PMID- 28779212 OWN - NLM STAT- MEDLINE DCOM- 20180702 LR - 20220409 IS - 1432-0428 (Electronic) IS - 0012-186X (Linking) VI - 60 IP - 11 DP - 2017 Nov TI - Topical administration of DPP-IV inhibitors prevents retinal neurodegeneration in experimental diabetes. PG - 2285-2298 LID - 10.1007/s00125-017-4388-y [doi] AB - 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 age-matched 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. FAU - Hernandez, Cristina AU - Hernandez C AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. FAU - Bogdanov, Patricia AU - Bogdanov P AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. FAU - Sola-Adell, Cristina AU - Sola-Adell C AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. FAU - Sampedro, Joel AU - Sampedro J AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain. FAU - Valeri, Marta AU - Valeri M AD - Unit of High Technology, Vall d'Hebron Research Institute, Barcelona, Spain. FAU - Genis, Xavier AU - Genis X AD - Banco de Sangre y Tejidos, Passeig Taulat 116, 08005, Barcelona, Spain. FAU - Simo-Servat, Olga AU - Simo-Servat O AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. FAU - Garcia-Ramirez, Marta AU - Garcia-Ramirez M AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. FAU - Simo, Rafael AU - Simo R AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain. rafael.simo@vhir.org. AD - Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. rafael.simo@vhir.org. LA - eng GR - SAF2016-77784/Ministerio de Economia y Competitividad/ PT - Journal Article DEP - 20170804 PL - Germany TA - Diabetologia JT - Diabetologia JID - 0006777 RN - 0 (Dipeptides) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9GB927LAJW (saxagliptin) RN - PJY633525U (Adamantane) RN - TS63EW8X6F (Sitagliptin Phosphate) SB - IM MH - Adamantane/analogs & derivatives/therapeutic use MH - Animals MH - Diabetes Mellitus, Experimental/*drug therapy/physiopathology MH - Dipeptides/therapeutic use MH - Dipeptidyl-Peptidase IV Inhibitors/*therapeutic use MH - Electroretinography MH - Glucagon-Like Peptide 1/metabolism MH - Humans MH - Immunohistochemistry MH - Male MH - Mice MH - Retina/*drug effects/*pathology MH - Sitagliptin Phosphate/therapeutic use OTO - NOTNLM OT - DPP-IV inhibitors OT - Diabetic retinopathy OT - Experimental diabetes OT - GLP-1 OT - Retinal neurodegeneration EDAT- 2017/08/06 06:00 MHDA- 2018/07/03 06:00 CRDT- 2017/08/06 06:00 PHST- 2017/02/02 00:00 [received] PHST- 2017/06/21 00:00 [accepted] PHST- 2017/08/06 06:00 [pubmed] PHST- 2018/07/03 06:00 [medline] PHST- 2017/08/06 06:00 [entrez] AID - 10.1007/s00125-017-4388-y [pii] AID - 10.1007/s00125-017-4388-y [doi] PST - ppublish SO - Diabetologia. 2017 Nov;60(11):2285-2298. doi: 10.1007/s00125-017-4388-y. Epub 2017 Aug 4.