title: Improved glycaemia in high-fat-fed neprilysin-deficient mice is associated with reduced DPP-4 activity and increased active GLP-1 levels.
abstract: 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.
  
  
  
  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.
  
  
  
  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-1min-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.
  
  
  
  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.
authors.affiliation: Veterans Affairs Puget Sound Health Care System, 1660 South Columbian Way (151), Seattle, WA, 98108, USA.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Willard
authors.affiliation: Veterans Affairs Puget Sound Health Care System, 1660 South Columbian Way (151), Seattle, WA, 98108, USA.
authors.forename: Breanne M
authors.initials: BM
authors.lastname: Barrow
authors.affiliation: Veterans Affairs Puget Sound Health Care System, 1660 South Columbian Way (151), Seattle, WA, 98108, USA. zraikas@uw.edu.|Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, WA, USA. zraikas@uw.edu.
authors.forename: Sakeneh
authors.initials: S
authors.lastname: Zraika
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002096:C-Peptide / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D015260:Neprilysin / Q000172:deficiency* / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D018819:Dipeptidyl Peptidase 4; D015260:Neprilysin; D005947:Glucose
keywords: DPP-4; GLP-1; Glucose tolerance; High fat diet; Insulin secretion; Mme; Mouse; Nep; Neprilysin