Objective To investigate the effect of adiponectin (APN) on the insulin pathway in the liver of OLETF rats and explore its molecular mechanism. Methods Twenty male OLETF rats and 10 male LETO rats were sacrificed at 8 and 32 weeks of age to examine the fasting blood glucose, serum insulin, adiponectin and blood lipid profiles. The APN, phosphotyrosine of insulin receptor substrate-1 (IRS-1), IKKβ and nuclear-kB (NF-kB) in the liver tissue were determined using ELISA, Western blotting or immunohistochemistry. Results The plasma adiponectin level in OLETF rats was significantly lower than that of LETO rats since 8 weeks of age (P<0.01). At 32 weeks of age, the blood lipid levels of OLETF rats increased significantly (P<0.05) with inverse correlations to plasma adiponectin (P<0.01). The liver APN, py-IRS-1, IKKβ and NF-kB levels in OLETF rats differed significantly from those of LETO rats at both 8 and 32 weeks. At 32 weeks of age, the APN level of both rats were correlated to the levels of NF-kB and py-IRS-1 (P< 0.01). Conclusion APN may decrease tyrosin phosphorylation of IRS-1 via the IKK/NFkB pathway and inhibit insulin signaling pathway in the liver, which contributes to hyerlipidemia, hyperglycemia and development of type 2 diabetes.%目的 探讨脂联素对自发性2型糖尿病(OLETF)大鼠肝脏胰岛素信号通路的影响及其分子信号机制.方法 自发性2型糖尿病大鼠OLETF鼠20只,同系健康对照LETO鼠10只.于8周和32周龄分别宰杀.检测空腹血糖、血浆胰岛素、脂联素、血脂水平,并以ELISA、免疫印迹和免疫组化法检测肝脏脂联素、胰岛素受体底物-1酪氨酸磷酸化水平(py-IRS-1)以及IKKβ和NFkB表达水平.结果 OLETF鼠血浆脂联素水平在8周龄和32周龄均显著低于LETO鼠(P<0.05).32周龄时OLETF鼠血清胰岛素、TG、FFA、ISI均显著升高(P<0.05).脂联素水平与FBG、血清胰岛素、TG、FFA、ISI数显著相关(P均<0.01).OLETF鼠肝脏脂联素和py-IRS-1水平在8周龄和32周龄均显著低于LETO鼠,IKKβ和NFkB水平也显著升高(P<0.01).py-IRS-1与肝组织脂联素、IKKβ和NFkB变化显著相关(P<0.01).32周龄时脂联素水平与NF-κB和py-IRS-1显著负相关(P<0.05).结论OLETF鼠脂联素可能通过NFkB通路影响肝脏IRS-1酪氨酸磷酸化水平,导致肝脏的胰岛素信号传导障碍及糖、脂代谢紊乱,参与2型糖尿病的发生发展.
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