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Improved glycaemia in high-fat-fed neprilysin-deficient mice is associated with reduced DPP-4 activity and increased active GLP-1 levels.

Citation
Willard, J. R., et al. “Improved Glycaemia In High-Fat-Fed Neprilysin-Deficient Mice Is Associated With Reduced Dpp-4 Activity And Increased Active Glp-1 Levels.”. Diabetologia, pp. 701-708.
Center University of Washington
Author Joshua R Willard, Breanne M Barrow, Sakeneh Zraika
Keywords DPP-4, GLP-1, glucose tolerance, high fat diet, insulin secretion, Mme, mouse, Nep, Neprilysin
Abstract

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 min, 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.

Year of Publication
2017
Journal
Diabetologia
Volume
60
Issue
4
Number of Pages
701-708
Date Published
12/2017
ISSN Number
1432-0428
DOI
10.1007/s00125-016-4172-4
Alternate Journal
Diabetologia
PMID
27933334
PMCID
PMC5342915
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