title: Acute hypoglycemia induces retinal cell death in mouse.
abstract: BACKGROUND
  Glucose is the most important metabolic substrate of the retina and maintenance of normoglycemia is an essential challenge for diabetic patients. Glycemic excursions could lead to cardiovascular disease, nephropathy, neuropathy and retinopathy. A vast body of literature exists on hyperglycemia namely in the field of diabetic retinopathy, but very little is known about the deleterious effect of hypoglycemia. Therefore, we decided to study the role of acute hypoglycemia in mouse retina.
  
  
  RESULTS
  To test effects of hypoglycemia, we performed a 5-hour hyperinsulinemic/hypoglycemic clamp; to exclude an effect of insulin, we made a hyperinsulinemic/euglycemic clamp as control. We then isolated retinas from each group at different time-points after the clamp to analyze cells apoptosis and genes regulation. In parallel, we used 661W photoreceptor cells to confirm in vivo results. We showed herein that hypoglycemia induced retinal cell death in mouse via caspase 3 activation. We then tested the mRNA expression of glutathione transferase omega 1 (Gsto1) and glutathione peroxidase 3 (Gpx3), two genes involved in glutathione (GSH) homeostasis. The expression of both genes was up-regulated by low glucose, leading to a decrease of reduced glutathione (GSH). In vitro experiments confirmed the low-glucose induction of 661W cell death via superoxide production and activation of caspase 3, which was concomitant with a decrease of GSH content. Moreover, decrease of GSH content by inhibition with buthionine sulphoximine (BSO) at high glucose induced apoptosis, while complementation with extracellular glutathione ethyl ester (GSHee) at low glucose restored GSH level and reduced apoptosis.
  
  
  CONCLUSIONS
  We showed, for the first time, that acute insulin-induced hypoglycemia leads to caspase 3-dependant retinal cell death with a predominant role of GSH content.
authors: Institute for Research in Ophthalmology, Sion, Switzerland.
authors: Martine
authors: M
authors: Emery
authors: Daniel F
authors: DF
authors: Schorderet
authors: Raphaël
authors: R
authors: Roduit
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D006943:Hyperglycemia / Q000503:physiopathology*; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D012160:Retina / Q000166:cytology* / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002352:Carrier Proteins; C117709:Gsto1 protein, mouse; D000255:Adenosine Triphosphate; C116888:Gpx3 protein, mouse; D005979:Glutathione Peroxidase; D005982:Glutathione Transferase; D053148:Caspase 3; D005978:Glutathione