Vasopeptidase Inhibitor Omapatrilat Induces Profound Insulin Sensitization and Increases Myocardial Glucose Uptake in Zucker Fatty Rats

Wang, Chao-Hung; Leung, Nathalie; Lapointe, Nathalie; Szeto, Linda; Uffelman, Kristine D.; Giacca, Adria; Rouleau, Jean L.; Lewis, Gary F.

doi:10.1161/01.cir.0000062646.09566.cc

Cited by 55 publications

(34 citation statements)

References 41 publications

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“…Nevertheless, the possibility cannot be excluded that candoxatril reduced endogenous GIP degradation in vivo, which contributed to the antihyperglycaemic effect, particularly when DPP-IV was simultaneously inhibited. There is also evidence that bradykinin is degraded by NEP [38], and several studies have shown that selective NEP or dual NEP/ACE (vasopeptidase) inhibitors lead to improved insulin sensitivity in obese, insulin-resistant rats [39][40][41][42] via a mechanism involving increased activation of the kinin-nitrous oxide pathway [39,42]. This improvement in whole-body insulin-mediated glucose disposal, effected by NEP inhibition, seemed to be a result of improvements in insulin sensitivity rather than secondary to changes in cardiovascular or renal function, because heart rate, blood pressure, femoral blood flow and GFR were unaltered [40,43].…”

Section: Discussionmentioning

confidence: 99%

Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig

et al. 2005

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Aims/hypothesis: The incretin hormone glucagon-like peptide 1 (GLP-1) has antihyperglycaemic effects, but its therapeutic usefulness is limited by its metabolic instability. Dipeptidyl peptidase IV (DPP-IV) is established as the primary inactivating enzyme, but the roles of other enzymes remain unclear. Methods: The effect of candoxatril, a selective inhibitor of neutral endopeptidase (NEP) 24.11, on GLP-1 pharmacokinetics/pharmacodynamics with or without DPP-IV inhibition was examined in anaesthetised pigs. Results: During GLP-1 infusion, candoxatril doubled C-terminal immunoreactivity, improving the pharmacokinetics (t ½ 2.3±0.1 to 8.

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Section: Discussionmentioning

confidence: 99%

Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig

et al. 2005

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“…We and others have demonstrated that reducing neprilysin activity may be beneficial via improving insulin secretion [4] and sensitivity [5–7]. …”

Section: Introductionmentioning

confidence: 99%

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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“…In another study, Arbin et al [30] observed that mixampril improves whole body insulinmediated disposal more effectively in animals with insulin resistance than in normal rats. The results obtained with mixampril were recently confirmed by a study using, in the same strain of rats, omapatrilat, another dual ACE/NEP inhibitor, and ramipril as ACE inhibitor [31]. All these studies clearly point out a role for kinins in the beneficial effect of ACE inhibitors on insulin sensitivity.…”

Section: Inhibition Of Ace Increase In Insulin Sensitivity and Kininsmentioning

confidence: 68%

“…In some studies, AT1 receptor antagonists have been reported to have no influence on insulin sensitivity [13,21,31,39], while in other works [40,41], these antagonists have been reported to improve glucose tolerance. Chronic administration of AT1 antagonist to insulin-resistant animals increased protein expression of GLUT-4, a glucose transporter, in muscle and myocardium [42].…”

Section: Inhibition Of Ace Increase In Insulin Sensitivity and Kininsmentioning

confidence: 99%

The kallikrein‐kinin system, angiotensin converting enzyme inhibitors and insulin sensitivity

Damas

Garbacki

Lefèbvre

2004

Diabetes Metabolism Res

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The therapeutic use of angiotensin converting enzyme (ACE) inhibitors, at a large scale, in arterial hypertension has showed that these molecules can exert beneficial effects on insulin sensitivity and may reduce the occurrence of type 2 diabetes mellitus. One hypothesis explaining these effects of ACE inhibitors may relate to their capacity to interfere with bradykinin (BK) metabolism and action. BK may participate in the regulation of substrate utilization by several tissues by improving blood flow and substrate delivery to the tissues and also by promoting translocation of glucose transporters. Moreover, BK has been shown to increase phosphorylation of insulin receptor and its cell substrates. BK also appears to improve the release of insulin. Furthermore, insulin may activate the kallikrein-kinin system, which consequently may increase its metabolic effects. However, in experimental diabetes mellitus, BK can participate to the inflammatory reaction leading to Langerhans islets destruction. In diabetes, whereas tissue kallikrein mRNA levels were reduced in several organs, an overexpression of kinin receptors, an increase in plasma levels of kininogens and kallikrein and an activation of the kinin system have all been reported. Lastly, kinins may be involved in the development of diabetic nephropathy. Reduction of kinin metabolism by ACE inhibitors might be involved in the beneficial effects exerted by these compounds in diabetic kidney functions.

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Vasopeptidase Inhibitor Omapatrilat Induces Profound Insulin Sensitization and Increases Myocardial Glucose Uptake in Zucker Fatty Rats

Cited by 55 publications

References 41 publications

Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig

Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig

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

The kallikrein‐kinin system, angiotensin converting enzyme inhibitors and insulin sensitivity

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