Stable and functional regeneration of pancreatic beta-cell population in nSTZ-rats treated with tungstate
Stable and functional regeneration of pancreatic beta-cell population in nSTZ-rats treated with tungstate
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DOI：
10.1007/s00125-004-1332-8
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发表时间：
2004-03-01
期刊：
影响因子：
8.2
通讯作者：
Gomis, R
中科院分区：
文献类型：
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作者：
Fernández-Alvarez, J;Barberà, A;Gomis, R
目的/假设。钨酸钠最近已成为一种有效的口服治疗糖尿病。我们研究了钨酸盐给药对胰腺β细胞团的影响及其治疗潜力。通过饮用水给予钨酸钠给健康和新生的链脲佐菌素（nSTZ）糖尿病大鼠一个月。从每只大鼠的胰腺被删除和形态计量学和免疫细胞化学研究进行。并对钨酸盐作用的分子机理进行了探讨。在nSTZ大鼠中，给予该化合物使高血糖正常化，并增加胰岛素血症和胰岛胰岛素含量。早在治疗的第4天血糖浓度就恢复正常，并且钨酸盐治疗产生了β细胞质量的部分恢复。停药后，大鼠的血流量保持正常。形态学研究表明，β细胞质量的增加不是由于β细胞肥大，而是由于增生，在治疗的糖尿病大鼠中胰岛密度增加。钨酸盐治疗增加了胰岛外β细胞的复制，而没有改变胰岛内β细胞的复制率。此外，治疗诱导位于导管附近的胰岛素阳性细胞增加;分散在外分泌组织中的PDX-1阳性细胞增加，表明活跃的新生。在糖尿病大鼠胰岛中，钨酸盐可通过激活p38来增加PDX-1的磷酸化状态。这些观察结果表明，钨酸盐治疗能够再生稳定的功能性胰腺β细胞群，其导致并维持正常血糖。
Aims/hypothesis. Sodium tungstate has recently emerged as an effective oral treatment for diabetes. We examined the effects of tungstate administration in the beta-cell mass of the pancreas as well as its therapeutic potential.Methods. Sodium tungstate was administered via drinking water to healthy and neonatal streptozotocin (nSTZ)-diabetic rats for one month. The pancreas from each rat was removed and morphometric and immunocytochemical studies were carried out. The molecular mechanism of tungstate's action was also studied.Results. In nSTZ rats administration of this compound normalised glycaemia, and increased insulinaemia and islet insulin content. Blood glucose concentrations were normalised as early as on day 4 of treatment, and tungstate treatment produced a partial recovery of beta-cell mass. The rats remained normoglycaemic after tungstate withdrawal. Morphometric studies showed that the increase in beta-cell mass was not due to beta-cell hypertrophy but to hyperplasia, with an increase in islet density in treated diabetic rats. Tungstate treatment increased extra-islet beta-cell replication without modifying intra-islet beta-cell replication rates. Moreover, the treatment induced increases in insulin-positive cells located close to ducts; and in PDX-1 positive cells scattered in the exocrine tissue, suggesting active neogenesis. In islets from treated diabetic rats, tungstate is able to increase the phosphorylation state of PDX-1 through the activation of p38.Conclusion/interpretation. These observations indicate that tungstate treatment is able to regenerate a stable, functional pancreatic beta-cell population which leads to and maintains normoglycaemia.