Increased expression of antioxidant and antiapoptotic genes in islets that may contribute to β-cell survival during chronic hyperglycemia
Increased expression of antioxidant and antiapoptotic genes in islets that may contribute to β-cell survival during chronic hyperglycemia
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DOI：
10.2337/diabetes.51.2.413
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发表时间：
2002-02-01
期刊：
影响因子：
7.7
通讯作者：
Weir, GC
中科院分区：
文献类型：
--
作者：
Laybutt, DR;Kaneto, H;Weir, GC
肥大是胰腺β细胞的一种机制。生长，并被视为对胰岛素抵抗的重要代偿反应。我们假设保护性基因的诱导有助于扩大（肥大）β细胞的存活。在此，我们评估了部分胰腺切除术（Px）后4周高血糖大鼠胰岛中伴随β细胞肥大的应激基因表达的变化。各种保护基因上调，显着增加表达的抗氧化基因血红素加氧酶-1和谷胱甘肽过氧化物酶和抗凋亡基因A20。Cu/Zn-超氧化物歧化酶（SOD）和Mn-SOD适度诱导，Bcl-2适度减少，但其他几个应激基因（过氧化氢酶，热休克蛋白70和p53）不变。mRNA水平的增加对应于高血糖的程度，并在Px大鼠中通过根皮苷治疗2周（使高血糖正常化的治疗）逆转，强烈表明高血糖在引发反应中的特异性。Px大鼠高脂血症还导致胰岛中核因子-κ B的活化。高血糖Px大鼠β细胞表型的深刻变化导致对β细胞毒素链脲佐菌素的敏感性降低。在根皮苷处理的Px大鼠胰岛中，对毒素的敏感性恢复，沿着β细胞表型。此外，Px大鼠的β细胞在体内用地塞米松进一步激发时不易凋亡，地塞米松增加胰岛素抵抗。总之，β细胞对慢性高血糖症的适应以及因此增加的胰岛素需求伴随着可能有助于肥大β细胞存活的保护性应激基因的诱导。
Hypertrophy is one mechanism of pancreatic beta-cell. growth and is seen as an important compensatory response to insulin resistance. We hypothesized that the induction of protective genes contributes to the survival of enlarged (hypertrophied) beta-cells. Here, we evaluated changes in stress gene expression that accompany beta-cell hypertrophy in islets from hyperglycemic rats 4 weeks after partial pancreatectomy (Px). A variety of protective genes were upregulated, with markedly increased expression of the antioxidant genes heme oxygenase-1 and glutathione peroxidase and the antiapoptotic gene A20. Cu/Zn-superoxide dismutase (SOD) and Mn-SOD were modestly induced, and Bcl-2 was modestly reduced; however, several other stress genes (catalase, heat shock protein 70, and p53) were unaltered. The increases in mRNA levels corresponded to the degree of hyperglycemia and were reversed in Px rats by 2-week treatment with phlorizin (treatment that normalized hyperglycemia), strongly suggesting the specificity of hyperglycemia in eliciting the response. Hyperglycemia in Px rats also led to activation of nuclear factor-kappaB in islets. The profound change in beta-cell phenotype of hyperglycemic Px rats resulted in a reduced sensitivity to the beta-cell toxin streptozotocin. Sensitivity to the toxin was restored, along with the beta-cell phenotype, in islets from phlorizin-treated Px rats. Furthermore, beta-cells of Px rats were not vulnerable to apoptosis when further challenged in vivo with dexamethasone, which increases insulin resistance. In conclusion, beta-cell adaptation to chronic hyperglycemia and, hence, increased insulin demand is accompanied by the induction of protective stress genes that may contribute to the survival of hypertrophied beta-cells.