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

May 24, 2018 updated by: Washington University School of Medicine

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

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.

Study Overview

Status

Completed

Conditions

Pre-diabetes

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

Phase

Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Yes

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).
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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Primary Purpose: BASIC_SCIENCE
Allocation: NA
Interventional Model: SINGLE_GROUP
Masking: SINGLE

Number of Arms

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Pre-diabetes Otherwise healthy individuals exhibiting hemoglobin A1c levels between 6.0% - 7.0%	Drug: Control Starting at 0 minutes, glucose infusion rates will be increased to 1, 2, 3, 4, 6, and 8 mg/kg/min every 40 minutes. The study is finished at 240 minutes. Starting at 0 minutes, an intravenous infusion of saline containing 1% human albumin will continue for 240 minutes. Other Names: No Peptide or Atropine Drug: Xenin-25 without atropine Starting at 0 minutes, glucose infusion rates will be increased to 1, 2, 3, 4, 6, and 8 mg/kg/min every 40 minutes. The study is finished at 240 minutes. Following a priming dose from 0-10 minutes, xenin-25 (in saline containing 1% human albumin) will be administered at a constant dose of 4 pmoles/kg/min until 240 minutes. Other Names: xenin without atropine Drug: GIP without atropine Starting at 0 minutes, glucose infusion rates will be increased to 1, 2, 3, 4, 6, and 8 mg/kg/min every 40 minutes. The study is finished at 240 minutes. Following a priming dose from 0-10 minutes, GIP (in saline containing 1% human albumin) will be administered at a dose of 4 pmoles/kg/min until 240 minutes. Drug: Placebo with atropine Starting at 0 minutes, glucose infusion rates will be increased to 1, 2, 3, 4, 6, and 8 mg/kg/min every 40 minutes. The study is finished at 240 minutes. Following a priming dose from -30 to -28 minutes, atropine will be administered at a constant dose of 0.3 mg/m2/hour until 240 minutes. Other Names: Albumin (no peptide) with atropine Drug: Xenin-25 with atropine Starting at 0 minutes, glucose infusion rates will be increased to 1, 2, 3, 4, 6, and 8 mg/kg/min every 40 minutes. The study is finished at 240 minutes. Following a priming dose from 0-10 minutes, xenin-25 (in saline containing 1% human albumin) will be administered at a dose of 4 pmoles/kg/min until 240 minutes. Following a priming dose from -30 to -28 minutes, atropine will be administered at a constant dose of 0.3 mg/m2/hour until 240 minutes. Other Names: xenin and atropine Drug: GIP with atropine Starting at 0 minutes, glucose infusion rates will be increased to 1, 2, 3, 4, 6, and 8 mg/kg/min every 40 minutes. The study is finished at 240 minutes. Following a priming dose from 0-10 minutes, GIP (iin saline containing 1% human albumin) will be administered at a dose of 4 pmoles/kg/min until 240 minutes. Following a priming dose from -30 to -28 minutes, atropine will be administered at a constant dose of 0.3 mg/m2/hour until 240 minutes. Other Names: GIP and atropine Drug: GIP plus Xenin-25 without atropine Starting at 0 minutes, glucose infusion rates will be increased to 1, 2, 3, 4, 6, and 8 mg/kg/min every 40 minutes. The study is finished at 240 minutes. Following a priming dose from 0-10 minutes, GIP and xenin-25 will each be administered at a dose of 4 pmoles/kg/min until 240 minutes. Other Names: GIP plus xenin without atropine Drug: GIP plus Xenin-25 with atropine Starting at 0 minutes, glucose infusion rates will be increased to 1, 2, 3, 4, 6, and 8 mg/kg/min every 40 minutes. The study is finished at 240 minutes. Following a priming dose from 0-10 minutes, GIP and xenin-25 will each be administered at a dose of 4 pmoles/kg/min until 240 minutes. Following a priming dose from -30 to -28 minutes, atropine will be administered at a constant dose of 0.3 mg/m2/hour until 240 minutes. Other Names: GIP plus xenin with atropine

Participant Group / Arm