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Dipeptidyl peptidase IV inhibition reduces the degradation and clearance of GIP and potentiates its insulinotropic and antihyperglycemic effects in anesthetized pigs.

Abstract：

:Glucose-dependent insulinotropic peptide (GIP) is known to be degraded by dipeptidyl peptidase IV (DPP IV), forming an inactive metabolite, but the extent of the enzyme's role in regulating the biological activity of GIP in vivo is still largely unknown. In nonfasted anesthetized pigs given an intravenous infusion of GIP, the intact peptide (determined by a novel NH(2)-terminally directed radioimmunoassay) accounts for only 14.5 +/- 2.5% of total immunoreactivity. This is increased (to 40.9 +/- 0.9%, P < 0.0001) by coadministration of valine-pyrrolidide (a specific DPP IV inhibitor) at a dose that completely inhibits plasma DPP IV activity. The plasma t(1/2) of intact GIP is prolonged by the inhibitor (from 3.3 +/- 0.3 to 8.1 +/- 0.6 min; P < 0.001), whereas the t(1/2) for COOH-terminal immunoreactivity is unaffected (13.2 +/- 0.5 and 11.5 +/- 0.8 min, pre- and postinhibitor). Measurement of arteriovenous concentration differences revealed that the liver, kidney, and extremities are the main sites of removal of exogenous intact GIP (organ extractions, 28.0 +/- 2.2, 26.3 +/- 5.7, and 21.8 +/- 3.0%, respectively). These organ extractions are reduced (P < 0.02) but not eliminated (kidney and extremities) by valine-pyrrolidide (to 6.5 +/- 4.6, 14.1 +/- 3.1, and 13.9 +/- 2.4%, respectively). Valine-pyrrolidide potentiates the insulinotropic effect of GIP (P < 0.02), resulting in an enhanced glucose disappearance rate (k, from 8.0 +/- 0.5 to 15.5 +/- 2.2%/min; P < 0.01) and a reduction in the glucose excursion after an intravenous glucose load (area under the curve, from 133 +/- 23 to 75 +/- 9 min. mmol/l; P < 0.05). These results suggest that DPP IV plays an important role in GIP metabolism but is not the sole enzyme responsible for its NH(2)-terminal degradation. Nevertheless, DPP IV inhibition increases the proportion of intact peptide sufficiently to enhance its insulinotropic and antihyperglycemic effects.

journal_name

Diabetes

journal_title

Diabetes

authors

Deacon CF,Danielsen P,Klarskov L,Olesen M,Holst JJ

doi

10.2337/diabetes.50.7.1588

subject

Has Abstract

pub_date

2001-07-01 00:00:00

pages

1588-97

issue

eissn

0012-1797

issn

1939-327X

journal_volume

pub_type

杂志文章

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Dipeptidyl peptidase IV inhibition reduces the degradation and clearance of GIP and potentiates its insulinotropic and antihyperglycemic effects in anesthetized pigs.