Biological Characterization of Gene Response to Insulin-Induced Hypoglycemia in Mouse Retina

• Published in: PloS one Vol. 11; no. 2; p. e0150266
• Main Authors: Emery, Martine, Nanchen, Natacha, Preitner, Frédéric, Ibberson, Mark, Roduit, Raphaël
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.02.2016; Public Library of Science (PLoS)
• Subjects: Activation; Acute Disease; Adaptation, Physiological; Analysis; Animals; Apoptosis; Apoptosis - genetics; Biology and Life Sciences; Cardiovascular diseases; Caspase; Caspase-3; Cell death; Chemical properties; Cluster analysis; Complications and side effects; Development and progression; Diabetes; Diabetes mellitus; Diabetic neuropathy; Diabetic retinopathy; Diabetic Retinopathy - prevention & control; DNA Fragmentation; DNA microarrays; Eye Proteins - biosynthesis; Eye Proteins - genetics; Female; Free Radical Scavengers; Gene expression; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Gene set enrichment analysis; Genes; Genetic aspects; Genomics; Glucose; Glucose Clamp Technique; Glutathione; Glutathione - metabolism; Heart diseases; Hypoglycemia; Hypoglycemia - chemically induced; Hypoglycemia - genetics; Hypoglycemia - metabolism; Insulin; Insulin - pharmacology; Insulin - toxicity; Insulin resistance; Lysosomes - metabolism; Medicine and Health Sciences; Metabolism; Mice; Mice, Inbred C57BL; Microarray Analysis; Mortality; Multigene Family - genetics; Mutation; Nephropathy; Neuropathy; Neurosciences; Oxidation-Reduction; Pathways; Physical Sciences; Physiological aspects; Random Allocation; Research and Analysis Methods; Retina; Retina - metabolism; Retina - pathology; Retinopathy; Rodents; Side effects; Superoxide; Time Factors; Switzerland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0150266

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.