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 (online)


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].


  • 1 Deacon CF. Diabetes. 2004;  53 2181-2189
  • 2 Nystrom T. Horm Metab Res. 2008;  40 593-606
  • 3 Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ. Diabetes. 1995;  44 1126-1131
  • 4 Dejager S, Razac S, Foley JE, Schweizer A. Horm Metab Res. 2007;  39 218-223
  • 5 Thum A, Hupe-Sodmann K, Goke R, Voigt K, Goke B, McGregor GP. Exp Clin Endocrinol Diabetes. 2002;  110 113-118
  • 6 Gee NS, Bowes MA, Buck P, Kenny AJ. Biochem J. 1985;  228 119-126
  • 7 Hupe-Sodmann K, McGregor GP, Bridenbaugh R, Goke R, Goke B, Thole H, Zimmermann B, Voigt K. Regul Pept. 1995;  58 149-156
  • 8 Plamboeck A, Holst JJ, Carr RD, Deacon CF. Diabetologia. 2005;  48 1882-1890
  • 9 Goto Y, Suzuki K, Ono T, Sasaki M, Toyota T. Adv Exp Med Biol. 1988;  246 29-31
  • 10 Nagakura T, Yasuda N, Yamazaki K, Ikuta H, Tanaka I. Metabolism. 2003;  52 81-86
  • 11 Selmeci L, Szokodi I, Horvat-Karajz K. Clin Chim Acta. 1996;  244 111-116
  • 12 Deacon CF, Wamberg S, Bie P, Hughes TE, Holst JJ. J Endocrinol. 2002;  172 355-362
  • 13 Trebbien R, Klarskov L, Olesen M, Holst JJ, Carr RD, Deacon CF. Am J Physiol Endocrinol Metab. 2004;  287 E431-E438


C. F. Deacon

Department of Biomedical Sciences

Panum Institute 12.2.23

Blegdamsvej 3

2200 Copenhagen N


Phone: +45/3532 7523

Fax: +45/3532 7537

Email: [email protected]