| First Author | Willard JR | Year | 2017 |
| Journal | Diabetologia | Volume | 60 |
| Issue | 4 | Pages | 701-708 |
| PubMed ID | 27933334 | Mgi Jnum | J:239956 |
| Mgi Id | MGI:5882133 | Doi | 10.1007/s00125-016-4172-4 |
| Citation | Willard JR, et al. (2017) 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 |
| abstractText | 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. |
