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

Glucose Intolerance Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03201952
• Other study ID #: 162023
• Status: Terminated
• Phase: Phase 1
• Start date: February 1, 2018
• Est. completion date: May 1, 2020

Study information

• Verified date: April 2021
• Source: Vanderbilt University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 2
• Est. completion date: May 1, 2020
• Est. primary completion date: May 1, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Gastric Bypass Surgery
• Glucose Intolerance

Intervention

Drug:
• Ursodeoxycholic Acid
Ileostomy administration of 300mg UDCA once
• Placebos
Ileostomy administration of 5cc saline placebo once

Locations

Country	Name	City	State
United States	Vanderbilt University Medical Center	Nashville	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
Vanderbilt University Medical Center

Country where clinical trial is conducted

United States, 

References & Publications (2)

Albaugh VL, Flynn CR, Cai S, Xiao Y, Tamboli RA, Abumrad NN. Early Increases in Bile Acids Post Roux-en-Y Gastric Bypass Are Driven by Insulin-Sensitizing, Secondary Bile Acids. J Clin Endocrinol Metab. 2015 Sep;100(9):E1225-33. doi: 10.1210/jc.2015-2467. Epub 2015 Jul 21. — View Citation

Flynn CR, Albaugh VL, Cai S, Cheung-Flynn J, Williams PE, Brucker RM, Bordenstein SR, Guo Y, Wasserman DH, Abumrad NN. Bile diversion to the distal small intestine has comparable metabolic benefits to bariatric surgery. Nat Commun. 2015 Jul 21;6:7715. doi: 10.1038/ncomms8715. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	3 hours
Secondary	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	Baseline to 3 hours
Secondary	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	Baseline to 3 hours