Pioglitazone Normalizes Insulin Signaling in the Diabetic Rat Retina through Reduction in Tumor Necrosis Factor α and Suppressor of Cytokine Signaling 3
Pioglitazone Normalizes Insulin Signaling in the Diabetic Rat Retina through Reduction in Tumor Necrosis Factor α and Suppressor of Cytokine Signaling 3
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DOI：
10.1074/jbc.m114.583880
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发表时间：
2014-09-19
影响因子：
4.8
通讯作者：
Steinle, Jena J.
中科院分区：
文献类型：
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作者：
Jiang, Youde;Thakran, Shalini;Steinle, Jena J.
胰岛素信号传导功能障碍是2型糖尿病的关键组成部分。系统性糖尿病对视网膜胰岛素信号传导的影响知之甚少。许多药物用于治疗2型糖尿病患者，以使血糖水平正常化并改善胰岛素信号传导;然而，很少有人研究这些药物对视网膜胰岛素信号转导的影响。我们假设吡格列酮，一种过氧化物酶体增殖物激活受体γ（过氧化物酶体增殖物激活受体γ）激动剂，将通过减少肿瘤坏死因子α使视网膜胰岛素信号转导正常化为了检测在整个视网膜和视网膜内皮细胞（REC）中TNF α和细胞因子信号传导抑制因子3（SOCS 3）的活性，Muller检验了这一假设，我们使用BBZDR/Wor 2型糖尿病大鼠模型，以及在血糖正常和高血糖条件下培养的REC和Muller细胞，以研究吡格列酮对TNF α、SOCS 3和下游胰岛素信号转导蛋白的影响。我们还使用视网膜电图和细胞凋亡标志物评估了吡格列酮对视网膜功能的影响。数据表明，2个月的吡格列酮显著增加了2型糖尿病肥胖大鼠的视网膜电图振幅，这与胰岛素受体活化的改善有关。这些变化发生在用吡格列酮处理的REC和Muller细胞中，表明这两种细胞类型是视网膜胰岛素抵抗的关键。综上所述，这些数据提供了2型糖尿病大鼠胰岛素信号传导受损的证据，通过增加PPAR γ活性可以改善。进一步研究视网膜中的PPAR γ作用可能会提供更好的治疗选择。
Dysfunctional insulin signaling is a key component of type 2 diabetes. Little is understood of the effects of systemic diabetes on retinal insulin signaling. Anumber 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 gamma (PPAR gamma) agonist, would normalize retinal insulin signal transduction through reduced tumor necrosis factor alpha (TNF alpha) and suppressor of cytokine signaling 3 (SOCS3) activities in whole retina and retinal endothelial cells (REC) and Muller test this hypothesis, we used the BBZDR/Wor type 2 diabetic rat model, as well as REC and Muller cells cultured in normoglycemia and hyperglycemic conditions, to investigate the effects of pioglitazone on TNF alpha, 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 Muller 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 PPAR gamma activity. Further investigations of PPAR gamma actions in the retina may provide improved treatment options.