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

• Status: Completed
• Trial end date: 2015-05-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Washington University School of Medicine
• Collaborator: American Diabetes Association
• Treatments: Atropine; Cholinergic Agents; Insulin

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