title: Biological Characterization of Gene Response to Insulin-Induced Hypoglycemia in Mouse Retina.
abstract: Glucose is the most important metabolic substrate of the retina and maintenance of normoglycemia is an essential challenge for diabetic patients. Chronic, exaggerated, glycemic excursions could lead to cardiovascular diseases, nephropathy, neuropathy and retinopathy. We recently showed that hypoglycemia induced retinal cell death in mouse via caspase 3 activation and glutathione (GSH) decrease. Ex vivo experiments in 661W photoreceptor cells confirmed the low-glucose induction of death via superoxide production and activation of caspase 3, which was concomitant with a decrease of GSH content. We evaluate herein retinal gene expression 4 h and 48 h after insulin-induced hypoglycemia. Microarray analysis demonstrated clusters of genes whose expression was modified by hypoglycemia and we discuss the potential implication of those genes in retinal cell death. In addition, we identify by gene set enrichment analysis, three important pathways, including lysosomal function, GSH metabolism and apoptotic pathways. Then we tested the effect of recurrent hypoglycemia (three successive 4h periods of hypoglycemia spaced by 48 h recovery) on retinal cell death. Interestingly, exposure to multiple hypoglycemic events prevented GSH decrease and retinal cell death, or adapted the retina to external stress by restoring GSH level comparable to control situation. We hypothesize that scavenger GSH is a key compound in this apoptotic process, and maintaining "normal" GSH level, as well as a strict glycemic control, represents a therapeutic challenge in order to avoid side effects of diabetes, especially diabetic retinopathy.
authors.affiliation: IRO, Institute for Research in Ophthalmology, Sion, Switzerland.
authors.forename: Martine
authors.initials: M
authors.lastname: Emery
authors.affiliation: IRO, Institute for Research in Ophthalmology, Sion, Switzerland.
authors.forename: Natacha
authors.initials: N
authors.lastname: Nanchen
authors.affiliation: Mouse Metabolic Evaluation Facility, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Preitner
authors.affiliation: Vital-IT Group, Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Mark
authors.initials: M
authors.lastname: Ibberson
authors.affiliation: IRO, Institute for Research in Ophthalmology, Sion, Switzerland.|Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Roduit
mesh_terms: D000208:Acute Disease; D000222:Adaptation, Physiological; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D053938:DNA Fragmentation; D003930:Diabetic Retinopathy / Q000517:prevention & control; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D016166:Free Radical Scavengers; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D015309:Glucose Clamp Technique; D005978:Glutathione / Q000378:metabolism; D007003:Hypoglycemia / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology / Q000633:toxicity*; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D005810:Multigene Family / Q000235:genetics*; D010084:Oxidation-Reduction; D011897:Random Allocation; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
chemical_list: D005136:Eye Proteins; D016166:Free Radical Scavengers; D007328:Insulin; D005978:Glutathione