Dipeptidyl peptidase-IV inhibition prevents blood–retinal barrier breakdown, inflammation and neuronal cell death in the retina of type 1 diabetic rats

Gonçalves, Ana Filipa; Marques, Catarina; Leal, Ermelindo C.; Ribeiro, Carlos Fontes; Reis, Flávio; Ambrósio, António Francisco; Fernandes, Rosa

doi:10.1016/j.bbadis.2014.04.013

Cited by 74 publications

(74 citation statements)

References 48 publications

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“…In addition, sitagliptin allowed for a recovery of the number of CD34 + cells present in the bloodstream to levels similar to their number in control animals, while the decreased ability of endothelial progenitor cells (EPCs) to adhere to the retinal vessels that was induced by diabetes was reversed. Even more interestingly, the same authors demonstrated that sitagliptin alleviated the increased BRB permeability in streptozotocin (STZ)-induced diabetic rats, which could not be attributed to a normalisation of glycaemia [31]. However, Lee et al [32] recently reported that the intraperitoneal administration of sitagliptin induced vascular leakage in the retinas of mice with either retinopathy of prematurity or STZ-induced diabetes.…”

Section: Discussionmentioning

confidence: 98%

“…The experimental evidence on the effects of the oral administration of DPP-IVi in diabetic retinopathy is limited and controversial [29][30][31][32]. Gonçalves et al [29] showed that sitagliptin prevented changes in the endothelial distribution of tight junction proteins and decreased nitrosative stress, the inflammatory state and cell death by apoptosis in Zucker Diabetic Fatty (ZDF) rats (a rat model of type 2 diabetes).…”

Section: Discussionmentioning

confidence: 99%

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Topical administration of DPP-IV inhibitors prevents retinal neurodegeneration in experimental diabetes

et al. 2017

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Aims/hypothesis The main aims of the present study were: (1) to assess the expression and content of dipeptidyl peptidase IV (DPP-IV) in human and db/db mouse retinas, and in human vitreous fluid; and (2) to determine whether the topical administration of the DPP-IV inhibitors (DPP-IVi) would prevent retinal neurodegeneration and vascular leakage in db/db mice by reducing endogenous glucagon-like peptide 1 (GLP-1) degradation. Methods To assess the expression and content of DPP-IV, human samples of vitreous fluid and retinas were obtained from participants with type 2 diabetes (n = 8) and agematched non-diabetic individuals (n = 8), as well as from db/db (n = 72) and db/+ (n = 28) mice. The interventional study, which included 72 db/db mice, consisted of the topical administration (eye drops) of saxagliptin, sitagliptin or vehicle for 14 days. DPP-IV mRNA levels were assessed by RT-PCR, and protein content was measured by ELISA or western blotting. GLP-1 was assessed by immunofluorescence, and its downstream effector exchange protein activated by cAMP-1 (EPAC-1) was used as a measure of GLP-1 receptor activation. Retinal analyses were performed in vivo by electroretinography and ex vivo by RT-PCR (Epac-1, Iba-1 [also known as Aif1]), western blotting (EPAC-1, glial fibrillar acidic protein [GFAP], glutamate−aspartate transporter [GLAST]) and immunofluorescence measurements (GLP-1, GFAP, ionised calcium binding adaptor molecule 1 [IBA-1], TUNEL, GLAST, albumin and collagen IV). Glutamate was quantified by HPLC. In addition, vascular leakage was examined by the Evans Blue method. Results DPP-IV was present in human vitreous fluid but in a range 100-fold less than in plasma. Both mRNA levels and protein content were much lower in the retina than in the liver or bowel, but were significantly higher in retinal pigment epithelium (RPE) from diabetic donors in comparison to non-diabetic donors (p < 0.05). Topical treatment with DPP-IVi prevented glial activation, apoptosis and vascular leakage induced by diabetes in db/db mice (p < 0.05). Moreover, it also significantly prevented diabetes-induced functional abnormalities in the electroretinogram. A significant increase of both GLP-1 and EPAC-1 was found after treatment with DPP-IVi (p < 0.05). Furthermore, GLAST downregulation induced by diabetes was prevented, resulting in a significant reduction of extracellular glutamate concentrations. All these effects were observed without any changes in blood glucose levels. Conclusions/interpretation The topical administration of DPP-IVi is effective in preventing neurodegeneration and vascular leakage in the diabetic retina. These effects can be attributed to an enhancement of GLP-1, but other mechanisms unrelated to the prevention of GLP-1 degradation cannot be ruled out.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Topical administration of DPP-IV inhibitors prevents retinal neurodegeneration in experimental diabetes

et al. 2017

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“…In patients with diabetes mellitus and/or arterial hypertension, this reflex arc is impaired, most probably caused by deterioration in the release and metabolism of nitric oxide [15][16][17][18]. Beneficial effects of DPP-IV inhibition on blood pressure, retinal and renal function have been suggested in experimental studies [19][20][21] and in individuals with type 2 diabetes mellitus [10,11,22,23]. In our study, treatment with linagliptin improved retinal capillary perfusion, retinal arterial blood flow and the hyperemic response to flicker light in nondiabetic, hypertensive individuals.…”

Section: Discussionmentioning

confidence: 99%

Microvascular effects of the inhibition of dipeptidylpeptidase IV by linagliptin in nondiabetic hypertensive patients

Forst

Michelson²,

Diessel

et al. 2016

Journal of Hypertension

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“…In another study, Maeda et al (104) showed that vildagliptin significantly increased retinal gene expression of vascular endothelial growth factor, intercellular adhesion molecule 1, plasminogen activator inhibitor 1, and pigment epithelium-derived factor. Gonçalves et al (105) have also shown that in the retina of STZ-induced T1D rats, sitagliptin prevented the increase in blood-retinal barrier permeability and inhibited the changes in immunoreactivity and endothelial subcellular distribution of occludin, claudin 5, and zonula occludens 1 proteins induced by diabetes. Furthermore, sitagliptin decreased the retinal inflammatory state and neuronal apoptosis, thus indicating a direct protective effect on diabetic retinal cells.…”

Section: Dpp4-i and Diabetic Retinopathymentioning

confidence: 92%

The Effects of Dipeptidyl Peptidase-4 Inhibition on Microvascular Diabetes Complications

2014

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We performed a review of the literature to determine whether the dipeptidyl peptidase-4 inhibitors (DPP4-I) may have the capability to directly and positively influence diabetic microvascular complications. The literature was scanned to identify experimental and clinical evidence that DPP4-I can ameliorate diabetic microangiopathy. We retrieved articles published between 1 January 1980 and 1 March 2014 in English-language peer-reviewed journals using the following terms: (“diabetes” OR “diabetic”) AND (“retinopathy” OR “retinal” OR “nephropathy” OR “renal” OR “albuminuria” OR “microalbuminuria” OR “neuropathy” OR “ulcer” OR “wound” OR “bone marrow”); (“dipeptidyl peptidase-4” OR “dipeptidyl peptidase-IV” OR “DPP-4” OR “DPP-IV”); and (“inhibition” OR “inhibitor”). Experimentally, DPP4-I appears to improve inflammation, endothelial function, blood pressure, lipid metabolism, and bone marrow function. Several experimental studies report direct potential beneficial effects of DPP4-I on all microvascular diabetes-related complications. These drugs have the ability to act either directly or indirectly via improved glucose control, GLP-1 bioavailability, and modifying nonincretin substrates. Although preliminary clinical data support that DPP4-I therapy can protect from microangiopathy, insufficient evidence is available to conclude that this class of drugs directly prevents or decreases microangiopathy in humans independently from improved glucose control. Experimental findings and preliminary clinical data suggest that DPP4-I, in addition to improving metabolic control, have the potential to interfere with the onset and progression of diabetic microangiopathy. Further evidence is needed to confirm these effects in patients with diabetes.

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Dipeptidyl peptidase-IV inhibition prevents blood–retinal barrier breakdown, inflammation and neuronal cell death in the retina of type 1 diabetic rats

Cited by 74 publications

References 48 publications

Topical administration of DPP-IV inhibitors prevents retinal neurodegeneration in experimental diabetes

Topical administration of DPP-IV inhibitors prevents retinal neurodegeneration in experimental diabetes

Microvascular effects of the inhibition of dipeptidylpeptidase IV by linagliptin in nondiabetic hypertensive patients

The Effects of Dipeptidyl Peptidase-4 Inhibition on Microvascular Diabetes Complications

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