Protection of exendin-4 analogue in early experimental diabetic retinopathy

Yu, Zhuang; Wang, Qingping; Zhang, Jingfa; Lei, Xia; Xu, Guo; Ye, Wen

doi:10.1007/s00417-008-1004-3

Cited by 56 publications

(67 citation statements)

References 42 publications

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“…6 (a, b) [34] showed that semaglutide (a longacting GLP-1 analogue with an extended half-life of approximately 1 week) reduced the rate of cardiovascular morbidity and mortality but increased the progression of diabetic retinopathy. This merits comment because it contravenes the experimental results showing the beneficial effects of GLP-1R agonists in the development of diabetic retinopathy [9,[35][36][37][38][39][40]. In this study, an unexpectedly higher rate of severe complications of diabetic retinopathy (i.e.…”

Section: Discussionmentioning

confidence: 50%

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: 50%

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

et al. 2017

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“…These findings indicate that the change of DPP IV in urine is probably associated with diabetic nephropathy. DPP IV inhibitors or incretin-based agents reportedly ameliorate diabetic neuropathy and retinopathy, at least in part, through delaying the degradation of GLP-1 and its binding affinity to the GLP-1R (Jin et al, 2009;Zhang et al, 2009). These observations suggest that DPP IV inhibitors, partly by increasing GLP-1 level, can exert renoprotective effects in the hyperglycemic state, because dia-betic nephropathy has a close relationship with other diabetic microvascular complications (Girach and Vignati, 2006).…”

Section: Introductionmentioning

confidence: 99%

Dipeptidyl Peptidase IV Inhibitor Attenuates Kidney Injury in Streptozotocin-Induced Diabetic Rats

Liu¹,

Xie²,

Liu³

et al. 2011

J Pharmacol Exp Ther

198

164

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Dipeptidyl peptidase (DPP) IV inhibitors are probably beneficial for preventing diabetic complication and modulating glucagonlike peptide-1 receptor (GLP-1R) expression. The aim of this study was to determine whether the DPP IV inhibitor LAF237 (vildagliptin) has renoprotective qualities in streptozotocin-induced diabetic rats. Diabetic and nondiabetic rats were treated with an oral dose of 4 or 8 mg/kg/day LAF237 or placebo for 24 weeks, and renal injury was observed by light and electron microscopy. We also assessed DPP IV activity, active GLP-1 level, cAMP and 8-hydroxy-deoxyguanosine excretion, and GLP-1R, cleaved caspase 3, and transforming growth factor-␤1 (TGF-␤1) expression. LAF237 significantly decreased proteinuria, albuminuria, and urinary albumin/creatinine ratio, improved creatinine clearance, and dose-dependently inhibited interstitial expansion, glomerulosclerosis, and the thickening of the glomerular basement membrane in diabetic rats. It is noteworthy that LAF237 markedly down-regulated DPP IV activity and increased active GLP-1 levels, which probably prevented oxidative DNA damage and renal cell apoptosis by activating the GLP-1R and modulating cAMP. Renoprotection was also associated with a reduction in TGF-␤1 overexpression. Our study suggests that DPP IV inhibitors may ameliorate diabetic nephropathy as well as reduce the overproduction of TGF-␤1. The observed renoprotection is probably attributable to inhibition of DPP IV activity, mimicking of incretin action, and activation of the GLP-1R.

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“…GLP-1R expression has been found in retinas from rats (19) and chickens (20), and in ARPE-19 cells (an immortalized line of human retinal pigment epithelium [RPE]) (21). However, the presence of GLP-1R has never been examined in the human retina.…”

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confidence: 99%

Topical Administration of GLP-1 Receptor Agonists Prevents Retinal Neurodegeneration in Experimental Diabetes

et al. 2015

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Retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy (DR). Since glucagonlike peptide 1 (GLP-1) exerts neuroprotective effects in the central nervous system and the retina is ontogenically a brain-derived tissue, the aims of the current study were as follows: 1) to examine the expression and content of GLP-1 receptor (GLP-1R) in human and db/db mice retinas; 2) to determine the retinal neuroprotective effects of systemic and topical administration (eye drops) of GLP-1R agonists in db/db mice; and 3) to examine the underlying neuroprotective mechanisms. We have found abundant expression of GLP-1R in the human retina and retinas from db/db mice. Moreover, we have demonstrated that systemic administration of a GLP-1R agonist (liraglutide) prevents retinal neurodegeneration (glial activation, neural apoptosis, and electroretinographical abnormalities). This effect can be attributed to a significant reduction of extracellular glutamate and an increase of prosurvival signaling pathways. We have found a similar neuroprotective effect using topical administration of native GLP-1 and several GLP-1R agonists (liraglutide, lixisenatide, and exenatide). Notably, this neuroprotective action was observed without any reduction in blood glucose levels. These results suggest that GLP-1R activation itself prevents retinal neurodegeneration. Our results should open up a new approach in the treatment of the early stages of DR.

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Protection of exendin-4 analogue in early experimental diabetic retinopathy

Cited by 56 publications

References 42 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

Dipeptidyl Peptidase IV Inhibitor Attenuates Kidney Injury in Streptozotocin-Induced Diabetic Rats

Topical Administration of GLP-1 Receptor Agonists Prevents Retinal Neurodegeneration in Experimental Diabetes

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