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

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 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.

Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial

“…28 In high-fat-fed neprilysin deficient mice, improved glycaemic status was associated with elevated active GLP-1 concentrations, reduced plasma dipeptidyl peptidase 4 (DPP-4) activity and improved beta cell function, suggesting beneficial metabolic effects of neprilysin inhibition. 29 Inhibition of the renin-angiotensin system has also improved glycaemic control, 30,31 and angiotensin II promotes insulin resistance, while angiotensin-1-receptor blockade modestly improves insulin sensitivity. 32 Nevertheless, the improvement of glucose metabolism by renin-angiotensin system inhibition alone is most likely to be modest.…”

Neprilysin inhibition: a new therapeutic option for type 2 diabetes?

“…Also, islets from neprilysin-deficient mice were protected against palmitate-induced insulin secretory dysfunction in vitro [24]. In vivo, we have shown that high-fat-fed neprilysin-deficient mice display improvements in insulin sensitivity, beta cell function and glucose tolerance, as well as beta cell mass expansion [12,25]. Furthermore, acute inhibition of neprilysin with subcutaneous or intravenous administration of a pharmacological inhibitor increased insulin secretion and sensitivity in a time-and/or dose-dependent manner in pigs, as well as in lean or obese insulin-resistant rats [3,[18][19][20] (Table 1).…”

“…Potential mechanisms by which neprilysin inhibition improves glucose homeostasis Neprilysin is known to degrade multiple peptides that have glucoregulatory properties (see text box). Some studies support a glucose-lowering effect of neprilysin inhibition via increased plasma levels of these substrates, including GLP-1 [3,12,17,22], bradykinin [18,26] and natriuretic peptides, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) [27].…”

“…Some of its substrates, such as the incretin glucagon-like peptide-1 (GLP-1) [2,3], natriuretic peptides [4,5] and bradykinin [5,6], are known to modulate glucose metabolism [7][8][9][10]. Neprilysin activity is increased in plasma and metabolic tissues of mice with diet-induced obesity, and its levels correlate with decreased insulin sensitivity and reduced beta cell function [11,12]. In humans, the data are less clear.…”

Τhe role of sacubitril/valsartan therapy on renal function and glucose metabolism in chronic heart failure patients

“…However, the underlying pathophysiologic mechanisms are not yet clear and may be attributed to changes in the production and concentrations of various metabolically active peptides by neprilysin inhibition (i.e. atrial natriuretic peptide, BNP, bradykinin, glucagon like peptide) necessitated further investigation [37][38][39][40][41][42]. In the whole PARADIGH-HF trial the risk ratio for the primary outcome, in participants with diabetes, was 0.84 (95% CI 0.74-0.95), very similar to the overall treatment effect for the entire cohort (HR 0.80, 95% CI 0.73-0.87).…”