Examination of the Metabolic Effects of Direct Bile Salt Delivery to the Ileum in Humans

Phase 1TerminatedNCT03201952

Vanderbilt University Medical Center2 enrolled

Overview

This project will evaluate distal intestinal bile salt administration in humans by deliving ursodeoxycholic acid (UDCA) into the terminal ileum of subjects with a pre-existing ileostomy and assessing several hormone levels following an oral glucose tolerance test compared to a placebo.

Ursodeoxycholic acid (UDCA) is currently FDA-approved for the treatment of gallstone dissolution and primary biliary cirrhosis. Other than these two diseases, exploratory research - both preclinical and clinical - has demonstrated other beneficial effects of UDCA. For example, systemic administration of UDCA for several weeks (4-6 weeks) has been shown to improve insulin sensitivity in non-diabetic, obese individuals. Whether or not these effects on insulin sensitivity may be acute in nature and are detectable by OGTT are unknown. Based on growing knowledge of bile salt receptors in the gastrointestinal tract, at least some of these effects of bile salts on metabolism appear to be mediated by receptors constitutively expressed in the terminal ileum (e.g. TGR5 receptor that is upstream of GLP-1 and insulin secretion that control blood glucose levels). Thus, metabolic effects may be inducible with acute UDCA administration directly into this region of the intestine that could be useful in screening compounds or designing future mechanistic studies. This pilot study is designed to examine the effects of UDCA on oral glucose tolerance versus a placebo in non-diabetic across a range of body mass indexes by infusing UDCA directly into the ileum of volunteering subjects with a pre-existing ileostomy and measuring hormone response. The investigators aim to recruit approximately 4-5 volunteers in a lean BMI range (18.5-25 kg/m2), overweight (\>25-29.9), class 1 obesity (\>30-35 kg/m2), and class 2 obesity (\>35-40 kg/m2) for a total of \~16-20 participants.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

SINGLE

Enrollment

Conditions

Glucose Intolerance Gastric Bypass Surgery

Interventions

Ursodeoxycholic AcidDRUG

Ileostomy administration of 300mg UDCA once

PlacebosDRUG

Ileostomy administration of 5cc saline placebo once

Eligibility

Sex: ALLMin age: 18 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Able to give informed consent * Presence of an ileostomy \> 2 months * Weight stable\* for \>2 months (i.e. no greater than 7% change in body weight the last 2 months) Exclusion Criteria: * Crohn's Disease * Steroid use in the last 3 months * Documented/known diagnosis of type 1 diabetes or type 2 diabetes, chronic liver disease, chronic kidney disease, heart failure, cardiac dysrhythmias, or familial hypercholesterolemia * Current use of any over-the-counter or prescription oral bile salt * Currently pregnant * Current use of medications that are known to interact with Ursodiol * Current or former smoker within the last year.

Locations (1)

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Outcomes

Primary Outcomes

Change in glucose level

Following UDCA administration and a 2 hour period to allow steady state, a 3 hour glucose tolerance test will be completed while measuring glucose change from baseline.

Time frame: 3 hours

Secondary Outcomes

Change in insulin Level

Following UDCA administration and a 2 hour period to allow steady state, a 3 hour glucose tolerance test will be completed while measuring insulin level

Time frame: Baseline to 3 hours

Change in GLP-1 Level

Following UDCA administration and a 2 hour period to allow steady state, a 3 hour glucose tolerance test will be completed while measuring GLP-1

Time frame: Baseline to 3 hours

Data from ClinicalTrials.gov

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