Clinical trial NCT03201952: Examination of the Metabolic Effects of Direct Bile Salt Delivery to the Ileum in Humans
Official title: Examination of the Metabolic Effects of Direct Bile Salt Delivery to the Ileum in Humans
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Glucose Intolerance
Gastric Bypass Surgery
Keywords: Glucose
Ileostomy
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
First posted: 2017-06-28
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Each volunteering subject will participate in 2 study visits, receiving the placebo at one visit and investigation medication at the other visit. The order of these visits will be randomized.
Primary purpose: BASIC_SCIENCE

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in glucose level
timeFrame: 3 hours
Secondary outcomes:
measure: Change in insulin Level
timeFrame: Baseline to 3 hours
measure: Change in GLP-1 Level
timeFrame: Baseline to 3 hours
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Vanderbilt University
name: Naji Abumrad, MD
role: STUDY_DIRECTOR
References:
citation: 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.
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.