Impact of Small-Molecule Glucokinase Activator on Glucose Metabolism and β-Cell Mass
Impact of Small-Molecule Glucokinase Activator on Glucose Metabolism and β-Cell Mass
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DOI：
10.1210/en.2008-1183
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发表时间：
2009-03-01
期刊：
影响因子：
4.8
通讯作者：
Koike, Takao
中科院分区：
文献类型：
--
作者：
Nakamura, Akinobu;Terauchi, Yasuo;Koike, Takao
我们研究了葡萄糖激酶激活剂 (GKA) 对葡萄糖代谢和 β 细胞质量的影响。我们分析了四个小鼠组：野生型小鼠和高脂肪（HF）饮食的葡萄糖激酶基因β细胞特异性单倍体不足（Gck（+/-））小鼠。每个基因型也用混合在 HF 饮食中的 GKA 进行治疗。使用啮齿动物胰岛素瘤细胞和分离的胰岛通过 GKA 评估 β 细胞增殖。采用上述饮食 20 周后，四组之间的体重、血脂和肝脏甘油三酯含量没有差异。两种基因型小鼠在接受 GKA 治疗后不久，葡萄糖耐量均得到改善。与 Gck(+/-) 小鼠相比，野生型小鼠的 β 细胞质量有所增加，但在两种基因型中施用 GKA 后均未观察到进一步的增加。有趣的是，GKA 能够上调胰岛素瘤细胞和分离胰岛中胰岛素受体底物 2 (Irs-2) 的表达。与没有 GKA 的小鼠相比，GKA 的施用增加了胰岛素瘤细胞中 5-溴-2-脱氧尿苷 (BrdU) 的掺入，并且 GKA 的 3 天施用显着增加了用 GKA 治疗的小鼠的两种基因型的 BrdU 掺入。总之，GKA 能够长期改善 HF 饮食小鼠的葡萄糖代谢。虽然长期GKA给药未能引起体内β细胞质量的进一步增加，但GKA能够在体外和体内给药3天后增加β细胞增殖。这种明显的差异可以通过 GKA 治疗导致环境血糖水平长期降低来解释。 （内分泌学 150：1147-1154，2009）
We investigated the effect of glucokinase activator (GKA) on glucose metabolism and beta-cell mass. We analyzed four mouse groups: wild-type mice and beta-cell-specific haploinsufficiency of glucokinase gene (Gck(+/-)) mice on a high-fat (HF) diet. Each genotype was also treated with GKA mixed in the HF diet. Rodent insulinoma cells and isolated islets were used to evaluate beta-cell proliferation by GKA. After 20 wk on the above diets, there were no differences in body weight, lipid profiles, and liver triglyceride content among the four groups. Glucose tolerance was improved shortly after the GKA treatment in both genotypes of mice. beta-Cell mass increased in wild-type mice compared with Gck(+/-) mice, but a further increase was not observed after the administration of GKA in both genotypes. Interestingly, GKA was able to up-regulate insulin receptor substrate-2 (Irs-2) expression in insulinoma cells and isolated islets. The administration of GKA increased 5-bromo-2-deoxyuridine (BrdU) incorporation in insulinoma cells, and 3 d administration of GKA markedly increased BrdU incorporation in mice treated with GKA in both genotypes, compared with those without GKA. In conclusion, GKA was able to chronically improve glucose metabolism for mice on the HF diet. Although chronic GKA administration failed to cause a further increase in beta-cell mass in vivo, GKA was able to increase beta cell proliferation in vitro and with a 3-d administration in vivo. This apparent discrepancy can be explained by a chronic reduction in ambient blood glucose levels by GKA treatment. (Endocrinology 150: 1147-1154, 2009)