Horm Metab Res 2009; 41(11): 851-853
DOI: 10.1055/s-0029-1225609
Short Communication

© Georg Thieme Verlag KG Stuttgart · New York

Inhibition of Neutral Endopeptidase 24.11 does not Potentiate the Improvement in Glycemic Control Obtained with Dipeptidyl Peptidase-4 Inhibition in Diabetic Goto–Kakizaki Rats

L. Simonsen1 , S. Pilgaard1 , R. D. Carr2 , 3 , A. B. Kanstrup2 , J. J. Holst1 , C. F. Deacon1
  • 1University of Copenhagen, Department of Biomedical Sciences, Panum Institute, Copenhagen, Denmark
  • 2Novo Nordisk A/S, Bagsvaerd, Denmark
  • 3Current Address: Merck, Sharp and Dohme, Glostrup, Denmark
Further Information

Publication History

received 26.02.2009

accepted 02.06.2009

Publication Date:
03 July 2009 (eFirst)

Introduction

The incretin hormone glucagon-like peptide-1 (GLP-1) has a number of effects (reviewed in [1]), which has made it a very attractive basis for the development of new therapies for type 2 diabetes. The effects include actions on the pancreatic islets as well as, for example, beneficial actions on the cardiovascular system [2]. The native peptide is, however, not clinically useful due to its rapid cleavage in vivo by dipeptidyl peptidase-4 (DPP-4) [3], whereby the peptide loses its insulinotropic action. By promoting the beneficial effects of endogenous GLP-1, DPP-4 inhibitors have shown great therapeutic potential [4], and therefore, have been implemented in the treatment of type 2 diabetes. DPP-4 is, however, not the only enzyme involved in the degradation of GLP-1. In vitro studies have shown that several enzymes located in the kidney brush border membrane are able to cleave GLP-1 [5], and although they are probably not all relevant in the in vivo metabolism of GLP-1, studies have indicated that at least neutral endopeptidase 24.11 (NEP) seems to be of importance. NEP is widely distributed [6], and is able to cleave GLP-1 at several sites in the mid-region and the COOH-terminal part of the peptide [7]. Furthermore, a physiological role of NEP in the degradation of GLP-1 has been demonstrated in the anaesthetized pig [8].

In the present study, we have investigated whether addition of a NEP inhibitor would potentiate the effect on glycemic control obtained with a DPP-4 inhibitor during 12 weeks of treatment in diabetic Goto–Kakizaki (GK)-rats. The GK-rat is a lean, polygenic model of type 2 diabetes, with impaired glucose-induced insulin secretion due to a decreased β-cell mass and moderate insulin resistance [9].

References

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Correspondence

C. F. Deacon

Department of Biomedical Sciences

Panum Institute 12.2.23

Blegdamsvej 3

2200 Copenhagen N

Denmark

Phone: +45/3532 7523

Fax: +45/3532 7537

Email: Deacon@mfi.ku.dk