GLUCOSE-MGH: Genetic Links Understood Through Challenge With Oral Semaglutide Exposure at MGH

Study Overview
=================
Brief Summary
-----------------
The goal of this research study is to evaluate the pathophysiologic mechanisms by which genetic variation impacts response to an FDA-approved medication commonly used to treat diabetes and obesity called oral semaglutide (Rybelsus) and to characterize the physiological response to a mixed meal tolerance test (MMTT) before and after a 14-day treatment with Rybelsus. The effect of oral semaglutide (Rybelsus) on human beings is similar regardless of whether the person taking them has diabetes or not. The investigators will do this by measuring factors in the blood, such as sugars, fats, metabolites, and proteins, after eating a standardized breakfast meal at the first visit and after taking 14 doses of oral semaglutide (Rybelsus) over two weeks before the second study visit. The food (mixed meal breakfast) we will be studying is specially prepared to contain a set amount of protein, carbohydrates, and fat. The investigators hypothesize that understanding how the acute biochemical response to oral semaglutide differs by genetic variation will generate insight into drug mechanisms and Type 2 Diabetes pathophysiology.

Official Title
-----------------
GLUCOSE-MGH: Genetic Links Understood Through Challenge With Oral Semaglutide Exposure at MGH

Conditions
-----------------
Genetic Predisposition, Metabolic Diseases, Type 2 Diabetes

Intervention / Treatment
-----------------
* Other: Mixed Meal Tolerance Test (MMTT)
* Drug: Rybelsus


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males or non-pregnant females Ages 18-50 (inclusive) Able/willing to give consent Span the metabolic range between normal glycemia and pre-diabetes (fasting glucose of 100-125 mg/dL based on chart review of existing laboratory data) Exclusion Criteria: Currently taking medications or intending to take medications for diabetes Currently taking medications or intending to take medications that affect glycemic parameters, such as glucocorticoids, growth hormone, or fluoroquinolones Personal history of intestinal malabsorption, bariatric surgery, celiac disease, gallbladder disease, or pancreatitis Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 Estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 per the Modification of Diet in Renal Disease equation History of cirrhosis and/or aspartate aminotransferase or alanine aminotransferase more than 3x upper limit of normal Dietary restrictions preventing consumption of a MMTT Women who are pregnant, nursing, or at risk of becoming pregnant Participation in other interventional studies during the current study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

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

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

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

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: GLUCOSE-MGH Study<br>Day 1: Mixed meal tolerance test Day 3-15: 7mg Rybelsus, once daily Day 16: 1 dose of 7mg Rybelsus, Mixed meal tolerance test in the presence of Rybelsus | Other: Mixed Meal Tolerance Test (MMTT)<br>* The MMTT meal will provide a standard amount of total calories, protein, fat and carbohydrate to each participant at both study visits. Pre-packaged and freshly prepared food will be given in this MMTT. The participants will undergo a MMTT at Visit 1 and Visit 2.<br>Drug: Rybelsus<br>* Rybelsus will be administered during this study. This medication is safely prescribed for the treatment of type 2 diabetes and obesity. We will give 14 doses (7mg each dose) to study participants over 14 days. Another MMTT will be performed after the 14th dose of Rybelsus.<br>* Other names: Oral Semaglutide;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin response to oral semaglutide treatment | Investigators will measure the change in insulin area under the curve (AUC) over 120 minutes of the MMTT, calculated using the trapezoidal method, between Visit 1 and Visit 2 as an index of response to oral semaglutide, and compare this outcome by genotype at selected loci. | 15 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fasting glucose response to oral semaglutide treatment | Investigators will measure the change in fasting glucose over 120 minutes of the MMTT, between the two visits, and compare this outcome by genotype at selected loci. | 15 days | 
| Cumulative glucose response to oral semaglutide treatment | Investigators will measure the change in glucose area under the curve (AUC) over 120 minutes of the MMTT, between the two visits, and compare this outcome by genotype at selected loci. | 15 days | 
| Baseline incretin level | Investigators will measure levels of GLP-1 during the length of the baseline MMTT (120 minutes) that takes place on Visit 1, and compare changes in the baseline levels by genotype at selected loci. | 120 minutes during Visit 1 |