Tauroursodeoxycholic Acid for Protease-inhibitor Associated Insulin Resistance

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.

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.

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