Improved glucose tolerance in rats treated with the dipeptidyl peptidase IV (CD26) inhibitor Ile-thiazolidide.
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.
Pauly
R P
RP
Department of Physiology, University of British Columbia, Vancouver, Canada.
Demuth
H U
HU
Rosche
F
F
Schmidt
J
J
White
H A
HA
Lynn
F
F
McIntosh
C H
CH
Pederson
R A
RA
D000818:Animals; D003124:Colorimetry; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1; D005947:Glucose / Q000502:physiology*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism; D007532:Isoleucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D015842:Serine Proteinase Inhibitors; D013844:Thiazoles; C114061:isoleucyl-thiazolidide; D007532:Isoleucine; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D018819:Dipeptidyl Peptidase 4; D005947:Glucose