title: Insulin treatment normalizes retinal neuroinflammation but not markers of synapse loss in diabetic rats.
abstract: Diabetic retinopathy is one of the leading causes of blindness in developed countries, and a majority of patients with type I and type II diabetes will develop some degree of vision loss despite blood glucose control regimens. The effects of different insulin therapy regimens on early metabolic, inflammatory and neuronal retinal disease processes such as retinal neuroinflammation and synapse loss have not been extensively investigated. This study compared 3 months non-diabetic and streptozotocin (STZ)-induced diabetic Sprague Dawley rats. Diabetic rats received either no insulin treatment, systemic insulin treatment beginning after 1 week uncontrolled diabetes (early intervention, 11 weeks on insulin), or after 1.5 months uncontrolled diabetes (late intervention, 6 weeks on insulin). Changes in both whole animal metabolic and retinal inflammatory markers were prevented by early initiation of insulin treatment. These metabolic and inflammatory changes were also normalized by the later insulin intervention. Insulin treatment begun 1 week after diabetes induction ameliorated loss of retinal synapse markers. Synapse markers and presumably synapse numbers were equivalent in uncontrolled diabetes and when insulin treatment began at 1.5 months of diabetes. These findings are in agreement with previous demonstrations that retinal synapses are lost within 1 month of uncontrolled diabetes and suggest that synapses are not regained with glycemic control and restoration of insulin signaling. However, increased expression of metabolic and inflammatory markers associated with diabetes was reversed in both groups of insulin treatment. This study also emphasizes the need for insulin treatment groups in diabetic retinopathy studies to provide a more faithful modeling of the human condition.
authors.affiliation: Department of Pharmacology, 500 University Drive, Penn State College of Medicine, Hershey, PA 17033, USA; Department of Physiology, BMSB 653, P.O. Box 26901, Oklahoma University Health Sciences Center, Oklahoma City, OK 73216, USA; Reynolds Oklahoma Center on Aging, SLY-BRC 1370, 975 NE 10th St, Oklahoma City, OK 73104, USA. Electronic address: dmasser@ouhsc.edu.
authors.forename: Dustin R
authors.initials: DR
authors.lastname: Masser
authors.affiliation: Department of Pharmacology, 500 University Drive, Penn State College of Medicine, Hershey, PA 17033, USA; Penn State Hershey Eye Center, 500 University Drive, Penn State College of Medicine, Hershey, PA 17033, USA. Electronic address: hdv108@psu.edu.
authors.forename: Heather D
authors.initials: HD
authors.lastname: VanGuilder Starkey
authors.affiliation: Department of Pharmacology, 500 University Drive, Penn State College of Medicine, Hershey, PA 17033, USA. Electronic address: gbixler2@hmc.psu.edu.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Bixler
authors.affiliation: Department of Cellular and Molecular Physiology, 500 University Drive, Penn State College of Medicine, Hershey, PA 17033, USA. Electronic address: wgd7n@virginia.edu.
authors.forename: Wendy
authors.initials: W
authors.lastname: Dunton
authors.affiliation: Penn State Hershey Eye Center, 500 University Drive, Penn State College of Medicine, Hershey, PA 17033, USA; Department of Cellular and Molecular Physiology, 500 University Drive, Penn State College of Medicine, Hershey, PA 17033, USA. Electronic address: sbronson@hmc.psu.edu.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Bronson
authors.affiliation: Department of Pharmacology, 500 University Drive, Penn State College of Medicine, Hershey, PA 17033, USA; Department of Physiology, BMSB 653, P.O. Box 26901, Oklahoma University Health Sciences Center, Oklahoma City, OK 73216, USA; Reynolds Oklahoma Center on Aging, SLY-BRC 1370, 975 NE 10th St, Oklahoma City, OK 73104, USA; Penn State Hershey Eye Center, 500 University Drive, Penn State College of Medicine, Hershey, PA 17033, USA. Electronic address: willard-freeman@ouhsc.edu.
authors.forename: Willard M
authors.initials: WM
authors.lastname: Freeman
mesh_terms: D000597:Amino Acids, Branched-Chain; D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D002096:C-Peptide / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020869:Gene Expression Profiling; D006442:Glycated Hemoglobin / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000494:pharmacology* / Q000627:therapeutic use; D007659:Ketones / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects* / Q000378:metabolism; D012173:Retinitis / Q000378:metabolism / Q000473:pathology; D013569:Synapses / Q000187:drug effects*
chemical_list: D000597:Amino Acids, Branched-Chain; D015415:Biomarkers; D001786:Blood Glucose; D002096:C-Peptide; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D007659:Ketones
keywords: diabetes; insulin; metabolic memory; neuroinflammation; retina; synapse