Improved glycaemia in high-fat-fed neprilysin-deficient mice is associated with reduced DPP-4 activity and increased active GLP-1 levels.
Diabetologia
; 60(4): 701-708, 2017 04.
Article
en En
| MEDLINE
| ID: mdl-27933334
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-1 min-1, p < 0.05). No difference in insulinC-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.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Glucemia
/
Neprilisina
/
Dipeptidil Peptidasa 4
/
Péptido 1 Similar al Glucagón
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Animals
Idioma:
En
Revista:
Diabetologia
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos