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The Role of Cholinergic Signaling for Mediating the Effects of GIP and/or Xenin-25 on Insulin Secretion

Information source: Washington University School of Medicine
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Pre-diabetes

Intervention: Control (Drug); Xenin-25 without atropine (Drug); GIP without atropine (Drug); Placebo with atropine (Drug); Xenin-25 with atropine (Drug); GIP with atropine (Drug); GIP plus Xenin-25 without atropine (Drug); GIP plus Xenin-25 with atropine (Drug)

Phase: Phase 1

Status: Active, not recruiting

Sponsored by: Washington University School of Medicine

Official(s) and/or principal investigator(s):
Burton M Wice, PhD, Principal Investigator, Affiliation: Washington University School of Medicine
Dominic Reeds, MD, Principal Investigator, Affiliation: Washington University School of Medicine

Summary

Glucose-dependent insulinotropic polypeptide (GIP) is a hormone produced in the intestine. It is released immediately after meal ingestion and increases insulin release. This, in turn, helps reduce blood glucose levels. This circuit does not work properly in humans with type 2 diabetes mellitus (T2DM). We have previously shown that a peptide called xenin-25 can amplify the effects of GIP on insulin secretion in humans. However, xenin-25 no longer does this when humans develop T2DM. Thus, it is important to understand how xenin-25 works in humans without T2DM so we know why it does not work in humans with T2DM. Acetylcholine is molecule produced by specific types of nerves. The effects of acetylcholine can be blocked by a drug called atropine. We have previously shown in mice that atropine prevents the ability of xenin-25 to increase the effects of GIP on insulin release. The purpose of this clinical trial is to determine if atropine also blocks the effects of xenin-25 in humans without T2DM. If it does, then impaired acetylcholine signaling may be one of the reasons humans develop T2DM and it could be possible to develop drugs that bypass this defect and increase insulin release in humans with T2DM.

Clinical Details

Official title: The Effects of GIP and/or Xenin-25, With and Without Atropine, on Insulin Secretion in Humans With Pre-diabetes

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Single Blind (Subject), Primary Purpose: Basic Science

Primary outcome: Insulin secretion rates during each treatment.

Secondary outcome:

Plasma glucose levels during each treatment.

Plasma glucagon levels during each treatment.

Plasma pancreatic polypeptide levels during each treatment.

Detailed description: Glucose-dependent insulinotropic polypeptide (GIP) is a hormone produced in the intestine. It is released immediately after meal ingestion and increases insulin release. This, in turn, helps reduce blood glucose levels. This circuit does not work properly in humans with type 2 diabetes mellitus (T2DM). We have previously shown that a peptide called xenin-25 can amplify the effects of GIP on insulin secretion in humans. However, xenin-25 no longer does this when humans develop T2DM. Thus, it is important to understand how xenin-25 works in humans without T2DM so we know why it does not work in humans with T2DM. Acetylcholine is molecule produced by specific types of nerves. The effects of acetylcholine can be blocked by a drug called atropine. We have previously shown in mice that atropine prevents the ability of xenin-25 to increase the effects of GIP on insulin release. The purpose of this clinical trial is to determine if atropine also blocks the effects of xenin-25 in humans without T2DM. If it does, then impaired acetylcholine signaling may be one of the reasons humans develop T2DM and it may be possible to develop drugs that bypass this defect and increase insulin release in humans with T2DM. To conduct this study, we will enroll humans with pre-diabetes since they respond very well to xenin-25. Potential subjects will first be checked to see if they do have pre-diabetes and also to verify that they can safely participate in the study. Once enrolled, subjects will come for 8 different visits, each separated by about 3 weeks. On each visit, 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 an infusion GIP alone, xenin-25 alone, GIP plus xenin-25, or placebo. Each of these 4 infusions will be conducted with and without an infusion of atropine (thus- the 8 visits). Blood glucose and insulin levels, as well as a host of other hormones, will be measured during each of the study visits. A comparison of the results will tell us if the effects of xenin-25 on insulin release are mediated by acetylcholine in humans.

Eligibility

Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Individuals must be able to consent for their own participation (no mental impairment

affecting cognition or willingness to follow study instructions).

- Otherwise healthy volunteers that have borderline diabetes or impaired glucose

tolerance.

- Women of childbearing potential must be currently taking/using an acceptable method

of birth control. 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:

- Lacks cognitive ability to sign the consent or follow the study directions.

- Women unwilling to use 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, hypercalcemia and/or the presence of gallstones.

- Volunteers with a history of gastrointestinal disorders, particularly related to

gastric motility/emptying such as gastric bypass

- Subjects taking medications known to affect glucose tolerance.

- Anemia

- Significant systemic illness including heart, kidney, inflammatory, liver, or

malignant disease requiring medications.

- Narrow-angle glaucoma

- Obstructive uropathy including benign prostatic hypertrophy, pyloric stenosis,

myasthenia gravis

- Asthma

- hyperthyroidism

- angina and cardiac arrhythmias including heart block

- Subjects unwilling to allow the use of human albumin in the preparation of the

peptides.

- Unwillingness to allow blood glucose level adjustment (if needed) with IV insulin

Locations and Contacts

Washington University School of Medicine, St. Louis, Missouri 63110, United States
Additional Information

Starting date: March 2013
Last updated: May 26, 2015

Page last updated: August 23, 2015

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