NCT01951729

Brief 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.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
15

participants targeted

Target at below P25 for phase_1

Timeline
Completed

Started Mar 2013

Typical duration for phase_1

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

March 13, 2013

Completed
6 months until next milestone

First Submitted

Initial submission to the registry

September 18, 2013

Completed
9 days until next milestone

First Posted

Study publicly available on registry

September 27, 2013

Completed
1.6 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

May 1, 2015

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

May 1, 2015

Completed
Last Updated

May 25, 2018

Status Verified

May 1, 2018

Enrollment Period

2.1 years

First QC Date

September 18, 2013

Last Update Submit

May 24, 2018

Conditions

Pre-diabetes

Keywords

Blood sugarGIPXenin-25Cholinergic SignalingAtropineInsulinGlucagonPancreatic polypeptide

Outcome Measures

Primary Outcomes (1)

  • Insulin secretion rates during each treatment.

    3 years

Secondary Outcomes (3)

  • Plasma glucose levels during each treatment.

    3 years

  • Plasma glucagon levels during each treatment.

    3 years

  • Plasma pancreatic polypeptide levels during each treatment.

    3 years

Other Outcomes (2)

  • Plasma GIP levels during each treatment

    3 years

  • Plasma xenin-25 levels during each treatment.

    3 years

Study Arms (1)

Pre-diabetes

EXPERIMENTAL

Otherwise healthy individuals exhibiting hemoglobin A1c levels between 6.0% - 7.0%

Drug: ControlDrug: Xenin-25 without atropineDrug: GIP without atropineDrug: Placebo with atropineDrug: Xenin-25 with atropineDrug: GIP with atropineDrug: GIP plus Xenin-25 without atropineDrug: GIP plus Xenin-25 with atropine

Interventions

ControlDRUG

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.

Also known as: No Peptide or Atropine
Pre-diabetes
Xenin-25 without atropineDRUG

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.

Also known as: xenin without atropine
Pre-diabetes
GIP without atropineDRUG

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.

Pre-diabetes
Placebo with atropineDRUG

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.

Also known as: Albumin (no peptide) with atropine
Pre-diabetes
Xenin-25 with atropineDRUG

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.

Also known as: xenin and atropine
Pre-diabetes
GIP with atropineDRUG

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.

Also known as: GIP and atropine
Pre-diabetes
GIP plus Xenin-25 without atropineDRUG

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.

Also known as: GIP plus xenin without atropine
Pre-diabetes
GIP plus Xenin-25 with atropineDRUG

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.

Also known as: GIP plus xenin with atropine
Pre-diabetes

Eligibility Criteria

Age18 Years - 65 Years
Sexall
Healthy VolunteersYes
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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.

You may not qualify if:

  • 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.
  • +1 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

MeSH Terms

Conditions

Glucose IntoleranceInsulin Resistance

Interventions

Atropinexenin 25Albumins

Condition Hierarchy (Ancestors)

HyperglycemiaGlucose Metabolism DisordersMetabolic DiseasesNutritional and Metabolic DiseasesHyperinsulinism

Intervention Hierarchy (Ancestors)

Atropine DerivativesTropanesAzabicyclo CompoundsAza CompoundsOrganic ChemicalsBelladonna AlkaloidsSolanaceous AlkaloidsAlkaloidsHeterocyclic CompoundsBridged Bicyclo Compounds, HeterocyclicHeterocyclic Compounds, Bridged-RingProteinsAmino Acids, Peptides, and Proteins

Study Officials

  • Burton M Wice, PhD

    Washington University School of Medicine

    PRINCIPAL INVESTIGATOR

  • Dominic Reeds, MD

    Washington University School of Medicine

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
interventional
Phase
phase 1
Allocation
NA
Masking
SINGLE
Who Masked
PARTICIPANT
Purpose
BASIC SCIENCE
Intervention Model
SINGLE GROUP
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

September 18, 2013

First Posted

September 27, 2013

Study Start

March 13, 2013

Primary Completion

May 1, 2015

Study Completion

May 1, 2015

Last Updated

May 25, 2018

Record last verified: 2018-05

Locations

US(1)