Pre-diabetes Clinical Trial
Official title:
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.
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.
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