Beneficial Effects of Vildagliptin on Retinal Injury in Obese Type 2 Diabetic Rats

Maeda, Shin; Yamagishi, Sho‐ichi; Matsui, Takanori; Nakashima, Sae; Ojima, Ayako; Maeda, Sayaka; Nishino, Yoshinori; Ishibashi, Yuji; Yoshida, Yumiko; Yamakawa, Ryoji

doi:10.1159/000354116

Cited by 27 publications

(19 citation statements)

References 17 publications

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“…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%

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: 99%

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

et al. 2017

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“…Similarly, vildagliptin has shown improved healing features for chronic foot ulcers in patients with T2DM [31]. Several pre-clinical studies also observed the importance of DPP-4 inhibitors in treating microvascular complications associated with diabetes [32–35]. Most of the studies on humans investigating importance of DPP-4 inhibitors in microvascular complications were preliminary and short-term studies, and further large and long-term trials are required to corroborate these findings.…”

Section: Discussionmentioning

confidence: 99%

Microvascular Outcomes in Patients with Type 2 Diabetes Treated with Vildagliptin vs. Sulfonylurea: A Retrospective Study Using German Electronic Medical Records

Kolaczyński

Hankins²,

Ong

et al. 2016

Diabetes Ther

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IntroductionPreliminary data suggest that dipeptidyl peptidase-4 (DPP-4) inhibitors may reduce microvascular events, but there is a little evidence to support this from adequate real-world studies. This study aimed to compare microvascular outcomes between patients-prescribed vildagliptin and those prescribed sulfonylurea (SU).MethodsThis retrospective cohort study was conducted on a large sample from the German electronic medical records database IMS Lifelink Disease Analyzer. We used propensity score-matched samples of patients prescribed either vildagliptin or SU. Exposure was defined as therapy (SU or vildagliptin); primary outcomes were a diagnosis of retinopathy, nephropathy, neuropathy, or diabetic foot ulcer over the observation period in patients with no previous record of these outcomes. Secondary outcome was a composite of any primary outcome occurring in the observation period.ResultsIn total, 16,321 patients prescribed SU and 4481 prescribed vildagliptin met the inclusion criteria. After propensity score matching, each sample comprised 3015 patients. Mean age was 63.7/64.6 years for SU/vildagliptin, respectively, with mean disease duration of 3.2/3.1 years, and mean treatment duration of 2.5/2.3 years. Treatment with vildagliptin was associated with a significant lower incidence of retinopathy [odds ratio (OR) = 0.55, P = 0.0004], neuropathy (OR 0.71, P = 0.0001), and composite outcome (OR 0.70, P < 0.0001). Incidences of nephropathy and diabetic foot ulcer were lower for vildagliptin, but not significantly so (OR 0.90, P = 0.3920; OR 0.76, P = 0.0742, respectively). There were no significant differences in incident rate ratios (all P > 0.05).ConclusionTreatment with vildagliptin was associated with a reduced incidence of microvascular complications, especially neuropathy and retinopathy, compared to treatment with SU in this clinical practice setting.FundingNovartis Pharma AG.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-016-0177-8) contains supplementary material, which is available to authorized users.

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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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Beneficial Effects of Vildagliptin on Retinal Injury in Obese Type 2 Diabetic Rats

Cited by 27 publications

References 17 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 Outcomes in Patients with Type 2 Diabetes Treated with Vildagliptin vs. Sulfonylurea: A Retrospective Study Using German Electronic Medical Records

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

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