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

Abstract

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.

Comparisons of diabetic retinopathy events associated with glucose‐lowering drugs in patients with type 2 diabetes mellitus: A network meta‐analysis

“…Preclinical data demonstrated beneficial pleiotropic effects of incretin therapies on DR, independent of the glucose‐lowering effect resulting from reducing blood‐retinal barrier breakdown, inflammation and neuronal cell death . Topical administration of DPP‐4i was shown to prevent neurodegeneration and vascular leakage in db/db mice by enhancing GLP‐1 . The results in patients with T2DM remain inconsistent.…”

Neurodegeneration in diabetic retinopathy: does it really matter?

“…This finding has important therapeutic implications. In this regard, neuroprotective effects have been reported by using insulin [55], PEDF [56, 57], somatostatin [58], GLP-1 [59, 60], dipeptidyl peptidase-IV (DPP-IV) inhibitors [61] and erythropoietin or erythropoietin-linked analogues [62, 63] in various experimental models. The European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR) clinical trial has recently shown that topical administration of somatostatin arrested the progression of neurodysfunction as assessed by mfERG (implicit time) in participants with some degree of neurodysfunction at baseline [64].…”

“…To our knowledge, there are no published studies in which cell-specific defects in microvascular or neural cells result in a diabetic retinopathy-like phenotype. In addition, although several studies using neuroprotective drugs, such GLP-1 and DPP-IV inhibitors, have prevented vascular leakage in rodents [59–61], it is unknown if this effect was due to neuroprotection or to direct vascular effects. In addition, recent results from the EUROCONDOR study showed that a significant proportion of individuals with type 2 diabetes present with early microvascular disease without detectable neurodysfunction [64, 80].…”

Effects of Liposomal Formulation of Citicoline in Experimental Diabetes-Induced Retinal Neurodegeneration

“…However, the mechanistic pathways were not examined. Although it could be argued that eye drops can hardly reach the posterior chamber of the eye (i.e., the vitreous and the retina), this and other studies showed the contrary, and in fact, a lot of drugs are able to reach the retina in pharmacological concentrations, at least in animal models [27,28,29,30,31]. Furthermore, we used a new formulation based on liposomal citicoline, phospholipids, sodium hyaluronate, phosphate buffer, and water, in which liposomal systems would act as a penetration enhancer and to avoid the use of eye drop preservatives [24].…”