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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Ursodeoxycholic Acid/Placebos | Active Comparator | During one of the subjects two randomized visits the subject will receive a 300mg elixir solution of ursodeoxycholic acid (UDCA) via their ileostomy that has been prepared by investigational drug services (IDS) in a 5cc elixir formulation during visit #1. During visit #2 subjects will receive a saline solution of totaling 5cc via their ileostomy that has been prepared by investigational drug services (IDS) in order to mimic the preparation of the medication comparator of ursodeoxycholic acid. |
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| Placebos/Ursodeoxycholic Acid | Active Comparator | Subjects will receive a saline solution of totaling 5cc via their ileostomy that has been prepared by investigational drug services (IDS) in order to mimic the preparation of the medication comparator of ursodeoxycholic acid during visit #1. During visit #2 subject will receive a 300mg elixir solution of ursodeoxycholic acid (UDCA) via their ileostomy that has been prepared by investigational drug services (IDS) in a 5cc elixir formulation. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ursodeoxycholic Acid | Drug | Ileostomy administration of 300mg UDCA once |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Change in GLP-1 Level |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Naji Abumrad, MD | Vanderbilt University | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Vanderbilt University Medical Center | Nashville | Tennessee | 37232 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26196952 | Background | 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. | |
| 26197299 | Background | 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. |
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| ID | Term |
|---|---|
| D018149 | Glucose Intolerance |
| ID | Term |
|---|---|
| D006943 | Hyperglycemia |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D014580 | Ursodeoxycholic Acid |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D003840 | Deoxycholic Acid |
| D002793 | Cholic Acids |
| D001647 | Bile Acids and Salts |
| D013256 | Steroids |
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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.
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| Placebos | Drug | Ileostomy administration of 5cc saline placebo once |
|
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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 |
| D000072473 |
| Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D002757 | Cholanes |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |