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

• Published in: Metabolism, clinical and experimental Vol. 48; no. 3; pp. 385 - 389
• Main Authors: Pauly, Robert P., Demuth, Hans-Ulrich, Rosche, Fred, Schmidt, Jörn, White, Heather A., Lynn, Francis, McIntosh, Christopher H.S., Pederson, Raymond A.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-03-1999; Elsevier
• Subjects: Animals; Biological and medical sciences; Colorimetry; Dipeptidyl Peptidase 4 - metabolism; Glucagon - metabolism; Glucagon-Like Peptide 1; Glucose - physiology; Glucose Tolerance Test; Hormones. Endocrine system; Insulin - metabolism; Isoleucine - analogs & derivatives; Isoleucine - pharmacology; Male; Medical sciences; Peptide Fragments - metabolism; Pharmacology. Drug treatments; Protein Precursors - metabolism; Radioimmunoassay; Rats; Rats, Wistar; Serine Proteinase Inhibitors - pharmacology; Thiazoles - pharmacology; Canada; North America; Europe; Germany; America; Dipeptidyl-peptidase IV; Pancreatic hormone; Rat; Enzyme; Treatment efficiency; Rodentia; Enzyme inhibitor; Glucose; Metabolism; Insulin; Glucagon like peptide 1; Endocrine secretion; Peptidases; Vertebrata; Chemotherapy; Mammalia; Treatment; Animal; Hormonal regulation; Hydrolases
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/S0026-0495(99)90090-2

The incretins glucose-dependent insulinotropic polypeptide (GIP
1–42) 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-1
7–36 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-1
7–36 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.