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DOI: 10.1055/s-0029-1225609
© 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
Publication History
received 26.02.2009
accepted 02.06.2009
Publication Date:
03 July 2009 (online)
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
-
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
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