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

Diabetologia. 1999 Nov;42(11):1324-31. doi: 10.1007/s001250051445.

Abstract

Aims/hypothesis: 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.

Conclusion/interpretation: 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]

MeSH terms

  • Animals
  • Dipeptidyl Peptidase 4 / drug effects
  • Dipeptidyl Peptidase 4 / metabolism*
  • Glucagon
  • Glucagon-Like Peptide 1
  • Glucagon-Like Peptides
  • Glucose / physiology*
  • Glucose Tolerance Test
  • Male
  • Nitriles / pharmacology*
  • Obesity / enzymology
  • Obesity / physiopathology*
  • Osmolar Concentration
  • Peptide Fragments / metabolism*
  • Pyrrolidines / pharmacology*
  • Rats
  • Rats, Zucker
  • Reference Values

Substances

  • 1-(((2-((5-cyanopyridin-2-yl)amino)ethyl)amino)acetyl)-2-cyano-(S)-pyrrolidine
  • Nitriles
  • Peptide Fragments
  • Pyrrolidines
  • glucagon-like peptide 1 (7-36)amide
  • Glucagon-Like Peptides
  • Glucagon-Like Peptide 1
  • Glucagon
  • Dipeptidyl Peptidase 4
  • Glucose