Inhibition of dipeptidyl peptidase IV with NVP-DPP728 increases plasma GLP-1 (7-36 amide) concentrations and improves oral glucose tolerance in obese Zucker rats.
OBJECTIVE
The potent incretin hormone glucagon-like peptide 1 (GLP-1) plays a pivotal role in prandial insulin secretion. In the circulation GLP-1 (7-36) amide is, however, rapidly (t(1/2):1-2 min) inactivated by the protease dipeptidyl peptidase IV (DPP-IV). We therefore investigated whether DPP-IV inhibition is a feasible approach to improve glucose homeostasis in insulin resistant, glucose intolerant fatty Zucker rats, a model of mild Type II (non-insulin-dependent) diabetes mellitus.


METHODS
An oral glucose tolerance test was done in lean and obese male Zucker rats while plasma DPP-IV was inhibited by the specific and selective inhibitor NVP-DPP728 given orally.


RESULTS
Inhibition of DPP-IV resulted in a significantly amplified early phase of the insulin response to an oral glucose load in obese fa/fa rats and restoration of glucose excursions to normal. In contrast, DPP-IV inhibition produced only minor effects in lean FA/? rats. Inactivation of GLP-1 (7-36) amide was completely prevented by DPP-IV inhibition suggesting that the effects of this compound on oral glucose tolerance are mediated by increased circulating concentrations of GLP-1 (7-36) amide. Reduced gastric emptying, as monitored by paracetamol appearance in the circulation after an oral bolus, did not appear to have contributed to the reduced glucose excursion.


CONCLUSIONS
It is concluded that NVP-DPP728 inhibits DPP-IV and improves insulin secretion and glucose tolerance, probably through augmentation of the effects of endogenous GLP-1. The improvement observed in prandial glucose homeostasis during DPP-IV inhibition suggests that inhibition of this enzyme is a promising treatment for Type II diabetes. [Diabetologia (1999) 42: 1324-1331]
Balkan
B
B
Novartis Institute for Biomedical Research, Summit, New Jersey 07901, USA.
Kwasnik
L
L
Miserendino
R
R
Holst
J J
JJ
Li
X
X
D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects / Q000378:metabolism*; D005934:Glucagon; D052216:Glucagon-Like Peptide 1; D004763:Glucagon-Like Peptides; D005947:Glucose / Q000502:physiology*; D005951:Glucose Tolerance Test; D008297:Male; D009570:Nitriles / Q000494:pharmacology*; D009765:Obesity / Q000201:enzymology / Q000503:physiopathology*; D009994:Osmolar Concentration; D010446:Peptide Fragments / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D012016:Reference Values
C121834:1-(((2-((5-cyanopyridin-2-yl)amino)ethyl)amino)acetyl)-2-cyano-(S)-pyrrolidine; D009570:Nitriles; D010446:Peptide Fragments; D011759:Pyrrolidines; C055453:glucagon-like peptide 1 (7-36)amide; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D018819:Dipeptidyl Peptidase 4; D005947:Glucose