Tissue-Specific Differences in the Development of Insulin Resistance in a Mouse Model for Type 1 Diabetes
Tissue-Specific Differences in the Development of Insulin Resistance in a Mouse Model for Type 1 Diabetes
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DOI：
10.2337/db13-1794
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发表时间：
2014-11-01
期刊：
影响因子：
7.7
通讯作者：
Roden, Michael
中科院分区：
文献类型：
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作者：
Jelenik, Tomas;Sequaris, Gilles;Roden, Michael
虽然胰岛素抵抗是2型糖尿病的基础，但它在1型糖尿病发展中的作用越来越受到关注。在1型糖尿病的模型中，非肥胖糖尿病（NOD）小鼠，我们发现由脂质和葡萄糖非依赖性机制驱动的胰岛素抵抗已经存在于糖尿病前期小鼠的肝脏中。肝脏胰岛素抵抗与线粒体呼吸短暂升高相关，随后脂质过氧化物和c-Jun N-末端激酶活性增加。在糖尿病发病时，脂肪组织脂解增加促进了肌细胞甘油二酯的积累。与此同时，肌细胞蛋白激酶C θ活性和血清胎球蛋白A水平增加。肌肉线粒体氧化能力在糖尿病发病时不变，但在后期阶段下降。总之，肝脏和肌肉胰岛素抵抗表现在不同的阶段，并涉及不同的细胞机制在NOD小鼠糖尿病的发展。
Although insulin resistance is known to underlie type 2 diabetes, its role in the development of type 1 diabetes has been gaining increasing interest. In a model of type 1 diabetes, the nonobese diabetic (NOD) mouse, we found that insulin resistance driven by lipid- and glucose-independent mechanisms is already present in the liver of prediabetic mice. Hepatic insulin resistance is associated with a transient rise in mitochondrial respiration followed by increased production of lipid peroxides and c-Jun N-terminal kinase activity. At the onset of diabetes, increased adipose tissue lipolysis promotes myocellular diacylglycerol accumulation. This is paralleled by increased myocellular protein kinase C theta activity and serum fetuin A levels. Muscle mitochondrial oxidative capacity is unchanged at the onset but decreases at later stages of diabetes. In conclusion, hepatic and muscle insulin resistance manifest at different stages and involve distinct cellular mechanisms during the development of diabetes in the NOD mouse.