The Role of Cholinergic Signaling for Mediating the Effects of GIP and/or Xenin-25 on Insulin Secretion
Condition: Pre-diabetes
MeSH terms: Prediabetic State; Glucose Intolerance
Study type: Interventional
Phase: Phase 1

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.
    

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.
    

Intervention name(s): Control; Xenin-25 without atropine; GIP without atropine; Placebo with atropine; Xenin-25 with atropine; GIP with atropine; GIP plus Xenin-25 without atropine; GIP plus Xenin-25 with atropine
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): 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.; 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.; 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.; 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.; 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.; 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.; 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.; 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 intervention name(s): No Peptide or Atropine; xenin without atropine; Albumin (no peptide) with atropine; xenin and atropine; GIP and atropine; GIP plus xenin without atropine; GIP plus xenin with atropine
Intervention MeSH terms: Atropine
Intervention model: Single Group Assignment
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: Blood sugar; GIP; Xenin-25; Cholinergic Signaling; Atropine; Insulin; Glucagon; Pancreatic polypeptide