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Characterization of the cellular and metabolic effects of a novel enzyme-resistant antagonist of glucose-dependent insulinotropic polypeptide.

Abstract：

:A novel N-terminally substituted Pro(3) analogue of glucose-dependent insulinotropic polypeptide (GIP) was synthesized and tested for plasma stability and biological activity both in vitro and in vivo. Native GIP was rapidly degraded by human plasma with only 39 +/- 6% remaining intact after 8 h, whereas (Pro(3))GIP was completely stable even after 24 h. In CHL cells expressing the human GIP receptor, (Pro(3))GIP antagonized the cyclic adenosine monophosphate (cAMP) stimulatory ability of 10(-7) M native GIP, with an IC(50) value of 2.6 microM. In the clonal pancreatic beta cell line BRIN-BD11, (Pro(3))GIP over the concentration range 10(-13) to 10(-8) M dose dependently inhibited GIP-stimulated (10(-7) M) insulin release (1.2- to 1.7-fold; P < 0.05 to P < 0.001). In obese diabetic (ob/ob) mice, intraperitoneal administration of (Pro(3))GIP (25 nmol/kg body wt) countered the ability of native GIP to stimulate plasma insulin (2.4-fold decrease; P < 0.001) and lower the glycemic excursion (1.5-fold decrease; P < 0.001) induced by a glucose load (18 mmol/kg body wt). Collectively these data demonstrate that (Pro(3))GIP is a novel and potent enzyme-resistant GIP receptor antagonist capable of blocking the ability of native GIP to increase cAMP, stimulate insulin secretion, and improve glucose homeostasis in a commonly employed animal model of type 2 diabetes.

journal_name

Biochem Biophys Res Commun

journal_title

Biochemical and biophysical research communications

authors

Gault VA,O'Harte FP,Harriott P,Flatt PR

doi

10.1006/bbrc.2002.6364

subject

Has Abstract

pub_date

2002-02-08 00:00:00

pages

1420-6

issue

5

eissn

0006-291X

issn

1090-2104

pii

S0006291X02963643

journal_volume

290

pub_type

杂志文章

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