Significance of Vascular Dipeptidyl Peptidase-4 Inhibition on Vascular Protection in Zucker Diabetic Fatty Rats

Saito, Hiroshi; Jin, Denan

doi:10.1254/jphs.14052fp

Cited by 31 publications

(24 citation statements)

References 32 publications

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“…Linagliptin is a potent antioxidant according to its 1-electron-oxidations, tested in the hydrogen peroxide/peroxidase system [36]. Indeed, a short-term reduction of oxidative stress in the diabetic retina by linagliptin was reported recently [37]. The antioxidative properties of linagliptin could also explain the systemic nephroprotective effects of DPP4 inhibitors [38].…”

Section: Discussionmentioning

confidence: 99%

The DPP4 Inhibitor Linagliptin Protects from Experimental Diabetic Retinopathy

et al. 2016

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Background/aimsDipeptidyl peptidase 4 (DPP4) inhibitors improve glycemic control in type 2 diabetes, however, their influence on the retinal neurovascular unit remains unclear.MethodsVasculo- and neuroprotective effects were assessed in experimental diabetic retinopathy and high glucose-cultivated C. elegans, respectively. In STZ-diabetic Wistar rats (diabetes duration of 24 weeks), DPP4 activity (fluorometric assay), GLP-1 (ELISA), methylglyoxal (LC-MS/MS), acellular capillaries and pericytes (quantitative retinal morphometry), SDF-1a and heme oxygenase-1 (ELISA), HMGB-1, Iba1 and Thy1.1 (immunohistochemistry), nuclei in the ganglion cell layer, GFAP (western blot), and IL-1beta, Icam1, Cxcr4, catalase and beta-actin (quantitative RT-PCR) were determined. In C. elegans, neuronal function was determined using worm tracking software.ResultsLinagliptin decreased DPP4 activity by 77% and resulted in an 11.5-fold increase in active GLP-1. Blood glucose and HbA1c were reduced by 13% and 14% and retinal methylglyoxal by 66%. The increase in acellular capillaries was diminished by 70% and linagliptin prevented the loss of pericytes and retinal ganglion cells. The rise in Iba-1 positive microglia was reduced by 73% with linagliptin. In addition, the increase in retinal Il1b expression was decreased by 65%. As a functional correlate, impairment of motility (body bending frequency) was significantly prevented in C. elegans.ConclusionOur data suggest that linagliptin has a protective effect on the microvasculature of the diabetic retina, most likely due to a combination of neuroprotective and antioxidative effects of linagliptin on the neurovascular unit.

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Section: Discussionmentioning

confidence: 99%

The DPP4 Inhibitor Linagliptin Protects from Experimental Diabetic Retinopathy

et al. 2016

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“…In an animal model (obese, hypertensive and insulinresistant mice fed with a western diet), elevated MCP-1 levels were documented, and these were diminished after DPP-4 inhibition [39]. Moreover, in Zucker diabetic fatty rats, vascular expression of the gene encoding MCP-1 was attenuated by the highly tissue-penetrating linagliptin even when compared with sitagliptin [11]. In individuals in whom diabetes was uncontrolled and who had coronary artery disease, additional DPP-4 inhibition was found to improve endothelial function (assessed by reactive hyperaemia peripheral arterial tonometry) and decrease hs-CRP, in contrast to the control group.…”

Section: Discussionmentioning

confidence: 99%

“…Linagliptin is a highly tissue-penetrative DPP-4 inhibitor. In Zucker diabetic fatty rats linagliptin augmented vascular relaxation [11]. In Dahlsensitive hypertensive rats linagliptin was found to improve vascular function and diabetic nephropathy, indicated by reduced albuminuria and renal mRNA levels of intercellular adhesion molecule-1 (ICAM-1), and in a rat model of type 1 diabetes it improved lymphocyte infiltration into the glomeruli [12,13].…”

Section: Introductionmentioning

confidence: 99%

Effects of linagliptin on renal endothelial function in patients with type 2 diabetes: a randomised clinical trial

et al. 2016

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Aims/hypothesis Endothelial dysfunction predicts cardiovascular damage and renal involvement. Animal experiments and human studies indicate an increased nitric oxide (NO) activity and endothelial NO synthase (NOS) expression in the early stage of type 2 diabetes. The aim of the study was to assess the effect of linagliptin on the endothelial function of the renal vasculature. Methods In this randomised, double-blind, parallel-group, investigator-initiated trial, 62 patients with type 2 diabetes were randomly assigned (by computer-generated random code) to receive linagliptin 5 mg (n = 30) or placebo (n = 32) for 4 weeks. The primary objective was to assess endothelial function of the renal vasculature, by constant-infusion inputclearance and urinary albumin/creatinine ratio (UACR), both before and after blockade of NOS withResults Treatment with linagliptin for 4 weeks reduced fasting, postprandial blood glucose and HbA 1c , although not significantly; no change occurred with placebo. Renal plasma flow (RPF) did not change after linagliptin or placebo. After 4 weeks the absolute change in RPF due to L-NMMA was smaller in the linagliptin group than in the placebo group (−46.8 ± 34 vs −65.1 ± 36 ml/min, p = 0.045), indicating a lower basal NO activity after treatment with linagliptin. Consistently, the response of UACR to L-NMMA increased in the placebo group (p = 0.059) but not in the linagliptin group (p = 0.276), pointing to an upregulation of NO activity in the placebo group. No clinically meaningful safety concerns were evident. Conclusions/interpretation Our data suggest that treatment with the dipeptidyl peptidase-4 inhibitor linagliptin for 4 weeks prevented the impairment of renal endothelial function due to hyperglycaemia in type 2 diabetes. Trial registration: ClinicalTrials.gov NCT01835678 Funding: This study was funded by Boehringer Ingelheim.

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“…Interestingly, in retrospective analysis, linagliptin reduced cardiovascular events compared with other glucose-lowering agents [13]. Several experiments have revealed that the vascular-protective effect of linagliptin involves incretin-dependent and -independent mechanisms, such as anti-oxidative stress [14], inhibition of advanced glycation end products (AGE) and the receptor for AGE axis [15], and inhibition of vascular DPP-4 activity [16]. On the other hand, we have previously reported the vascular-protective effects of exendin-4, a GLP-1R agonist, including attenuation of atheroma formation in apoE-deficient mice via inhibition of NFκB activation in macrophages [17], and reduction of neointima formation after vascular injury via 5′ AMP-activated protein kinase activation in VSMCs [18].…”

Section: Introductionmentioning

confidence: 99%

Dipeptidyl peptidase-4 inhibitor linagliptin attenuates neointima formation after vascular injury

Terawaki

Nomiyama

Kawanami

et al. 2014

Cardiovasc Diabetol

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BackgroundRecently, glucagon-like peptide-1 (GLP-1)-based therapy, including dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 receptor agonists, has emerged as one of the most popular anti-diabetic therapies. Furthermore, GLP-1-based therapy has attracted increased attention not only for its glucose-lowering ability, but also for its potential as a tissue-protective therapy. In this study, we investigated the vascular-protective effect of the DPP-4 inhibitor, linagliptin, using vascular smooth muscle cells (VSMCs).MethodsSix-week-old male C57BL/6 mice were divided into control (n =19) and linagliptin (3 mg/kg/day, n =20) treated groups. Endothelial denudation injuries were induced in the femoral artery at 8 weeks of age, followed by evaluation of neointima formation at 12 weeks. To evaluate cell proliferation of rat aortic smooth muscle cells, a bromodeoxyuridine (BrdU) incorporation assay was performed.ResultsLinagliptin treatment reduced vascular injury-induced neointima formation, compared with controls (p <0.05). In these non-diabetic mice, the body weight and blood glucose levels did not change after treatment with linagliptin. Linagliptin caused an approximately 1.5-fold increase in serum active GLP-1 concentration, compared with controls. In addition, the vascular injury-induced increase in the oxidative stress marker, urinary 8-OHdG, was attenuated by linagliptin treatment, though this attenuation was not statistically significant (p =0.064). Moreover, linagliptin did not change the serum stromal cell-derived factor-1α (SDF-1α) or the serum platelet-derived growth factor (PDGF) concentration. However, linagliptin significantly reduced in vitro VSMC proliferation.ConclusionLinagliptin attenuates neointima formation after vascular injury and VSMC proliferation beyond the glucose-lowering effect.

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Significance of Vascular Dipeptidyl Peptidase-4 Inhibition on Vascular Protection in Zucker Diabetic Fatty Rats

Cited by 31 publications

References 32 publications

The DPP4 Inhibitor Linagliptin Protects from Experimental Diabetic Retinopathy

The DPP4 Inhibitor Linagliptin Protects from Experimental Diabetic Retinopathy

Effects of linagliptin on renal endothelial function in patients with type 2 diabetes: a randomised clinical trial

Dipeptidyl peptidase-4 inhibitor linagliptin attenuates neointima formation after vascular injury

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