Development of diabetes in obese, insulin-resistant mice:: essential role of dietary carbohydrate in beta cell destruction
Development of diabetes in obese, insulin-resistant mice:: essential role of dietary carbohydrate in beta cell destruction
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DOI：
10.1007/s00125-007-0662-8
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发表时间：
2007-07-01
期刊：
影响因子：
8.2
通讯作者：
Joost, H.-G.
中科院分区：
文献类型：
--
作者：
Juergens, H. S.;Neschen, S.;Joost, H.-G.
目的/假设饮食中碳水化合物在2型糖尿病发病机制中的作用仍然是一个有争议的话题。在这里，我们分析了含碳水化合物和不含碳水化合物饮食对肥胖、易患糖尿病的新西兰肥胖(NZO)小鼠肥胖、胰岛素抵抗和β细胞衰竭的影响。材料与方法将NZO小鼠饲养在标准饮食(4%[w/w]脂肪、51%碳水化合物、19%蛋白质)、高脂肪饮食(分别为15%、47%和17%)和无碳水化合物饮食(分别为68%和20%)。在22周的时间里测量了身体成分和血糖。糖耐量试验和正常血糖-高胰岛素钳夹试验分析胰岛素敏感性。结果含碳水化合物标准或高脂饮食的小鼠由于选择性破坏胰岛β细胞，并伴有胰岛素、葡萄糖转运蛋白2(GLUT2)和肌腱膜纤维肉瘤癌基因同源物A(MafA)的免疫反应严重丧失，而形成严重的糖尿病(血糖和GT；16.6 mmol/L，葡萄糖尿)。相比之下，尽管病态肥胖伴随着严重的胰岛素抵抗和脂肪组织中巨噬细胞的大量聚集，但无碳水化合物饮食的小鼠仍保持正常血糖和胰岛增生。结论/解释这些数据表明，在没有饮食碳水化合物的情况下，肥胖、胰岛素抵抗和脂肪组织的炎症反应的组合不足以导致β细胞的破坏。
Aims/hypothesis The role of dietary carbohydrate in the pathogenesis of type 2 diabetes is still a subject of controversial debate. Here we analysed the effects of diets with and without carbohydrate on obesity, insulin resistance and development of beta cell failure in the obese, diabetes-prone New Zealand Obese (NZO) mouse.Materials and methods NZO mice were kept on a standard diet (4% [w/w] fat, 51% carbohydrate, 19% protein), a high-fat diet (15, 47 and 17%, respectively) and a carbohydrate-free diet in which carbohydrate was exchanged for fat (68 and 20%, respectively). Body composition and blood glucose were measured over a period of 22 weeks. Glucose tolerance tests and euglycaemic-hyperinsulinaemic clamps were performed to analyse insulin sensitivity. Islet morphology was assessed by immunohistochemistry.Results Mice on carbohydrate-containing standard or high-fat diets developed severe diabetes (blood glucose > 16.6 mmol/l, glucosuria) due to selective destruction of pancreatic beta cells associated with severe loss of immunoreactivity of insulin, glucose transporter 2 (GLUT2) and musculoaponeurotic fibrosarcoma oncogene homologue A (MafA). In contrast, mice on the carbohydrate-free diet remained normoglycaemic and exhibited hyperplastic islets in spite of a morbid obesity associated with severe insulin resistance and a massive accumulation of macrophages in adipose tissue.Conclusions/interpretation These data indicate that the combination of obesity, insulin resistance and the inflammatory response of adipose tissue are insufficient to cause beta cell destruction in the absence of dietary carbohydrate.