Shertzer Howard G, Schneider Scott N, Kendig Eric L, Clegg Deborah J, D'Alessio David A, Johansson Elisabet, Genter Mary Beth
Department of Environmental Health and Center for Environmental Genetics; University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA.
Chem Biol Interact. 2009 Jan 15;177(1):71-80. doi: 10.1016/j.cbi.2008.09.001. Epub 2008 Sep 7.
Diabetes is characterized by elevated fasting blood glucose (FBG) resulting from improper insulin regulation and/or insulin resistance. Herein we used female C57BL/6J mouse models for type 1 diabetes (streptozotocin [STZ] treatment) and type 2 diabetes (high-fat diet) to examine the ability of 4b,5,9b,10-tetrahydroindeno[1,2-b]indole (THII) to intervene in the progression of diabetes. THII (100 microM in drinking water) significantly diminished and partially reversed the increase in FBG levels produced by STZ. After 10 weeks on a high-fat diet, mice had normal FBG levels, but exhibited fasting hyperinsulemia and loss of glucose tolerance. THII significantly diminished these changes in glucose and insulin. In isolated liver mitochondria, THII inhibited succinate-dependent H(2)O(2) production, while in white adipose tissue, THII inhibited NADPH oxidase-mediated H(2)O(2) production and lipid peroxidation. Without intervention, such oxidative processes might otherwise promote diabetogenesis via inflammatory pathways. THII also increased O(2) consumption and lowered respiratory quotient (CO(2) produced/O(2) consumed) in vivo, indicating a greater utilization of fat for metabolic fuel. Increased metabolic utilization of fat correlated with a decrease in the rate of body weight gain in THII-treated mice fed the high-fat diet. We conclude that THII may retard the progression of diabetes via multiple pathways, including the inhibition of oxidative and inflammatory pathways.
糖尿病的特征是由于胰岛素调节不当和/或胰岛素抵抗导致空腹血糖（FBG）升高。在此，我们使用1型糖尿病（链脲佐菌素[STZ]处理）和2型糖尿病（高脂饮食）的雌性C57BL/6J小鼠模型来研究4b,5,9b,10-四氢茚并[1,2-b]吲哚（THII）干预糖尿病进展的能力。THII（饮用水中浓度为100 microM）显著降低并部分逆转了STZ引起的FBG水平升高。高脂饮食10周后，小鼠的FBG水平正常，但出现空腹高胰岛素血症和葡萄糖耐量丧失。THII显著减轻了这些葡萄糖和胰岛素的变化。在分离的肝线粒体中，THII抑制琥珀酸依赖性H(2)O(2)的产生，而在白色脂肪组织中，THII抑制NADPH氧化酶介导的H(2)O(2)产生和脂质过氧化。若无干预，此类氧化过程可能会通过炎症途径促进糖尿病发生。THII还增加了体内的O(2)消耗并降低了呼吸商（产生的CO(2)/消耗的O(2)），表明更多地利用脂肪作为代谢燃料。在喂食高脂饮食的THII处理小鼠中，脂肪代谢利用率的增加与体重增加速率的降低相关。我们得出结论，THII可能通过多种途径延缓糖尿病进展，包括抑制氧化和炎症途径。
