Direct evidence for susceptibility genes for type 2 diabetes on mouse chromosomes 11 and 14
Direct evidence for susceptibility genes for type 2 diabetes on mouse chromosomes 11 and 14
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DOI：
10.1007/s00125-010-1737-5
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发表时间：
2010-07-01
期刊：
影响因子：
8.2
通讯作者：
Ikegami, H.
中科院分区：
文献类型：
--
作者：
Babaya, N.;Fujisawa, T.;Ikegami, H.
2型糖尿病的致糖尿病基因座已被定位到Nagoya-Shibata-Yasuda（NSY）小鼠（2型糖尿病的动物模型）的小鼠染色体（Chr）11和14。我们建立了三个纯合的致糖尿病基因NSY-Chr 11、NSY-Chr 14或两者均纯合的同源株，以对照C3 H为背景，（分别为C3 H-11（NSY）、C3 H-14（NSY）和C3 H-11（NSY）14（NSY）），并纵向监测糖尿病相关表型。将葡萄糖激酶基因作为Chr11.C3H-11（NSY）小鼠的位置候选基因进行测序，显示与胰岛素分泌受损和年龄依赖性胰岛素抵抗相关的高血糖症，但无肥胖。C3 H-14（NSY）小鼠表现出主要由于胰岛素抵抗引起的高血脂症，体脂百分比略有增加。C3 H-11（NSY）14（NSY）双染色体小鼠表现出明显的高脂血症和肥胖，而单染色体小鼠则无此现象。NSY和C3 H小鼠葡萄糖激酶基因的序列存在等位变异，这些数据为Chr 11和Chr 14携带2型糖尿病的主要易感基因提供了直接证据。这两个染色体相互作用，导致更严重的高血脂症和肥胖症，这是没有观察到的存在下，任何一个单一的染色体，表明不同的模式的基因-基因相互作用取决于表型。在consomic菌株中保留的表型的显著变化将有助于精细定位和鉴定负责基因及其与彼此、其它基因和环境因子的相互作用。
Diabetogenic loci for type 2 diabetes have been mapped to mouse chromosome (Chr) 11 and 14 in the Nagoya-Shibata-Yasuda (NSY) mouse, an animal model of type 2 diabetes. We aimed to obtain direct evidence of these genes on each chromosome and to clarify their function and interaction in conferring susceptibility to type 2 diabetes.We established three consomic strains homozygous for diabetogenic NSY-Chr11, NSY-Chr14 or both on the control C3H background (C3H-11(NSY), C3H-14(NSY) and C3H-11(NSY)14(NSY), respectively), and monitored diabetes-related phenotypes longitudinally. The glucokinase gene was sequenced as a positional candidate gene on Chr11.C3H-11(NSY) mice showed hyperglycaemia associated with impaired insulin secretion and age-dependent insulin resistance without obesity. C3H-14(NSY) mice exhibited hyperglycaemia mainly due to insulin resistance, with a slight increase in percentage body fat. C3H-11(NSY)14(NSY) double consomic mice showed marked hyperglycaemia and obesity, which was not observed in single consomic strains. Sequences of the glucokinase gene were allelically variant between NSY and C3H mice.These data provide direct evidence that Chr11 and Chr14 harbour major susceptibility genes for type 2 diabetes. These two chromosomes interact to cause more severe hyperglycaemia and obesity, which was not observed with the presence of either single chromosome, indicating different modes of gene-gene interaction depending on the phenotype. Marked changes in the phenotypes retained in the consomic strains will facilitate fine mapping and the identification of the responsible genes and their interaction with each other, other genes and environmental factors.