will receive 1.75 grams of tauroursodeoxycholic acid daily for 30 days.<br>* Other names: tudcabil;|
| Placebo Comparator: placebo<br>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. | Other: Placebo tablet<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Glucose uptake is measured at baseline and 30 days after study intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body Composition | We will measure how much fat is present in each subject before and after treatment with TUDCA or placebo. | Pre-Treatment and Post 30 day-Treatment | 
| 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 | Pre-Treatment and Post 30 day-Treatment | 
| 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. | Pre-Treatment and Post 30 day-Treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Protease inhibitor, insulin resistance, Tauroursodeoxycholic acid