Tauroursodeoxycholic Acid for Protease-inhibitor Associated Insulin Resistance
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.
HIV Related Insulin Resistance
Protease Inhibitor Related Insulin Resistance
Endoplasmic Reticulum Stress
Drug: Tauroursodeoxycholic acid
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
|Official Title:||Tauroursodeoxycholic Acid for Protease-inhibitor Associated Insulin Resistance|
- Insulin sensitivity [ Time Frame: 30 days ] [ Designated as safety issue: No ]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 during insulin infusion before and after 30 days of treatment with drug or placebo.
- Endoplasmic reticulum stress [ Time Frame: 30 days ] [ Designated as safety issue: No ]It is believed that protease inhibitors cause stress to the part of the fat cell that folds proteins; referred to as endoplasmic reticulum stress. When endoplasmic reticulum stress increases, and changes in protein levels in fat cells occur. We will measure markers of endoplasmic reticulum stress in fat samples taken from subjects before and after 30 days of treatment with TUDCA or placebo.
- Thyroid hormone deiodinase expression in muscle [ Time Frame: 30 days ] [ Designated as safety issue: No ]We will measure changes in proteins that metabolize thyroid hormone in muscle at baseline and after 30 days of treatment with TUDCA or placebo to determine if this is one of the mechanisms by which TUDCA improves how well insulin works in the body.
- body composition [ Time Frame: 30 days ] [ Designated as safety issue: No ]We will measure how much fat is present in each subject before and after treatment with TUDCA or placebo.
- liver fat [ Time Frame: 30 days ] [ Designated as safety issue: No ]We will use MRI to measure the 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.
- liver function tests [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]We will measure liver function tests before and after the study drug to ensure that no abnormalities in liver function occurs with the drug.
|Study Start Date:||September 2013|
|Estimated Study Completion Date:||July 2018|
|Estimated Primary Completion Date:||July 2018 (Final data collection date for primary outcome measure)|
Active Comparator: tauroursodeoxycholic acid
This group will receive 1.75 grams per day of tauroursodeoxycholic acid given once daily for 30 days.
Drug: Tauroursodeoxycholic acid
The intervention group will receive 1.75 grams of tauroursodeoxycholic acid daily for 30 days.
Placebo Comparator: 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.
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.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01877551
|Contact: Janet Winkelmannfirstname.lastname@example.org|
|United States, Missouri|
|Washington University School of Medicine||Recruiting|
|St. Louis, Missouri, United States, 63110|
|Principal Investigator: Dominic N. Reeds, M.D.|
|Sub-Investigator: Rachel Presti, M.D., Ph.D.|
|Sub-Investigator: Brian Finck, Ph.D.|
|Principal Investigator:||Dominic N Reeds, M.D.||Washington University School of Medicine|