Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide.
The hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP)-1 act on the pancreas to potentiate glucose-induced insulin secretion (enteroinsular axis). These hormones (incretins) are rapidly hydrolyzed by the circulating enzyme dipeptidyl peptidase IV (DP IV) into biologically inactive NH2-terminally truncated fragments. This study describes the effect of inhibiting endogenous DP IV with a specific DP IV inhibitor, isoleucine thiazolidide (Ile-thiazolidide), on glucose tolerance and insulin secretion in the obese Zucker rat. In initial studies, the specificity of Ile-thiazolidide as an inhibitor of incretin degradation was determined using matrix-assisted laser desorption/ionization-time of flight mass spectrometry. These results showed that inhibiting DP IV activity with Ile-thiazolidide blocked the formation of NH2-terminally truncated GIP and GLP-1. Oral administration of Ile-thiazolidide resulted in rapid inhibition of circulating DP IV levels by 65% in obese and lean Zucker rats. Suppression of DP IV levels enhanced insulin secretion in both phenotypes with the most dramatic effect occurring in obese animals (150% increase in integrated insulin response vs. 27% increase in lean animals). Ile-thiazolidide treatment improved glucose tolerance in both phenotypes and restored glucose tolerance to near-normal levels in obese animals. This was attributed to the glucose-lowering actions of increasing the circulating half-lives of the endogenously released incretins GIP and, particularly, GLP-1. This study suggests that drug manipulation of plasma incretin activity by inhibiting the enzyme DP IV is a valid therapeutic approach for lowering glucose levels in NIDDM and other disorders involving glucose intolerance.
Pederson
R A
RA
Department of Physiology, University of British Columbia, Vancouver, Canada. pederson@unixg.ubc.ca
White
H A
HA
Schlenzig
D
D
Pauly
R P
RP
McIntosh
C H
CH
Demuth
H U
HU
D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors*; D005260:Female; D005947:Glucose / Q000502:physiology; D018149:Glucose Intolerance / Q000503:physiopathology*; D007328:Insulin / Q000097:blood; D007532:Isoleucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009765:Obesity / Q000097:blood / Q000503:physiopathology; D051381:Rats; D011924:Rats, Zucker / Q000502:physiology*; D012016:Reference Values; D013844:Thiazoles / Q000494:pharmacology*
D001786:Blood Glucose; D007328:Insulin; D013844:Thiazoles; C114061:isoleucyl-thiazolidide; D007532:Isoleucine; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D005947:Glucose