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Erschienen in:
08.12.2016 | Article
Improved glycaemia in high-fat-fed neprilysin-deficient mice is associated with reduced DPP-4 activity and increased active GLP-1 levels
Erschienen in: Diabetologia | Ausgabe 4/2017
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Aim/hypothesis
Neprilysin, a widely expressed peptidase, is upregulated in metabolically altered states such as obesity and type 2 diabetes. Like dipeptidyl peptidase-4 (DPP-4), neprilysin can degrade and inactivate the insulinotropic peptide glucagon-like peptide-1 (GLP-1). Thus, we investigated whether neprilysin deficiency enhances active GLP-1 levels and improves glycaemia in a mouse model of high fat feeding.
Methods
Nep
+/+ and Nep
−/− mice were fed a 60% fat diet for 16 weeks, after which active GLP-1 and DPP-4 activity levels were measured, as were glucose, insulin and C-peptide levels during an OGTT. Insulin sensitivity was assessed using an insulin tolerance test.
Results
High-fat-fed Nep
−/− mice exhibited elevated active GLP-1 levels (5.8 ± 1.1 vs 3.5 ± 0.8 pmol/l, p < 0.05) in association with improved glucose tolerance, insulin sensitivity and beta cell function compared with high-fat-fed Nep
+/+ mice. In addition, plasma DPP-4 activity was lower in high-fat-fed Nep
−/− mice (7.4 ± 1.0 vs 10.7 ± 1.3 nmol ml−1 min−1, p < 0.05). No difference in insulin:C-peptide ratio was observed between Nep
−/− and Nep
+/+ mice, suggesting that improved glycaemia does not result from changes in insulin clearance.
Conclusions/interpretation
Under conditions of increased dietary fat, an improved glycaemic status in neprilysin-deficient mice is associated with elevated active GLP-1 levels, reduced plasma DPP-4 activity and improved beta cell function. Thus, neprilysin inhibition may be a novel treatment strategy for type 2 diabetes.