title: Pioglitazone normalizes insulin signaling in the diabetic rat retina through reduction in tumor necrosis factor α and suppressor of cytokine signaling 3.
abstract: Dysfunctional insulin signaling is a key component of type 2 diabetes. Little is understood of the effects of systemic diabetes on retinal insulin signaling. A number of agents are used to treat patients with type 2 diabetes to normalize glucose levels and improve insulin signaling; however, little has been done to investigate the effects of these agents on retinal insulin signal transduction. We hypothesized that pioglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist, would normalize retinal insulin signal transduction through reduced tumor necrosis factor α (TNFα) and suppressor of cytokine signaling 3 (SOCS3) activities in whole retina and retinal endothelial cells (REC) and Müller cells. To test this hypothesis, we used the BBZDR/Wor type 2 diabetic rat model, as well as REC and Müller cells cultured in normoglycemia and hyperglycemic conditions, to investigate the effects of pioglitazone on TNFα, SOCS3, and downstream insulin signal transduction proteins. We also evaluated pioglitazone's effects on retinal function using electroretinogram and markers of apoptosis. Data demonstrate that 2 months of pioglitazone significantly increased electroretinogram amplitudes in type 2 diabetic obese rats, which was associated with improved insulin receptor activation. These changes occurred in both REC and Müller cells treated with pioglitazone, suggesting that these two cell types are key to insulin resistance in the retina. Taken together, these data provide evidence of impaired insulin signaling in type 2 diabetes rats, which was improved by increasing PPARγ activity. Further investigations of PPARγ actions in the retina may provide improved treatment options.
authors.affiliation: Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Youde
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Shalini
authors.initials: S
authors.lastname: Thakran
authors.affiliation: Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Rajini
authors.initials: R
authors.lastname: Bheemreddy
authors.affiliation: Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Eun-Ah
authors.initials: EA
authors.lastname: Ye
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and.
authors.forename: Hui
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee 38163; Department of Biology, Philander Smith College, Little Rock, Arkansas 72202.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Walker
authors.affiliation: Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee 38163; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and; Department of Anatomy and Neurobiology, and University of Tennessee Health Science Center, Memphis, Tennessee 38163. Electronic address: jsteinl1@uthsc.edu.
authors.forename: Jena J
authors.initials: JJ
authors.lastname: Steinle
mesh_terms: D000818:Animals; D017209:Apoptosis; D001611:Beta Rhythm / Q000187:drug effects; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000517:prevention & control; D004353:Drug Evaluation, Preclinical; D007328:Insulin / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007429:Intraocular Pressure / Q000187:drug effects; D008297:Male; D047495:PPAR gamma / Q000378:metabolism; D010766:Phosphorylation; D000077205:Pioglitazone; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011924:Rats, Zucker; D011972:Receptor, Insulin / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D047495:PPAR gamma; C491410:Socs3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D000077205:Pioglitazone
keywords: Diabetic Retinopathy; Insulin Receptor; Insulin Receptor Substrate 1 (IRS-1); Insulin Resistance; Suppressor of Cytokine Signaling 3 (SOCS3); Tumor Necrosis Factor (TNF); Type 2 Diabetes
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