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

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].

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