Nakamura Akinobu, Terauchi Yasuo, Ohyama Sumika, Kubota Junko, Shimazaki Hiroko, Nambu Tadahiro, Takamoto Iseki, Kubota Naoto, Eiki Junichi, Yoshioka Narihito, Kadowaki Takashi, Koike Takao
Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
Endocrinology. 2009 Mar;150(3):1147-54. doi: 10.1210/en.2008-1183. Epub 2008 Nov 13.
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.
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。我们分析了四组小鼠：野生型小鼠和高脂（HF）饮食下葡萄糖激酶基因（Gck(+/-)）β细胞特异性单倍体不足的小鼠。每种基因型的小鼠也用添加在HF饮食中的GKA进行处理。使用啮齿动物胰岛素瘤细胞和分离的胰岛来评估GKA对β细胞增殖的影响。在上述饮食喂养20周后，四组小鼠在体重、血脂谱和肝脏甘油三酯含量方面没有差异。在两种基因型的小鼠中，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细胞质量增加，但在两种基因型小鼠中给予GKA后均未观察到进一步增加。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。给予GKA可增加胰岛素瘤细胞中5-溴-2-脱氧尿苷（BrdU）的掺入，与未给予GKA的小鼠相比，在两种基因型中给予GKA的小鼠连续3天给予GKA后，BrdU掺入量明显增加。总之，GKA能够长期改善HF饮食小鼠的葡萄糖代谢。尽管长期给予GKA未能在体内使β细胞质量进一步增加，但GKA能够在体外以及在体内连续给药3天时增加β细胞增殖。这种明显的差异可以通过GKA治疗使周围血糖水平长期降低来解释。
