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.

Study Overview

• Status: Completed
• Conditions: Endoplasmic Reticulum Stress; HIV Related Insulin Resistance; Protease Inhibitor Related Insulin Resistance
• Intervention / Treatment: Drug: Tauroursodeoxycholic acid; Other: Placebo tablet

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.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.; Other Names: taurolite; tudcabil
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.	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institutes of Health (NIH)
• Investigators: Principal Investigator: Dominic N. Reeds, M.D., Washington University School of Medicine

Publications and helpful links

General Publications

• 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.

Helpful Links

• Washington University AIDS Clinical Trials Unit

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2013
• Primary Completion (Actual): May 1, 2018
• Study Completion (Actual): May 1, 2018

Study Registration Dates

• First Submitted: June 11, 2013
• First Submitted That Met QC Criteria: June 12, 2013
• First Posted (Estimate): June 13, 2013

Study Record Updates

• Last Update Posted (Actual): January 27, 2020
• Last Update Submitted That Met QC Criteria: January 23, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: HIV; insulin resistance; Protease inhibitor; Tauroursodeoxycholic acid
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Insulin Resistance; Anti-Infective Agents; Antiviral Agents; Gastrointestinal Agents; Cholagogues and Choleretics; Ursodoxicoltaurine
• Other Study ID Numbers: 201306105; R01DK096982 (U.S. NIH Grant/Contract)