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

The incretins glucose-dependent insulinotropic polypeptide (GIP(1-42)) and truncated forms of glucagon-like peptide-1 (GLP-1) are hormones released fr om the gut in response to ingested nutrients, which act on the pancreas to potentiate glucose-induced insulin secretion. These hormones are rapidly in activated 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 I-125-labeled peptides showed th at inhibition of DPIV by about 70% prevented the degradation of 90.0% of in jected I-125-GLP-1(7-36) after 5 minutes, while only 13.4% remained unhydro lyzed in rats not treated with the DPIV-inhibiting agent after only 2 minut es. Ile-thiazolidide treatment also increased the circulating half-life of intact GLP-1(7-36) released in response to intraduodenal (ID) glucose las m easured by hi-terminal specific radioimmunoassay [RIA]). In addition, inhib ition of DPIV in vivo resulted in an earlier increase and peak of plasma in sulin 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 inhibiti on resulting in improved glucose tolerance may have therapeutic potential f or the management of type 2 diabetes mellitus. Copyright (C) 1999 by W.B. S aunders Company.