Up-Regulating the Hemeoxygenase System Enhances Insulin Sensitivity and Improves Glucose Metabolism in Insulin-Resistant Diabetes in Goto-Kakizaki Rats
Up-Regulating the Hemeoxygenase System Enhances Insulin Sensitivity and Improves Glucose Metabolism in Insulin-Resistant Diabetes in Goto-Kakizaki Rats
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DOI：
10.1210/en.2008-1370
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发表时间：
2009-06-01
期刊：
影响因子：
4.8
通讯作者：
Jadhav, Ashok
中科院分区：
文献类型：
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作者：
Ndisang, Joseph Fomusi;Jadhav, Ashok
胰岛素介导的信号转导与脂联素、一磷酸腺苷活化蛋白激酶(AMPK)和葡萄糖转运蛋白4(GLUT4)呈正相关，而与氧化/炎症介质如核因子-kappaB、活化蛋白(AP)-1、AP-2和c-Jun-N末端激酶呈负相关。虽然血红素加氧酶(HO)抑制氧化损伤，但它对胰岛素增敏剂AMPK和GLUT4的影响尚不清楚，并使用Goto-Kakizaki大鼠(GK)进行了研究，GK是一种非肥胖的胰岛素抵抗的2型糖尿病模型。用氯化高铁血红素诱导HO或用铬中卟啉(CRMP)抑制HO。在GK大鼠中应用氯化血红素可产生3个月的降糖效果，而HO抑制剂CRMP则加剧高血糖，并使胰岛素信号/葡萄糖代谢无效。有趣的是，降糖药物伴随着胰岛素的矛盾增加，同时也伴随着胰岛素增敏剂如脂联素、AMPK和GLUT4在腓肠肌中的增强。此外，氯化血红素通过上调腓肠肌中的HO-1、HO活性、超氧化物歧化酶、过氧化氢酶和总抗氧化能力，增强了胰岛素信号转导的中介/调节因子，如cGMP和cAMP，并抑制了氧化损伤。相应地，包括核因子-kappaB、AP-1、AP-2、c-Jun-N末端激酶和8-异前列腺素在内的氧化标记物/介质减少，而CRMP使氯化血红素的细胞保护和抗糖尿病作用失效。相应地，IP葡萄糖耐量、胰岛素耐量和稳态模型评估胰岛素抵抗分析显示，经氯化高铁血红素处理的GK大鼠的葡萄糖耐量得到改善，胰岛素耐受减少，胰岛素敏感性增强，胰岛素抵抗减少。相反，CRMP消除了胰岛素增敏作用，恢复和/或加剧了胰岛素抵抗。我们的研究揭示了氯化血红素持续3个月的降糖作用，并揭示了HO系统、脂联素、AMPK和GLUT4之间的协同作用，可以探索在胰岛素抵抗糖尿病中增强胰岛素信号转导和改善糖代谢。(内分泌学150：2627-2636,2009)
Insulin-mediated signal transduction is positively correlated to adiponectin, adenosine monophosphate-activated protein kinase (AMPK), and glucose-transporter-4 (GLUT4) but negatively to oxidative/inflammatory mediators such as nuclear factor-kappa B, activating-protein (AP)-1, AP-2, and c-Jun-N-terminal-kinase. Although hemeoxygenase (HO) suppresses oxidative insults, its effects on insulin-sensitizing agents like AMPK and GLUT4 remains unclear and were investigated using Goto-Kakizaki rats (GK), a nonobese insulin-resistant type-2 diabetic model. HO was induced with hemin or inhibited with chromium mesoporphyrin (CrMP). The application of hemin to GK rats evoked a 3-month antidiabetic effect, whereas the HO-inhibitor, CrMP, exacerbated hyperglycemia and nullified insulin-signaling/glucose metabolism. Interestingly, the antidiabetic was accompanied by a paradoxical increase of insulin alongside the potentiation of insulin-sensitizing agents such as adiponectin, AMPK, and GLUT4 in the gastrocnemius muscle. Furthermore, hemin enhanced mediators/regulators of insulin signaling like cGMP and cAMP and suppressed oxidative insults by up-regulating HO-1, HO activity, superoxide dismutase, catalase, and the total antioxidant capacity in the gastrocnemius muscle. Accordingly, oxidative markers/mediators including nuclear factor-kappa B, AP-1, AP-2, c-Jun-N-terminal-kinase, and 8-isoprostane were abated, whereas CrMP annulled the cytoprotective and antidiabetic effects of hemin. Correspondingly, ip glucose tolerance, insulin tolerance, and homeostasis model assessment insulin resistance analyses revealed improved glucose tolerance, reduced insulin intolerance, enhanced insulin sensitivity, and reduced insulin resistance in hemin-treated GK rats. In contrast, CrMP, abolished the insulin-sensitizing effects and restored and/or exacerbated insulin resistance. Our study unveils a 3-month enduring antidiabetic effect of hemin and unmasks the synergistic interaction among the HO system, adiponectin, AMPK, and GLUT4 that could be explored to enhance insulin signaling and improve glucose metabolism in insulin-resistant diabetes. (Endocrinology 150: 2627-2636, 2009)