Tauroursodeoxycholic Acid for Protease-inhibitor Associated Insulin Resistance

Endoplasmic Reticulum Stress Clinical Trial

Official title:

Tauroursodeoxycholic Acid for Protease-inhibitor Associated Insulin Resistance

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01877551
• Other study ID #: 201306105
• Secondary ID: R01DK096982
• Status: Completed
• Phase: N/A
• Start date: September 2013
• Est. completion date: May 2018

Study information

• Verified date: January 2020
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 27
• Est. completion date: May 2018
• Est. primary completion date: May 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Endoplasmic Reticulum Stress
• HIV Related Insulin Resistance
• Insulin Resistance
• Protease Inhibitor Related Insulin Resistance

Intervention

Drug:
• Tauroursodeoxycholic acid
The intervention group will receive 1.75 grams of tauroursodeoxycholic acid daily for 30 days.

Other:
• 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.

Locations

Country	Name	City	State
United States	Washington University School of Medicine	Saint Louis	Missouri

Sponsors (3)

Lead Sponsor	Collaborator
Washington University School of Medicine	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

References & Publications (1)

Kars M, Yang L, Gregor MF, Mohammed BS, Pietka TA, Finck BN, Patterson BW, Horton JD, Mittendorfer B, Hotamisligil GS, Klein S. Tauroursodeoxycholic Acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes. 2010 Aug;59(8):1899-905. doi: 10.2337/db10-0308. Epub 2010 Jun 3. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Glucose uptake is measured at baseline and 30 days after study intervention
Secondary	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
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	Pre-Treatment and Post 30 day-Treatment
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.	Pre-Treatment and Post 30 day-Treatment

External Links

•   Washington University AIDS Clinical Trials Unit