Shimoyama Tatsuhiro, Yamaguchi Shinya, Takahashi Kazuto, Katsuta Hidenori, Ito Eisuke, Seki Hiroyuki, Ushikawa Kenji, Katahira Hiroshi, Yoshimoto Katsuhiko, Ohno Hideki, Nagamatsu Shinya, Ishida Hitoshi
Third Department of Internal Medicine, Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan.
Metabolism. 2006 Jun;55(6):722-30. doi: 10.1016/j.metabol.2006.01.019.
Increased oxidative stress under hyperglycemia may contribute to progressive deterioration of peripheral insulin sensitivity. In this study, we investigated whether gliclazide, a second-generation sulfonylurea, can protect 3T3L1 adipocytes from insulin resistance induced by oxidative stress, and whether gliclazide can restore insulin-stimulated glucose transporter 4 (GLUT4) translocation under oxidative stress. We incubated 3T3L1 adipocytes in hydrogen peroxide to produce oxidative stress, then administered various concentrations of gliclazide, N-acetylcystein (NAC), or glibenclamide. Cells treated with these drugs were next exposed to insulin, subsequent glucose uptake was measured, and the insulin-stimulated GLUT4 translocation was monitored in living cells. We found that hydrogen peroxide treatment alone suppressed glucose uptake by insulin stimulation to 65.9%+/-7.8% of the corresponding controls (P<.01). However, addition of 0.1 to 10 micromol/L gliclazide to hydrogen peroxide-treated cells dose-dependently restored glucose uptake, with 5 micromol/L gliclazide significantly restoring glucose uptake to 93.3+/-6.6% (P<.01) even under hydrogen peroxide. Treatment with the known anti-oxidant NAC also dose-dependently (0.1-10 mmol/L) restored insulin-induced glucose uptake in the presence of hydrogen peroxide. However, glibenclamide (0.1-10 micromol/L), another second-generation sulfonylurea, failed to improve glucose uptake. Similarly, treatment with 5 micromol/L gliclazide or 10 mmol/L NAC significantly overcome the reduction in insulin-stimulated GLUT4 translocation by hydrogen peroxide (P<.01), whereas 5 micromol/L glibenclamide did not. Therefore our data regarding gliclazide further characterize its mechanism of hypoglycemic effect: the observed improvements in insulin sensitivity and in GLUT4 translocation indicate that gliclazide counters the hydrogen peroxide-induced insulin resistance in 3T3L1 adipocytes and also would further augment the hypoglycemic effect of this drug as insulinotropic sulfonylurea.
高血糖状态下氧化应激增加可能导致外周胰岛素敏感性逐渐恶化。在本研究中，我们调查了第二代磺脲类药物格列齐特是否能保护3T3L1脂肪细胞免受氧化应激诱导的胰岛素抵抗，以及格列齐特是否能在氧化应激状态下恢复胰岛素刺激的葡萄糖转运蛋白4（GLUT4）转位。我们将3T3L1脂肪细胞置于过氧化氢中孵育以产生氧化应激，然后给予不同浓度的格列齐特、N-乙酰半胱氨酸（NAC）或格列本脲。接下来，用这些药物处理的细胞暴露于胰岛素，测量随后的葡萄糖摄取，并在活细胞中监测胰岛素刺激的GLUT4转位。我们发现，单独用过氧化氢处理可将胰岛素刺激的葡萄糖摄取抑制至相应对照组的65.9%±7.8%（P<0.01）。然而，向用过氧化氢处理的细胞中添加0.1至10μmol/L格列齐特可剂量依赖性地恢复葡萄糖摄取，即使在过氧化氢存在的情况下，5μmol/L格列齐特也能将葡萄糖摄取显著恢复至93.3±6.6%（P<0.01）。用已知的抗氧化剂NAC处理（0.1 - 10 mmol/L）在过氧化氢存在的情况下也剂量依赖性地恢复了胰岛素诱导的葡萄糖摄取。然而，另一种第二代磺脲类药物格列本脲（0.1 - 10μmol/L）未能改善葡萄糖摄取。同样，用5μmol/L格列齐特或10 mmol/L NAC处理可显著克服过氧化氢对胰岛素刺激的GLUT4转位的降低作用（P<0.01），而5μmol/L格列本脲则不能。因此，我们关于格列齐特的数据进一步阐明了其降糖作用机制：观察到的胰岛素敏感性和GLUT4转位的改善表明，格列齐特可对抗过氧化氢诱导的3T3L1脂肪细胞胰岛素抵抗，并且作为促胰岛素分泌的磺脲类药物，还会进一步增强该药物的降糖作用。
