Improved glucose tolerance in rats treated with the dipeptidyl peptidase IV (CD26) inhibitor Ile-thiazolidide

Metabolism. 1999 Mar;48(3):385-9. doi: 10.1016/s0026-0495(99)90090-2.


The incretins glucose-dependent insulinotropic polypeptide (GIP1-42) and truncated forms of glucagon-like peptide-1 (GLP-1) are hormones released from the gut in response to ingested nutrients, which act on the pancreas to potentiate glucose-induced insulin secretion. These hormones are rapidly inactivated by the circulating enzyme dipeptidyl peptidase IV ([DPIV] CD26). This study describes the effect on glucose tolerance and insulin secretion of inhibiting endogenous DPIV in the rat using Ile-thiazolidide, a specific DPIV inhibitor. High-performance liquid chromatography (HPLC) analysis of plasma following in vivo administration of 125I-labeled peptides showed that inhibition of DPIV by about 70% prevented the degradation of 90.0% of injected 125I-GLP-17-36 after 5 minutes, while only 13.4% remained unhydrolyzed in rats not treated with the DPIV-inhibiting agent after only 2 minutes. Ile-thiazolidide treatment also increased the circulating half-life of intact GLP-17-36 released in response to intraduodenal (ID) glucose (as measured by N-terminal specific radioimmunoassay [RIA]). In addition, inhibition of DPIV in vivo resulted in an earlier increase and peak of plasma insulin and a more rapid clearance of blood glucose in response to ID glucose challenge. When considered with the HPLC data, these results suggest that the altered insulin profile is an incretin-mediated response. DPIV inhibition resulting in improved glucose tolerance may have therapeutic potential for the management of type 2 diabetes mellitus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colorimetry
  • Dipeptidyl Peptidase 4 / metabolism*
  • Glucagon / metabolism
  • Glucagon-Like Peptide 1
  • Glucose / physiology*
  • Glucose Tolerance Test
  • Insulin / metabolism
  • Isoleucine / analogs & derivatives*
  • Isoleucine / pharmacology
  • Male
  • Peptide Fragments / metabolism
  • Protein Precursors / metabolism
  • Radioimmunoassay
  • Rats
  • Rats, Wistar
  • Serine Proteinase Inhibitors / pharmacology*
  • Thiazoles / pharmacology*


  • Insulin
  • Peptide Fragments
  • Protein Precursors
  • Serine Proteinase Inhibitors
  • Thiazoles
  • isoleucyl-thiazolidide
  • Isoleucine
  • Glucagon-Like Peptide 1
  • Glucagon
  • Dipeptidyl Peptidase 4
  • Glucose