Insulin Is a Stronger Inducer of Insulin Resistance than Hyperglycemia in Mice with Type 1 Diabetes Mellitus (T1DM)
Insulin Is a Stronger Inducer of Insulin Resistance than Hyperglycemia in Mice with Type 1 Diabetes Mellitus (T1DM)
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DOI：
10.1074/jbc.m109.016675
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发表时间：
2009-10-02
影响因子：
4.8
通讯作者：
Cao, Wenhong
中科院分区：
文献类型：
--
作者：
Liu, Hui-Yu;Cao, Sophia Y.;Cao, Wenhong
1型糖尿病（T1 DM）受试者最终会出现胰岛素抵抗和其他T2 DM特征，如心血管疾病。确切的机制尚未完全了解。在这项研究中，我们检验了过度或不适当的胰岛素暴露是T1 DM胰岛素抵抗的主要介质的假设。我们发现，非肥胖型糖尿病小鼠持续暴露于地特胰岛素（类似于目前对人类T1 DM的一些常规治疗）可诱导严重的胰岛素抵抗，而相同时间（2周）未经治疗的高血糖不会引起明显的胰岛素抵抗。胰岛素抵抗伴随着减少线粒体生产的线粒体DNA和水平的转录和蛋白质的线粒体相关基因，增加异位脂肪积累的肝脏和骨骼肌（腓肠肌）的甘油三酯含量的测量，并检测GSH/GSSG比值升高的氧化应激。长时间暴露于培养的肝细胞胰岛素诱导显著的胰岛素抵抗，而相同长度的暴露于高水平的葡萄糖（33 mM）没有引起明显的胰岛素抵抗。此外，我们的研究结果表明，长期暴露于胰岛素引起的氧化应激，和封锁的锰超氧化物歧化酶的过表达的钙离子衍生的氧化应激防止胰岛素抵抗诱导的长期暴露于胰岛素。总之，我们的研究结果表明，过度暴露于胰岛素是T1 DM小鼠胰岛素抵抗的主要诱导因素。
Subjects with type 1 diabetes mellitus (T1DM) eventually develop insulin resistance and other features of T2DM such as cardiovascular disorders. The exact mechanism has been not been completely understood. In this study, we tested the hypothesis that excessive or inappropriate exposure to insulin is a primary mediator of insulin resistance in T1DM. We found that continuous exposure of mice with non-obese diabetes to insulin detemir, which is similar to some current conventional treatment of human T1DM, induced severe insulin resistance, whereas untreated hyperglycemia for the same amount of time (2 weeks) did not cause obvious insulin resistance. Insulin resistance was accompanied by decreased mitochondrial production as evaluated by mitochondrial DNA and levels of transcripts and proteins of mitochondrion-associated genes, increased ectopic fat accumulation in liver and skeletal muscle (gastrocnemius) evaluated by measurements of triglyceride content, and elevated oxidative stress detected by the GSH/GSSG ratio. Prolonged exposure of cultured hepatocytes to insulin induced significant insulin resistance, whereas the same length of exposure to a high level of glucose (33mM) did not cause obvious insulin resistance. Furthermore, our results showed that prolonged exposure to insulin caused oxidative stress, and blockade of mitochondrion-derived oxidative stress by overexpression of manganese-superoxide dismutase prevented insulin resistance induced by the prolonged exposure to insulin. Together, our results show that excessive exposure to insulin is a primary inducer of insulin resistance in T1DM in mice.