Effects of Xenin-25 on Insulin Secretion and Gastric Emptying in Humans With and Without a Complete Truncal Vagotomy

Study Overview
=================
Brief Summary
-----------------
Glucose-dependent Insulinotropic Polypeptide (GIP) and xenin-25 are peptide hormones produced/released from your intestines and help regulate blood sugar levels after you eat. We have previously performed studies in humans that measured the effects of xenin-25 and GIP (alone and together) on blood sugar levels. One study was conducted with an intravenous infusion of glucose but without ingestion of a meal. In this study, xenin-25 increased the effects of GIP on insulin secretion- but only in humans without type 2 diabetes mellitus (T2DM). A second study was conducted in conjunction with ingestion of a meal. In this study, xenin-25 reduced blood glucose levels by delaying gastric emptying and this effect was similar in humans with and without T2DM. A variety of studies that we have performed suggest that xenin-25 works by activating nerves. A specific nerve called the vagus nerve plays an important role in regulating insulin secretion. This study will determine if the vagus nerve (which was disrupted if you had a vagotomy) is needed for the effects of xenin-25 on insulin secretion and/or gastric emptying.

Detailed Description
-----------------
Two groups of subjects, both without T2DM, will be studied. One group will consist of people who previously received a complete truncal vagotomy as part of a surgical treatment unrelated to this research project. The other group will be subjects who have not had a truncal vagotomy. Initially, each potential participant will be administered an oral glucose tolerance test at the screening visit to make sure that they do not have type 2 diabetes. They will also have a sham feeding test to check for the completeness (or absence) of the vagotomy. As outlined below, each subject will then receive 4 graded glucose infusions (GGI) and 2 meal tolerance tests (MTT)- each on a separate occasion following an overnight fast. For each GGI, the subject will be given an intravenous infusion of glucose such that blood glucose levels slowly increase over a 4 hour period. On separate occasions, the participant will also receive a primed-continuous infusion of GIP alone, xenin-25 alone, GIP plus xenin-25, or placebo (constant dose of 4 pmoles x kg-1 x min-1). Blood samples will be collected before and during the GGI for the measurement of glucose, insulin, C-peptide, glucagon, pancreatic polypeptide, GIP and xenin-25 levels. Insulin secretion rates will also be calculated. By comparing results for the two groups, we will learn if the vagus nerve mediates the effects of GIP, xenin-25, or the combination of GIP plus xenin-25 on insulin secretion in humans and thus, if this signaling circuit is impaired in humans with T2DM. For the MTTs, the participant will ingest a liquid meal (Boost Plus) plus acetaminophen (Tylenol). On separate occasions, a primed-continuous infusion of vehicle alone or xenin-25 alone (constant dose of 12 pmoles x kg-1 x min-1) will be initiated at the same time the meal is ingested. Blood samples will be collected before and during the MTT for the measurement of acetaminophen, glucose, insulin, C-peptide, glucagon, GIP and xenin-25 levels. Insulin secretion rates will also be calculated. The rate of acetaminophen appearance in the blood is an indirect measure of the rate of gastric emptying. By comparing results for the two groups, we will learn if the vagus nerve mediates the effects of xenin-25 on gastric emptying in humans.

Official Title
-----------------
Effects of Xenin-25 on Insulin Secretion and Gastric Emptying in Humans With and Without a Complete Truncal Vagotomy

Conditions
-----------------
Does the Vagus Nerve Mediate the Effects of Xenin-25

Intervention / Treatment
-----------------
* Drug: Graded Glucose Infusion with Placebo
* Drug: Graded Glucose Infusion with GIP Alone
* Drug: Graded Glucose Infusion with xenin-25 alone
* Drug: Graded Glucose Infusion with GIP plus xenin-25
* Drug: Meal Tolerance Test with Placebo
* Drug: Meal Tolerance Test with xenin-25


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Ages 18-70. No minors will be studied. Individuals must be able to consent for their own participation (no mental impairment affecting cognition or willingness to follow study instructions). Healthy volunteers with no clinical evidence of Type 2 Diabetes Healthy volunteers who have undergone a complete truncal vagotomy Healthy volunteers who have not had a complete truncal vagotomy Women of childbearing potential must be currently taking/using a method of birth control that is acceptable to the investigators. A pregnancy test will be done at the beginning of each visit. Any woman with a positive pregnancy test will be removed from the study. Willingness to complete all required visits Exclusion Criteria: <18years of age or >70 years of age Lacks cognitive ability to sign the consent &/or follow the study directions for themselves Women unwilling to comply with using an acceptable method of contraception during the course of the study, or who are currently breast-feeding. Volunteers with Type 2 diabetes Volunteers with a history of Acute Pancreatitis Volunteer with a history of Chronic Pancreatitis and/or risk factors for chronic pancreatitis including hypertriglyceridemia (triglycerides >400mg/ml) hypercalcemia (blood calcium level >11.md/dl) and/or the presence of gallstones. Volunteers with a history of gastrointestinal disorders, particularly related to gastric motility/emptying such as gastric bypass, documented gastro-paresis in diabetic volunteers. Volunteers with a history of cancer. Exception: skin cancer. Known heart, kidney. liver or pancreatic disease requiring medications. Subjects unwilling to allow the use of their own blood or the human albumin in the preparation of the peptides. Unwillingness to allow blood glucose level adjustment (if needed) with IV insulin.

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

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Truncal Vagotomy<br>Healthy participants without diabetes who have undergone a complete truncal vagotomy | Drug: Graded Glucose Infusion with Placebo<br>* Starting at 0 minutes, glucose infusion rates will be increased to 1, 2, 3, 4, 6, and 8 mg/kg/min every 40 minutes. Starting at 0 minutes, a primed-continuous intravenous infusion of saline containing 1% human albumin will continue for 240 minutes. The study is finished at 240 minutes.<br>* Other names: GGI with Albumin Alone;Drug: Graded Glucose Infusion with GIP Alone<br>* Starting at 0 minutes, glucose infusion rates will be increased to 1, 2, 3, 4, 6, and 8 mg/kg/min every 40 minutes. Starting at 0 minutes, a primed-continuous intravenous infusion of GIP in saline containing 1% human albumin will continue for 240 minutes. The study is finished at 240 minutes.<br>* Other names: GGI with GIP;Drug: Graded Glucose Infusion with xenin-25 alone<br>* Starting at 0 minutes, glucose infusion rates will be increased to 1, 2, 3, 4, 6, and 8 mg/kg/min every 40 minutes. Starting at 0 minutes, a primed-continuous intravenous infusion of xenin-25 in saline containing 1% human albumin will continue for 240 minutes. The study is finished at 240 minutes.<br>* Other names: GGI with Xenin;Drug: Graded Glucose Infusion with GIP plus xenin-25<br>* Starting at 0 minutes, glucose infusion rates will be increased to 1, 2, 3, 4, 6, and 8 mg/kg/min every 40 minutes. Starting at 0 minutes, a primed-continuous intravenous infusion of GIP plus xenin-25 in saline containing 1% human albumin will continue for 240 minutes. The study is finished at 240 minutes.<br>* Other names: GGI with GIP plus Xenin;Drug: Meal Tolerance Test with Placebo<br>* At 0 minutes, a liquid mixed meal (Boost Plus) plus acetaminophen will be ingested. Starting at 0 minutes, a primed-continuous intravenous infusion of saline containing 1% human albumin will continue for 300 minutes. The study is finished at 300 minutes.<br>* Other names: MTT with Albumin Alone;Drug: Meal Tolerance Test with xenin-25<br>* At 0 minutes, a liquid mixed meal (Boost Plus) plus acetaminophen will be ingested. Starting at 0 minutes, a primed-continuous intravenous infusion of xenin-25 in saline containing 1% human albumin will continue for 300 minutes. The study is finished at 300 minutes.<br>* Other names: MTT with xenin;|
| Experimental: No Vagotomy<br>Healthy participants without diabetes who have not had a complete truncal vagotomy | Drug: Graded Glucose Infusion with Placebo<br>* Starting at 0 minutes, glucose infusion rates will be increased to 1, 2, 3, 4, 6, and 8 mg/kg/min every 40 minutes. Starting at 0 minutes, a primed-continuous intravenous infusion of saline containing 1% human albumin will continue for 240 minutes. The study is finished at 240 minutes.<br>* Other names: GGI with Albumin Alone;Drug: Graded Glucose Infusion with GIP Alone<br>* Starting at 0 minutes, glucose infusion rates will be increased to 1, 2, 3, 4, 6, and 8 mg/kg/min every 40 minutes. Starting at 0 minutes, a primed-continuous intravenous infusion of GIP in saline containing 1% human albumin will continue for 240 minutes. The study is finished at 240 minutes.<br>* Other names: GGI with GIP;Drug: Graded Glucose Infusion with xenin-25 alone<br>* Starting at 0 minutes, glucose infusion rates will be increased to 1, 2, 3, 4, 6, and 8 mg/kg/min every 40 minutes. Starting at 0 minutes, a primed-continuous intravenous infusion of xenin-25 in saline containing 1% human albumin will continue for 240 minutes. The study is finished at 240 minutes.<br>* Other names: GGI with Xenin;Drug: Graded Glucose Infusion with GIP plus xenin-25<br>* Starting at 0 minutes, glucose infusion rates will be increased to 1, 2, 3, 4, 6, and 8 mg/kg/min every 40 minutes. Starting at 0 minutes, a primed-continuous intravenous infusion of GIP plus xenin-25 in saline containing 1% human albumin will continue for 240 minutes. The study is finished at 240 minutes.<br>* Other names: GGI with GIP plus Xenin;Drug: Meal Tolerance Test with Placebo<br>* At 0 minutes, a liquid mixed meal (Boost Plus) plus acetaminophen will be ingested. Starting at 0 minutes, a primed-continuous intravenous infusion of saline containing 1% human albumin will continue for 300 minutes. The study is finished at 300 minutes.<br>* Other names: MTT with Albumin Alone;Drug: Meal Tolerance Test with xenin-25<br>* At 0 minutes, a liquid mixed meal (Boost Plus) plus acetaminophen will be ingested. Starting at 0 minutes, a primed-continuous intravenous infusion of xenin-25 in saline containing 1% human albumin will continue for 300 minutes. The study is finished at 300 minutes.<br>* Other names: MTT with xenin;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin secretion rates will be measured during the GGI and MTTs |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma acetaminophen levels will be measured during MTTs |  | 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Vagotomy, Vagus Nerve, Xenin-25, GIP, Insulin Secretion, Glucagon Secretion, Gastric Emptying