Identification of interactive loci linked to insulin and leptin in mice with genetic insulin resistance
Identification of interactive loci linked to insulin and leptin in mice with genetic insulin resistance
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DOI：
10.2337/diabetes.52.6.1535
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发表时间：
2003-06-01
期刊：
影响因子：
7.7
通讯作者：
Kahn, CR
中科院分区：
文献类型：
--
作者：
Almind, K;Kulkarni, RN;Kahn, CR
胰岛素受体和胰岛素受体底物-1缺失的双杂合（DH）小鼠是瘦的、胰岛素抵抗的，并且具有强烈依赖于小鼠遗传背景的表型。在C57 BL/6（B6）背景下，DH小鼠出现明显的高胰岛素血症和糖尿病，而在12956背景下，DH小鼠仅表现出胰岛素轻度升高，并且没有糖尿病。通过这两个品系之间的杂交产生的F2雄性小鼠表现出60%的糖尿病发病率和与葡萄糖相关的胰岛素水平的钟形分布，这让人想起患有2型糖尿病的人类。这些小鼠还表现出与体重相关的广泛的瘦素水平。对F2小鼠的全基因组扫描揭示了14号染色体上与高胰岛素血症相关的数量性状位点（QTL）（D14 Mit 55），其比值对数（LOD）得分的峰值为5.6，占该性状的69%。与高瘦素血症相关的LOD得分为3.7的QTL存在于7号染色体上的解偶联蛋白2/3基因簇区域中的D12 Mit 38（先前分配给12号染色体的标记）处。该基因座还与D14 Mit 55在高胰岛素血症的发展中协同相互作用，并与染色体12上与高胰岛素血症相关的QTL（D12 Mit 231）协同相互作用。这些数据证明了多种遗传修饰剂如何相互作用并影响糖尿病的发展和具有遗传程序性胰岛素抵抗的动物的表型，并提供了这些基因的位置和性质的证据。糖尿病52：1535- 1543，2003。
Mice double heterozygous (DH) for deletion of insulin receptor and insulin receptor substrate-1 are lean, insulin resistant, and have a phenotype that strongly depends on the genetic background of the mouse. On the C57BL/6 (B6) background, DH mice develop marked hyperinsulinemia and diabetes, whereas on the 12956 background, DH mice exhibit only mild elevations of insulin and remain free of diabetes. F2 male mice created by an intercross between these two strains exhibit a 60% incidence of diabetes and a bell-shaped distribution of insulin levels as related to glucose, reminiscent of that in humans with type 2 diabetes. These mice also exhibit a wide range of leptin levels as related to body weight. A genome-wide scan of F2 mice reveals a quantitative trait locus (QTL) related to hyperinsulinemia on chromosome 14 (D14Mit55) with a peak logarithm of odds (LOD) score of 5.6, accounting for up to 69% of this trait. A QTL with a LOD score of 3.7 related to hyperleptinemia is present on chromosome 7 at D12Mit38 (a marker previously assigned to chromosome 12) in the area of the uncoupling protein 2/3 gene cluster. This locus also interacts synergistically with D14Mit55 in development of hyperinsulinemia and with a QTL on chromosome 12 (D12Mit231) related to hyper-glycemia. These data demonstrate how multiple genetic modifiers can interact and influence the development of diabetes and the phenotype of animals with genetically programmed insulin resistance and provide evidence as to the location and nature of these genes. Diabetes 52: 1535-1543,2003.