June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Topical administration of dipeptidyl peptidase IV (DPP-IV) inhibitors prevents retinal neurodegeneration in experimental diabetes
Author Affiliations & Notes
  • Cristina Hernández
    Diabetes and Metabolism Unit, Vall Hebron Research Institute. CIBERDEM, Barcelona, Spain
  • Patricia Bogdanov
    Vall d'Hebron Research Institute, Barcelona, Spain
  • Cristina Solà-Adell
    Diabetes and Metabolism Unit, Vall Hebron Research Institute. CIBERDEM, Barcelona, Spain
  • Joel Sampedro
    Diabetes and Metabolism Unit, Vall Hebron Research Institute. CIBERDEM, Barcelona, Spain
  • Marta Valeri
    Vall d'Hebron Research Institute, Barcelona, Spain
  • Olga Simó-Servat
    Diabetes and Metabolism Unit, Vall Hebron Research Institute. CIBERDEM, Barcelona, Spain
  • Raul Herance
    Vall d'Hebron Research Institute, Barcelona, Spain
  • Rafael Simó
    Diabetes and Metabolism Unit, Vall Hebron Research Institute. CIBERDEM, Barcelona, Spain
  • Footnotes
    Commercial Relationships   Cristina Hernández, None; Patricia Bogdanov, None; Cristina Solà-Adell, None; Joel Sampedro, None; Marta Valeri, None; Olga Simó-Servat, None; Raul Herance, None; Rafael Simó, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 5795. doi:
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      Cristina Hernández, Patricia Bogdanov, Cristina Solà-Adell, Joel Sampedro, Marta Valeri, Olga Simó-Servat, Raul Herance, Rafael Simó; Topical administration of dipeptidyl peptidase IV (DPP-IV) inhibitors prevents retinal neurodegeneration in experimental diabetes. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5795.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Glucagon-like peptide 1 (GLP-1) and GLP-1 receptor (GLP-1R) have recently been found in the human retina, and topical administration of GLP-1R agonists prevents retinal neurodegeneration and vascular leakage in experimental diabetes. Since GLP-1 is rapidly degradable by DPP-IV, it is possible that DPP-IV inhibitors (DPP-IVi) can enhance the beneficial effects of retinal production of GLP-1. The main aims of the present study are: a) To determine whether the topical administration (eye drops) of DPP-IVi is able to reduce GLP-1 degradation, thus preventing retinal neurodegeneration and vascular leakage in db/db mice; b) To investigate whether, as occurs with GLP-1, the reduction of glutamate mediated excitotoxicity is among their mechanisms of action.

Methods : Eye-drops containing sitagliptin, saxagliptin or vehicle were administered for 14 days (twice per day) to db/db mice (n=10 per group). Neurodegeneration was assessed by measuring glial activation (GFAP-IF), the rate of apoptosis (TUNEL) and ERG (Ganzfeld) features. Vascular leakage was examined by assessing the extravasated albumin. The retinal content of GLP-1 and its downstream effector AMPc were assessed before and after the administration of DPP-IV inhibitors. Glutamate and GLAST were determined by HPLC and IF, respectively.

Results : Topical treatment with saxagliptin or sitagliptin prevented glial activation, apoptosis and vascular leakage induced by diabetes. In addition, they also significantly prevented the diabetes induced functional abnormalities in the ERG. A significant increase of GLP-1 was found after treatment with either saxagliptin or sitagliptin. Furthermore, a dramatic prevention of GLAST downregulation induced by diabetes was found, which resulted in a significant reduction of extracellular concentration of glutamate. All these effects were observed without any change in blood glucose levels and, therefore, they cannot be attributed to changes in the diabetic milieu. However, activation of other pathways unrelated to GLP-1R cannot be ruled out.

Conclusions : Topical treatment with DPP-IVi prevents the neurodegenerative process, as well as vascular leakage, that occur in early stages of diabetic retinopathy (DR). This non-invasive treatment can be contemplated (alone or in combination with GLP-1) as a new strategy for treating DR.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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