GLUT2 in Pancreatic Islets: Crucial Target Molecule in Diabetes Induced With Multiple Low Doses of Streptozotocin in Mice
GLUT2 in Pancreatic Islets: Crucial Target Molecule in Diabetes Induced With Multiple Low Doses of Streptozotocin in Mice
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DOI：
10.2337/diab.47.1.50
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发表时间：
1998-01
期刊：
影响因子：
7.7
通讯作者：
Zhiyong Wang;H. Gleichmann
中科院分区：
文献类型：
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作者：
Zhiyong Wang;H. Gleichmann
在小鼠中，糖尿病可以通过多次低剂量的链脲佐菌素（MLD-STZ）诱导，即，连续5天每天40 mg/kg体重。在该模型中，只有当STZ诱导β细胞毒性和T细胞依赖性免疫反应时，糖尿病才会发生。然而，MLD-STZ诱导的β细胞毒性的靶分子尚不清楚。在这项研究中，我们报告GLUT 2是MLD-STZ毒性的靶分子。在离体条件下，从MLDSTZ处理的C57 BL/6雄性小鼠分离的胰岛中发现GLUT 2蛋白和mRNA表达逐渐减少，而β-肌动蛋白、葡萄糖激酶和胰岛素原的mRNA表达不受影响。在第三次STZ注射后1天，GLUT 2蛋白和mRNA表达均首次显著降低，明显早于高血糖症的发作。减少的程度随着STZ注射次数的增加而增加，并随着时间的推移而增加，在最后一次注射后，即，第五，STZ注射。STZ诱导的GLUT 2蛋白和mRNA的减少不是由于β细胞的基本损失，因为离体，不仅分离的胰岛中的总RNA产量和蛋白含量，而且胰岛素原mRNA表达在不同处理组中没有显著差异。此外，从MLD-STZ处理的供体分离的胰岛对非葡萄糖促分泌素精氨酸的反应模式与溶剂处理的供体相似。有趣的是，MLD-STZ诱导的GLUT 2蛋白和mRNA的减少可以通过在每次STZ注射前给小鼠预注射5-硫代-D-葡萄糖来预防。显然，GLUT 2是MLD-STZ毒性的关键靶分子，并且这种毒性似乎先于针对β细胞的免疫反应。
In mice, diabetes can be induced by multiple low doses of streptozotocin (MLD-STZ), i.e., 40 mg/kg body wt on each of 5 consecutive days. In this model, diabetes develops only when STZ induces both β-cell toxicity and T-cell- dependent immune reactions. The target molecule(s) of MLD-STZ-induced β-cell toxicity are not known, however. In this study, we report that GLUT2 is a target molecule for MLD-STZ toxicity. Ex vivo, a gradual decrement of both GLUT2 protein and mRNA expression was found in pancreatic islets isolated from MLDSTZ-treated C57BL/6 male mice, whereas mRNA expression of β-actin, glucokinase, and proinsulin remained unaffected. Significant reduction of both GLUT2 protein and mRNA expression was first noted 1 day after the third STZ injection, clearly preceding the onset of hyperglycemia. The extent of reduction increased with the number of STZ injections administered and increased over time, after the last, i.e., fifth, STZ injection. The STZ-induced reduction of GLUT2 protein and mRNA was not due to an essential loss of β-cells, because ex vivo, not only the total RNA yield and protein content in isolated islets, but also proinsulin mRNA expression, failed to differ significantly in the differently treated groups. Furthermore, islets isolated from MLD-STZ-treated donors responded to the nonglucose secretagogue arginine in a pattern similar to that of solvent-treated donors. Interestingly, the MLD-STZ-induced reduction of both GLUT2 protein and mRNA was prevented by preinjecting mice with 5-thio-D-glucose before each STZ injection. Apparently, GLUT2 is a crucial target molecule of MLD-STZ toxicity, and this toxicity seems to precede the immune reactions against β-cells.