Tauroursodeoxycholic Acid for Protease-inhibitor Associated Insulin Resistance

The Washington University

Status: Completed

Conditions: HIV Related Insulin Resistance; Endoplasmic Reticulum Stress; Protease Inhibitor Related Insulin Resistance

Treatments: Other: Placebo tablet; Drug: Tauroursodeoxycholic acid

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT01877551

201306105

R01DK096982 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 27 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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27 participants in 2 patient groups, including a placebo group

tauroursodeoxycholic acid

Active Comparator group

Description:

This group will receive 1.75 grams per day of tauroursodeoxycholic acid given once daily for 30 days.

Treatment:

Drug: Tauroursodeoxycholic acid

placebo

Placebo Comparator group

Description:

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.

Treatment:

Other: Placebo tablet