The role of insulin resistance in experimental diabetic retinopathy-Genetic and molecular aspects.
The role of insulin resistance in experimental diabetic retinopathy-Genetic and molecular aspects.
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DOI：
10.1371/journal.pone.0178658
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Wohlfart P
中科院分区：
文献类型：
--
作者：
Järgen P;Dietrich A;Herling AW;Hammes HP;Wohlfart P
糖尿病视网膜病变的特征是视网膜神经血管单位的缺陷。损伤的潜在机制--包括反应中间体和生长因子依赖的信号通路--及其可能的相互作用尚不完全清楚。本研究旨在评估高血糖和高胰岛素血症单独或联合对糖尿病动物模型视网膜基因表达模式的相对作用。作为反映1型糖尿病的胰岛素缺乏、高血糖模型，雄性STZ-Wistar大鼠(60 mg/kg bw；ip.7周龄时注射。以肥胖雄性ZDF大鼠(FA/FA)为模型，建立以持续性高血糖和短暂性高胰岛素血症为特征的2型糖尿病模型。雄性肥胖ZF大鼠(FA/FA)反映正常血糖和严重的胰岛素抵抗。所有组在各自的条件下保存到20周龄，并设置适当的年龄匹配的对照组。使用Affymetrix基因阵列对每组进行无偏基因表达分析。生物信息学分析包括基因聚集性和差异表达分析，以及通路和上游激活子分析。用微流控卡片聚合酶链式反应技术证实基因表达的差异。在视网膜中观察到最复杂的遗传调控是ZDF大鼠，与STZ-Wistar大鼠有很强的重叠。令人惊讶的是，在没有伴随高血糖的ZF大鼠中，单纯的全身性胰岛素抵抗并没有引起视网膜基因表达模式的任何显著变化。通路分析表明，ZDF大鼠和STZ治疗大鼠在补体系统激活、急性时相反应信号和抑瘤素-M信号等通路上存在重叠。主要的阵列基因表达变化可以通过后续的聚合酶链式反应来确认。对上游转录调控因子的分析发现，在STZ和ZDF大鼠中存在干扰素-γ、白介素6和抑瘤素-M。结论：无高血糖的全身性高胰岛素血症不会导致视网膜基因表达的显著变化。相比之下，持续的全身性高血糖通过有限数量的已知和新的关键调节因子促进更强烈的表达变化。
Diabetic retinopathy is characterized by defects in the retinal neurovascular unit. The underlying mechanisms of impairment–including reactive intermediates and growth-factor dependent signalling pathways and their possible interplay are incompletely understood. This study aims to assess the relative role of hyperglycemia and hyperinsulinemia alone or in combination on the gene expression patterning in the retina of animal models of diabetes. As insulinopenic, hyperglycemic model reflecting type 1 diabetes, male STZ-Wistar rats (60mg/kg BW; i.p. injection at life age week 7) were used. Male obese ZDF rats (fa/fa) were used as type-2 diabetes model characterized by persisting hyperglycemia and transient hyperinsulinemia. Male obese ZF rats (fa/fa) were used reflecting euglycemia and severe insulin resistance. All groups were kept till an age of 20 weeks on respective conditions together with appropriate age-matched controls. Unbiased gene expression analysis was performed per group using Affymetrix gene arrays. Bioinformatics analysis included analysis for clustering and differential gene expression, and pathway and upstream activator analysis. Gene expression differences were confirmed by microfluidic card PCR technology. The most complex genetic regulation in the retina was observed in ZDF rats with a strong overlap to STZ-Wistar rats. Surprisingly, systemic insulin resistance alone in ZF rats without concomitant hyperglycemia did not induce any significant change in retinal gene expression pattern. Pathway analysis indicate an overlap between ZDF rats and STZ-treated rats in pathways like complement system activation, acute phase response signalling, and oncostatin-M signalling. Major array gene expression changes could be confirmed by subsequent PCR. An analysis of upstream transcriptional regulators revealed interferon-γ, interleukin-6 and oncostatin-M in STZ and ZDF rats. CONCLUSIONS: Systemic hyperinsulinaemia without hyperglycemia does not result in significant gene expression changes in retina. In contrast, persistent systemic hyperglycemia boosts much stronger expression changes with a limited number of known and new key regulators.