To Define the Role of GLP-1 for Improving Glucose Homeostasis in Humans Following Gastric Bypass Surgery

There is a marked and long-lasting improvement in glucose homeostasis that follows Roux-en-y gastric bypass surgery (RYGB) in humans. This improvement has been attributed in large part to an intestinal hormone, called GLP-1, that is released into the circulation immediately after eating. The purpose of this study is to determine if GLP-1 mediates the beneficial effects of RYGB surgery on glucose homeostasis in humans.

Study Overview

• Status: Completed
• Conditions: Roux-en-Y Gastric Bypass; Bariatric Surgery; Vertical Sleeve Gastrectomy; Gastric Banding; Bypass, Gastric
• Intervention / Treatment: Drug: Placebo; Drug: Lo-Xenin; Drug: Hi-Xenin; Drug: Extra Hi-Xenin

Detailed Description

To conduct this study, we will enroll humans who previously underwent Roux-en-Y gastric bypass surgery, who are medically and weight stable and with no signs of type 2 diabetes either before or after surgery. Potential subjects will first be screened for eligibility and also to verify that they can safely participate in the study. Each study subject will be administered a meal tolerance test (MTT) on 3 separate occasions. For the MTT, a liquid meal (Boost Plus) will be ingested following an overnight fast. A primed-continuous infusion of vehicle alone (human albumin) or xenin-25 alone (at a dose of 4 or 12 pmoles x kg-1 x min-1) will be initiated 15 minutes before the meal is ingested. Blood samples will be collected before and during the MTT for the measurement of glucose and insulin levels, as well as a host of other hormones. A comparison of the results will tell us if the effects of xenin-25 on insulin release are mediated by GLP-1 in humans.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Individuals must be able to consent for their own participation (no mental impairment affecting cognition or willingness to follow study instructions).
• Healthy, weight stable, with previous Roux-en-Y gastric bypass surgery and no clinical evidence of type 2 diabetes either before and after Roux-en-Y gastric bypass surgery.
• 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 return have 8-10ml of blood drawn 25-30 days after the last Xenin infusion; to check for Xenin peptide antibodies that MAY develop. (All efforts will be made to complete this visit during study participation.)

Exclusion Criteria:

• 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 a history of Acute Pancreatitis.
• Volunteers with a history of cancer (except for skin cancer).
• 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.
• Subjects taking medications known to affect glucose tolerance.
• Hematocrit from the lab is below 33% (or if the finger stick hemoglobin measured with the HemoCue 201+ is <11.2 g/dl).
• Any major medical conditions, or conditions that in the opinion of the PI make the subject unsuitable for the study.
• Subjects with abnormal kidney function as measured by the Creatinine concentration will be excluded.
• Subjects with a history of active liver disease or AST/ALT levels >2X upper limit of normal will also be excluded.
• Total Bilirubin levels should be <2.
• Subjects unwilling to allow the use of their own blood or albumin in the preparation of the peptides. (The blood will prevent sticking of the peptide to the tubing; an alternative method has been sought but not found.)
• Unwillingness to return have 8-10ml of blood drawn 25-30 days after the last Xenin infusion; to check for Xenin peptide antibodies that MAY develop. (All efforts will be made to complete this visit during study participation.)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Post RYGB Surgery; Healthy, weight stable individuals, with previous Roux-en-Y gastric bypass surgery. No clinical evidence of type 2 diabetes before and after surgery. Each participant will receive placebo or the indicated doses of xenin-25.

Drug: Placebo; A liquid mixed meal containing 1.5 grams of acetaminophen will be ingested in 7 equal portions from 0-30 minutes. Starting at minus 15 minutes, an intravenous infusion of albumin alone (placebo) will be administered for 5.25 hours.; Other Names: Control; Albumin Alone; Drug: Lo-Xenin; A liquid mixed meal containing 1.5 grams of acetaminophen will be ingested in 7 equal portions from 0-30 minutes. Starting at minus 15 minutes, an intravenous infusion of xenin-25 at a dose of 4 pmoles/kg/min will be administered for 5.25 hours.; Other Names: Lo-Xen; Drug: Hi-Xenin; A liquid mixed meal containing 1.5 grams of acetaminophen will be ingested in 7 equal portions from 0-30 minutes. Starting at minus 15 minutes, an intravenous infusion of xenin-25 at a dose of 12 pmoles/kg/min will be administered for 5.25 hours.; Other Names: Hi-Xen; Drug: Extra Hi-Xenin; A liquid mixed meal containing 1.5 grams of acetaminophen will be ingested in 7 equal portions from 0-30 minutes. Starting at minus 15 minutes, an intravenous infusion of xenin-25 at a dose of 24 pmoles/kg/min will be administered for 5.25 hours.; Other Names: XHi-Xen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin secretion rates (ISRs) during each treatment	ISRs will be measured at various times before and after ingestion of a liquid mixed meal.	5.5 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma glucose levels during each treatment.	Plasma glucose levels will be measured at various times before and after ingestion of a liquid mixed meal.	5.5 hours
Plasma glucagon levels during each treatment.	Plasma glucagon levels will be measured at various times before and after ingestion of a liquid mixed meal.	5.5 hours
Plasma GLP-1 during each treatment.	Plasma GLP-1 levels will be measured at various times before and after ingestion of a liquid mixed meal.	5.5 hours
Plasma C-peptide levels during each treatment.	Plasma C-peptide levels will be measured at various times before and after ingestion of a liquid mixed meal.	5.5 hours
The rate of gastric emptying during each treatment.	The rate of gastric emptying will be estimated after ingestion of a liquid mixed meal.	5.5 hours

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Publications and helpful links

General Publications

• Sterl K, Wang S, Oestricker L, Wallendorf MJ, Patterson BW, Reeds DN, Wice BM. Metabolic responses to xenin-25 are altered in humans with Roux-en-Y gastric bypass surgery. Peptides. 2016 Aug;82:76-84. doi: 10.1016/j.peptides.2016.06.001. Epub 2016 Jun 7.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2014
• Primary Completion (Actual): November 17, 2015
• Study Completion (Actual): November 17, 2015

Study Registration Dates

• First Submitted: July 28, 2014
• First Submitted That Met QC Criteria: July 28, 2014
• First Posted (Estimate): July 30, 2014

Study Record Updates

• Last Update Posted (Actual): April 27, 2018
• Last Update Submitted That Met QC Criteria: April 25, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: GLP-1; Glucose Homeostasis; Insulin Secretion; Gastric Bypass; RYGB; Xenin; Vertical Sleeve; Lap Band
• Other Study ID Numbers: 08-0861F; R01DK088126 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO