Ursodiol on Insulin Sensitivity, Gastric Emptying and Body Weight With Type 2 Diabetes on Metformin

Study Overview
=================
Brief Summary
-----------------
This study will evaluate whether bile acids are able to increase insulin sensitivity and enhance glycemic control in T2DM patients, as well as exploring the mechanisms that enhance glycemic control. These observations will provide the preliminary data for proposing future therapeutic as well as further mechanistic studies of the role of bile acids in the control of glycemia in T2DM.

Detailed Description
-----------------
Background: Intra-jejunal administration of bile acids improves insulin sensitivity. Hypothesis: The bile acid, ursodeoxycholic acid (UDCA) in delayed (ileocolonic)-release formulation, stimulates bile acid membrane receptor (TGR-5) and farnesol X (FXR) receptors in the ileum and colon, increasing the secretion of Fibroblast growth factor 19 (FGF-19), GLP-1, oxyntomodulin (OXM), and Peptide (PYY3-36), improving insulin sensitivity and inducing weight loss. Aim: To study the effect of an ileocolonic formulation of UDCA on insulin sensitivity, postprandial plasma glycemia and incretin levels, gastric emptying and body weight in overweight or obese type 2 diabetic subjects on monotherapy with metformin. Study design: This is a single center, placebo-controlled, parallel group, single dose randomized controlled trial to study the effect of delayed (ileocolonic)-release UDCA 600 mg twice daily on insulin sensitivity, gastric emptying of liquids and solids (measured by scintigraphy)and weight loss in overweight or obese type 2 diabetic subjects. Participants will be receiving monotherapy with metformin. Blood samples will be collected at defined times to measure glycemia and the incretin (GLP-1, OXM, PYY3-36) fasting levels and responses to the meal. Anticipated Results: In comparison with placebo, UDCA will increase insulin sensitivity, enhance glycemic control, increase postprandial incretins, and delay gastric emptying (GE) of liquids. Significance: This study will prove that ileocolonic-release UDCA enhances glycemic control in T2DM patients.

Official Title
-----------------
Effect of Delayed-Release Ursodeoxycholic Acid on Insulin Sensitivity, Gastric Emptying and Body Weight in Overweight or Obese Patients With Type 2 Diabetes on Metformin Treatment

Conditions
-----------------
Type 2 Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: Ursodiol


Participation Criteria
=================
Eligibility Criteria
-----------------
Overweight or Obese subjects with BMI> 25 Kg/m2 with Type 2 Diabetes mellitus on Metformin, receiving standard of care for Type 2 DM. Otherwise individuals who are not currently on treatment for cardiac, pulmonary, gastrointestinal, hepatic, renal, hematological, neurological, endocrine (other than T2DM) and unstable psychiatric disease. Men or women. Women of childbearing potential will have a negative pregnancy test before initiation of medication.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ursodiol<br>Ursodeoxycholic acid (UDCA) 600mg in delayed (ileocolonic)-release to be taken twice daily | Drug: Ursodiol<br> <br> * Other names: Ursodeoxycholic acid;|
| Placebo Comparator: Placebo<br>matching placebo capsules to be taken twice daily | Drug: Ursodiol<br> <br> * Other names: Ursodeoxycholic acid;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Area Above Basal (AAB) for Glucose | Mixed meal glucose results are used to calculate the area above basal (AAB) for glucose. The glycemic index of a food is defined as the incremental area under the two-hour blood glucose response curve (AUC) following an overnight fast and ingestion of a food with a certain quantity of available carbohydrate (usually 50 g). | baseline, post-treatment approximately 14 - 17 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Fasting Glucose | Serum glucose measurements taken after 10 hours of fasting. | baseline, post-treatment approximately 14 - 17 days | 
| Change in Insulin Sensitivity | Insulin sensitivity will be calculated by the oral minimal model. | baseline, post-treatment approximately 14 - 17 days | 
| Gastric Emptying of Liquids (T1/2) | The time for half of the ingested liquids to leave the stomach. Following a meal with milk labeled with indium In111 diethylenetriaminepentaacetate (0.1 mCi), gastric emptying of liquids was assessed with scintigraphy imaging. | post-treatment, approximately 14-17 days | 
| Gastric Emptying of Solids (T1/2) | The time for half of the ingested solids to leave the stomach. Following a meal consisting of two eggs labeled with technetium Tc 99m sulfur colloid (1 mCi) served with 50g of Canadian bacon and one slice of bread gastric emptying of solids was assessed with scintigraphy imaging. | post-treatment, approximately 14-17 days | 
| Change in Weight | Change in subject's weight, in kilograms | baseline, post-treatment approximately 14 - 17 days | 
| Change in Body Mass Index | Change in subjects BMI, in kilograms per meter squared. | baseline, post-treatment approximately 14 - 17 days | 
| Change in FGF-19 | Change in fasting fibroblast growth factor (FGF)-19 expression. | baseline, post-treatment approximately 14 - 17 days |