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

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: American Diabetes Association Country of Publication: United States NLM ID: 0372763 Publication Model: Print Cited Medium: Print ISSN: 0012-1797 (Print) Linking ISSN: 00121797 NLM ISO Abbreviation: Diabetes Subsets: MEDLINE
    • Publication Information:
      Publication: Alexandria, VA : American Diabetes Association
      Original Publication: [New York, American Diabetes Association]
    • Subject Terms:
      Blood Glucose/*metabolism ; Dipeptidyl Peptidase 4/*metabolism ; Enzyme Inhibitors/*pharmacology ; Gastric Inhibitory Polypeptide/*metabolism ; Insulin/*blood; Anesthesia ; Animals ; Chromatography, High Pressure Liquid ; Ketamine ; Midazolam ; Pyrroles/pharmacology ; Radioimmunoassay ; Swine ; Valine/pharmacology
    • 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.
    • Accession Number:
      0 (Blood Glucose)
      0 (Enzyme Inhibitors)
      0 (Insulin)
      0 (Pyrroles)
      0 (valine-pyrrolidide)
      59392-49-3 (Gastric Inhibitory Polypeptide)
      690G0D6V8H (Ketamine)
      EC 3.4.14.5 (Dipeptidyl Peptidase 4)
      HG18B9YRS7 (Valine)
      R60L0SM5BC (Midazolam)
    • Publication Date:
      Date Created: 20010626 Date Completed: 20010719 Latest Revision: 20190515
    • Publication Date:
      20240829
    • Accession Number:
      10.2337/diabetes.50.7.1588
    • Accession Number:
      11423480