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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01951716
Recruitment Status : Withdrawn
First Posted : September 27, 2013
Last Update Posted : April 26, 2018
Sponsor:
Collaborator:
American Diabetes Association
Information provided by (Responsible Party):
Washington University School of Medicine

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.

Condition or disease Intervention/treatment Phase
Does the Vagus Nerve Mediate the Effects of Xenin-25 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 Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: Effects of Xenin-25 on Insulin Secretion and Gastric Emptying in Humans With and Without a Complete Truncal Vagotomy
Study Start Date : January 2013
Estimated Primary Completion Date : July 2018
Estimated Study Completion Date : July 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Insulin

Arm Intervention/treatment
Experimental: Truncal Vagotomy
Healthy participants without diabetes who have undergone a complete truncal vagotomy
Drug: Graded Glucose Infusion with Placebo

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.

Other Name: GGI with Albumin Alone

Drug: Graded Glucose Infusion with GIP Alone

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.

Other Name: GGI with GIP

Drug: Graded Glucose Infusion with xenin-25 alone

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.

Other Name: GGI with Xenin

Drug: Graded Glucose Infusion with GIP plus xenin-25

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.

Other Name: GGI with GIP plus Xenin

Drug: Meal Tolerance Test with Placebo

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.

Other Name: MTT with Albumin Alone

Drug: Meal Tolerance Test with xenin-25

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.

Other Name: MTT with xenin

Experimental: No Vagotomy
Healthy participants without diabetes who have not had a complete truncal vagotomy
Drug: Graded Glucose Infusion with Placebo

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.

Other Name: GGI with Albumin Alone

Drug: Graded Glucose Infusion with GIP Alone

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.

Other Name: GGI with GIP

Drug: Graded Glucose Infusion with xenin-25 alone

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.

Other Name: GGI with Xenin

Drug: Graded Glucose Infusion with GIP plus xenin-25

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.

Other Name: GGI with GIP plus Xenin

Drug: Meal Tolerance Test with Placebo

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.

Other Name: MTT with Albumin Alone

Drug: Meal Tolerance Test with xenin-25

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.

Other Name: MTT with xenin




Primary Outcome Measures :
  1. Insulin secretion rates will be measured during the GGI and MTTs [ Time Frame: 3 years ]

Secondary Outcome Measures :
  1. Plasma acetaminophen levels will be measured during MTTs [ Time Frame: 3 years ]

Other Outcome Measures:
  1. Plasma glucose levels will be measured during the GGIs and MTTs. [ Time Frame: 3 years ]
  2. Plasma glucagon levels will be measured during the GGIs and MTTs. [ Time Frame: 3 years ]
  3. Plasma insulin levels will be measured during the GGIs and MTTs. [ Time Frame: 3 years ]
  4. Plasma C-peptide levels will be measured during the GGIs and MTTs. [ Time Frame: 3 years ]
  5. Plasma pancreatic polypeptide levels will be measured during the GGIs and MTTs. [ Time Frame: 3 years ]
  6. Plasma GIP levels will be measured during the GGIs and MTTs. [ Time Frame: 3 years ]
  7. Plasma xenin-25 levels will be measured during the GGIs and MTTs. [ Time Frame: 3 years ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01951716


Locations
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United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
American Diabetes Association
Investigators
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Principal Investigator: Burton M Wice, PhD Washington University School of Medicine
Principal Investigator: Dominic Reeds, MD Washington University School of Medicine

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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT01951716    
Other Study ID Numbers: 08-0861 D
First Posted: September 27, 2013    Key Record Dates
Last Update Posted: April 26, 2018
Last Verified: April 2018
Keywords provided by Washington University School of Medicine:
Vagotomy
Vagus Nerve
Xenin-25
GIP
Insulin Secretion
Glucagon Secretion
Gastric Emptying
Additional relevant MeSH terms:
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Insulin
Hypoglycemic Agents
Physiological Effects of Drugs