Control of beta cell function and proliferation in mice stimulated by small-molecule glucokinase activator under various conditions
Control of beta cell function and proliferation in mice stimulated by small-molecule glucokinase activator under various conditions
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DOI：
10.1007/s00125-012-2521-5
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发表时间：
2012-06-01
期刊：
影响因子：
8.2
通讯作者：
Terauchi, Y.
中科院分区：
文献类型：
--
作者：
Nakamura, A.;Togashi, Y.;Terauchi, Y.
我们研究了葡萄糖激酶激活剂（GKA）刺激小鼠胰岛β细胞功能和增殖相关基因的表达变化，以阐明GKA刺激β细胞功能和增殖的机制。从小鼠胰岛分离，研究GKA刺激β细胞功能和增殖相关基因表达的变化。此外，在高脂肪饮食或含有GKA的高脂肪饮食中使用敲除（(-/-)）小鼠来研究GKA对体内β细胞增殖的影响。在野生型小鼠中，GKA增加了表达。在（-/-）小鼠中，GKA增加了葡萄糖刺激的胰岛素分泌和表达，但没有增加β细胞的增殖。特别值得注意的是，氧化应激抑制了GKA诱导的和基因的上调。此外，GKA或exendin-4均未上调小鼠胰岛中和的表达，但事先给小鼠exendin-4可使GKA增加这些基因的表达。gka刺激的IRS2产生影响β细胞增殖，但不影响β细胞功能。氧化应激降低了GKA对β细胞功能和增殖相关基因表达变化的影响。因此，GKA和肠促胰岛素相关药物的联合治疗可能是有效的。
We investigated changes in the expression of genes involved in beta cell function and proliferation in mouse islets stimulated with glucokinase activator (GKA) in order to elucidate the mechanisms by which GKA stimulates beta cell function and proliferation.Islets isolated from mice were used to investigate changes in the expression of genes related to beta cell function and proliferation stimulated by GKA. In addition, knockout ( (-/-)) mice on a high-fat diet or a high-fat diet containing GKA were used to investigate the effects of GKA on beta cell proliferation in vivo.In wild-type mice, and expression was increased by GKA. In (-/-) mice, GKA administration increased the glucose-stimulated secretion of insulin and expression, but not beta cell proliferation. It was particularly noteworthy that oxidative stress inhibited the upregulation of the and genes induced by GKA. Moreover, whereas neither GKA alone nor exendin-4 alone upregulated the expression of and in the islets of / mice, prior administration of exendin-4 to the mice caused GKA to increase the expression of these genes.GKA-stimulated IRS2 production affected beta cell proliferation but not beta cell function. Oxidative stress diminished the effects of GKA on the changes in expression of genes involved in beta cell function and proliferation. A combination of GKA and an incretin-related agent might therefore be effective in therapy.