Destruction of pancreatic β-cells by transgenic induction of prostaglandin E2 in the islets
Destruction of pancreatic β-cells by transgenic induction of prostaglandin E2 in the islets
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DOI：
10.1074/jbc.m602424200
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发表时间：
2006-09-29
影响因子：
4.8
通讯作者：
Oshima, Masanobu
中科院分区：
文献类型：
--
作者：
Oshima, Hiroko;Taketo, Makoto Mark;Oshima, Masanobu
2型糖尿病的特征是外周组织的胰岛素抵抗和胰腺β细胞功能障碍。此外，胰腺β细胞的数量减少是晚期2型糖尿病的继发性影响，尽管分子机制尚未阐明。最近，研究表明，高血糖条件诱导胰岛中环氧合酶-2的表达，并增加下游产物前列腺素E-2（PGE（2））。为了研究高糖诱导的PGE（2）是否对胰腺β细胞有不良影响，我们使用大鼠胰岛素-2基因启动子（RIP）在其β细胞中产生表达环氧合酶-2和微粒体前列腺素E合酶-1的转基因小鼠（RIP-C2mE）。纯合子RIP-C2mE（Tg/Tg）小鼠从6周龄开始表现出严重的高血糖症。尽管杂合RIP-C2mE（Tg/-）小鼠在其一生中显示出正常的血糖水平，但当葡萄糖负荷时，该水平与野生型小鼠相比显著增加。在RIP-C2mE（Tg/-）和（Tg/Tg）小鼠中，β细胞相对于总胰岛细胞数的相对数量分别减少至54和14%，而在野生型小鼠中为84%。重要的是，与野生型小鼠相比，4周龄的RIP-C2mE（Tg/Tg）小鼠胰岛中的增殖率显著降低。由于β细胞不仅在出生后时期复制，而且在成人胰腺中也以基础水平复制，因此增加的PGE 2信号传导可能通过抑制增殖而有助于胰腺β细胞质量的减少，从而进一步加重糖尿病。
Type 2 diabetes mellitus is characterized by insulin resistance of peripheral tissues and dysfunction of pancreatic beta-cells. Furthermore, the number of pancreatic beta-cells decreases as a secondary effect of advanced type 2 diabetes, although the molecular mechanism has not been elucidated. Recently, it has been shown that hyperglycemic conditions induce the expression of cyclooxygenase-2 in pancreatic islets and increase the downstream product prostaglandin E-2 (PGE(2)). To investigate whether high glucose-induced PGE(2) has an adverse effect on pancreatic beta-cells, we generated transgenic mice (RIP-C2mE) that express cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in their beta-cells using the rat insulin-2 gene promoter (RIP). The homozygous RIP-C2mE (Tg/Tg) mice showed severe hyperglycemia from six weeks of age. Although the heterozygous RIP-C2mE (Tg/-) mice showed normal blood glucose levels throughout their lifetime, this level increased significantly compared with that of wild-type mice when glucose was loaded. The relative number of beta-cells to the total islet cell number was reduced to 54 and 14% in the RIP-C2mE (Tg/-) and (Tg/Tg) mice, respectively, whereas that in the wild-type mice was 84%. Importantly, the proliferation rate in the islets of the RIP-C2mE (Tg/Tg) mice at four weeks of age decreased significantly in comparison to that in the wild-type mice. Because beta-cells replicate not only during the postnatal period but also in the adult pancreas at a basal level, it is possible that increased PGE2 signaling thus contributes to the reduction of the pancreatic beta-cell mass through inhibition of proliferation, thereby aggravating diabetes further.