Clinical trial NCT01877551: Tauroursodeoxycholic Acid for Protease-inhibitor Associated Insulin Resistance
Official title: Tauroursodeoxycholic Acid for Protease-inhibitor Associated Insulin Resistance
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: HIV Related Insulin Resistance
Protease Inhibitor Related Insulin Resistance
Endoplasmic Reticulum Stress
Keywords: HIV
Protease inhibitor
insulin resistance
Tauroursodeoxycholic acid
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2013-06-13
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Glucose Uptake
timeFrame: Glucose uptake is measured at baseline and 30 days after study intervention
Secondary outcomes:
measure: Body Composition
timeFrame: Pre-Treatment and Post 30 day-Treatment
measure: Liver Fat
timeFrame: Pre-Treatment and Post 30 day-Treatment
measure: Liver Function Tests
timeFrame: Pre-Treatment and Post 30 day-Treatment
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Dominic N. Reeds, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.