Inhibition of Neutral Endopeptidase 24.11 does not Potentiate the Improvement in Glycemic Control Obtained with Dipeptidyl Peptidase-4 Inhibition in Diabetic Goto–Kakizaki Rats

Simonsen, Lene; Pilgaard, S.; Carr, Richard D.; Kanstrup, Anders; Holst, Jens J.; Deacon, Carolyn F.

doi:10.1055/s-0029-1225609

Cited by 10 publications

(18 citation statements)

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“…glucose challenge were no different from those observed in high-fat fed wild-type control mice or rats. Similarly, as mentioned above, in diabetic Goto–Kakizaki rats, treatment with a neprilysin inhibitor for 12 weeks did not affect oral glucose tolerance [22]. Also, 1-year-old neprilysin-deficient mice with late-onset obesity exhibited impaired oral glucose tolerance [27].…”

Section: Discussionmentioning

confidence: 96%

“…In fact, previous studies showed that when combined with DPP-4 inhibition, short-term pharmacological neprilysin inhibition increased exogenously infused active GLP-1 levels by 40% and its half-life by sixfold [12]. In terms of whether this translates to a glycaemic benefit in the setting of endogenous GLP-1, a separate study showed that co-administration of a neprilysin inhibitor to diabetic Goto–Kakizaki rats for 12 weeks did not potentiate the antihyperglycaemic effects of DPP-4 inhibition alone [22]. Moreover, the study showed that neprilysin inhibition alone conferred no glycaemic benefit.…”

Section: Discussionmentioning

confidence: 99%

“…Data from previous studies may contradict ours because (1) i.p. glucose administration does not stimulate GLP-1 secretion [3, 24, 25, 26]; (2) in some cases, C57BL/6J purchased from The Jackson Laboratory were used as controls for neprilysin-deficient mice (rather than being bred from mice heterozygous for the null allele) [3, 24, 25], or rats were used [22, 26]; (3) pharmacological inhibition may not completely ablate neprilysin activity as is the case with genetic deletion, (4) in 1-year-old neprilysin-deficient mice, glucose tolerance may have been confounded by weight gain due to their increased food intake [27]; and (5) variances in the duration or timing of dietary/inhibitor intervention may result in different outcomes. Reconciling these differences in future work will be critical for developing a better understanding of the role of neprilysin in modulating glucose homeostasis.…”

Section: Discussionmentioning

confidence: 99%

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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

2016

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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.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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

2016

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“…Relative to the basal period, administration of vildagliptin resulted in 86.0±4.0% inhibition of plasma DPP-4 activity in the portal vein, but, taking the dilution of the sample in the assay incubation mixture into account, this is probably equivalent to close to 100% inhibition in vivo [4]. This assumption is supported by the finding that, after DPP-4 inhibition, the concentrations of intact GLP-1 equalled the concentrations measured with the assay for total GLP-1, indicating complete protection of GLP-1 from DPP-4-mediated degradation.…”

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confidence: 96%

Dipeptidyl peptidase-4 inhibition increases portal concentrations of intact glucagon-like peptide-1 (GLP-1) to a greater extent than peripheral concentrations in anaesthetised pigs

2011

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Abbreviations DPP-4 Dipeptidyl peptidase GLP-1 Glucagon-like peptide-1 NC Neuromedin CTo the Editor: The dipeptidyl peptidase (DPP-4) inhibitors widely used for diabetes treatment may be viewed as being surprisingly effective, particularly when compared with the other class of incretin-based therapy, the glucagon-like peptide-1 (GLP-1) analogues (mimetics), because the inhibitors are associated with only modest increases in peripheral intact GLP-1, whereas much higher agonist concentrations can be achieved using the analogues. It has been calculated that only 10-15% of newly secreted GLP-1 reaches the pancreas as the intact hormone via the circulation [1, 2] because of local and hepatic DPP-4-mediated degradation, leading to the suggestion that GLP-1 may act more locally by interacting with afferent neurons within the intestine or portal vein before it is degraded by DPP-4. Thus it could be speculated that local concentrations of intact GLP-1, particularly after administration of DPP-4 inhibitor, may be much higher than peripheral venous concentrations, which could, at least partially, explain the effectiveness of the inhibitors [3]. However, it is at present unknown what the actual concentrations of endogenous GLP-1 are in the various vascular beds and how much intact GLP-1 concentrations in sites such as the portal vein rise following DPP-4 inhibition. We therefore measured the concentrations of GLP-1 in different vascular compartments before and after DPP-4 inhibition with vildagliptin (1 mg/kg) in anaesthetised (α-chloralose) pigs (n=6) given intravenous neuromedin C (NC, 120 nmol), a known stimulus for GLP-1. Blood samples were obtained simultaneously from a carotid artery and the femoral, hepatic and portal veins and analysed for total GLP-1 using the 'side-viewing' antiserum 2135, reacting with a mid-sequence of GLP-1, and intact GLP-1 concentrations by sandwich ELISA. DPP-4 activity was assayed by a fluorescence assay (see electronic supplementary material [ESM] Methods).NC augmented concentrations of total GLP-1 six-to eightfold, both before and after vildagliptin administration (see Fig. 1). Both total and intact GLP-1 concentrations were highest in the portal vein and decreased progressively as the distance from the site of release increased, with lowest concentrations being found in the peripheral venous plasma. Before vildagliptin administration, GLP-1 was extensively degraded by DPP-4 at all sites (incremental AUC for intact arterial GLP-1 before being 79.2±14.8 pmol/l × min, while intact portal GLP-1 after was 460.0±65.5 pmol/l×min), indicating that the peripheral (and therefore pancreatic islet) exposure to intact GLP-1 amounts to only 20% of the splanchnic/portal exposure (see Fig. 1). Similarly, the increase in GLP-1 concentration in peripheral venous plasma during stimulation amounted to only 8% of the increase in the portal concentration.Diabetologia (2011) 54:2206-2208 DOI 10.1007/s00125-011-2168-7 ESMIn contrast, total GLP-1 concentrations were reduced after vildagliptin administration. To...

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“…In contrast to the above-mentioned positive effects of reduced neprilysin activity on glucose homeostasis, some studies on deficiency/pharmacological inhibition of neprilysin have raised some uncertainty with respect to the potential glycaemic effects of neprilysin inhibitors [11,[30][31][32][33][34][35]. Importantly, none of these studies showed detrimental effects on glycaemic status, except one [30].…”

Section: Arguments Against a Beneficial Effect Of Neprilysin Inhibitimentioning

confidence: 99%

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

Esser

Zraika

2019

Diabetologia

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Neprilysin is a widely expressed peptidase with broad substrate specificity that preferentially hydrolyses oligopeptide substrates, many of which regulate the cardiovascular, nervous and immune systems. Emerging evidence suggests that neprilysin also hydrolyses peptides that play an important role in glucose metabolism. In recent studies in humans, a dual angiotensin receptor-neprilysin inhibitor (ARNi) improved glycaemic control and insulin sensitivity in individuals with type 2 diabetes and/or obesity. Moreover, preclinical studies have also reported that neprilysin inhibition, alone or in combination with renin-angiotensin system blockers, elicits beneficial effects on glucose homeostasis. Since neprilysin inhibitors have been approved for the treatment of heart failure, their repurposing for treating type 2 diabetes would provide a novel therapeutic strategy. In this review, we evaluate existing evidence from preclinical and clinical studies in which neprilysin is deleted/inhibited, we highlight potential mechanisms underlying the beneficial glycaemic effects of neprilysin inhibition, and discuss possible deleterious effects that may limit the efficacy and safety of neprilysin inhibitors in the clinic. We also review the favourable impact neprilysin inhibition can have on diabetic complications, in addition to glucose control. Finally, we conclude that neprilysin inhibitors may be a useful therapeutic option for treating type 2 diabetes; however, their combination with angiotensin II receptor blockers is needed to circumvent deleterious consequences of neprilysin inhibition alone.

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Inhibition of Neutral Endopeptidase 24.11 does not Potentiate the Improvement in Glycemic Control Obtained with Dipeptidyl Peptidase-4 Inhibition in Diabetic Goto–Kakizaki Rats

Cited by 10 publications

References 13 publications

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

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

Dipeptidyl peptidase-4 inhibition increases portal concentrations of intact glucagon-like peptide-1 (GLP-1) to a greater extent than peripheral concentrations in anaesthetised pigs

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

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