Both genetic and environmental factors contribute to type 2 diabetes development. We used consomic mice established from an animal type 2 diabetes model to identify susceptibility genes that contribute to type 2 diabetes development under specific environments. We previously established consomic strains (C3H-Chr 11NSY and C3H-Chr 14NSY) that possess diabetogenic Chr 11 or 14 of the Nagoya-Shibata-Yasuda (NSY) mouse, an animal model of spontaneous type 2 diabetes, in the genetic background of C3H mice. To search genes contribute to type 2 diabetes under specific environment, we first investigated whether sucrose administration deteriorates type 2 diabetes-related traits in the consomic strains. We dissected loci on Chr 11 by establishing congenic strains possessing different segments of NSY-derived Chr 11 under sucrose administration. In C3H-Chr 11NSY mice, sucrose administration for 10 weeks deteriorated hyperglycemia, insulin resistance, and impaired insulin secretion, which is comparable to NSY mice with sucrose. In C3H-Chr 14NSY mice, sucrose administration induced glucose intolerance, but not insulin resistance and impaired insulin secretion. To dissect the gene(s) existing on Chr 11 for sucrose-induced type 2 diabetes, we constructed four novel congenic strains (R1, R2, R3, and R4) with different segments of NSY-derived Chr 11 in C3H mice. R2 mice showed marked glucose intolerance and impaired insulin secretion comparable to C3H-Chr 11NSY mice. R3 and R4 mice also showed impaired insulin secretion. R4 mice showed significant decreases in white adipose tissue, which is in the opposite direction from parental C3H-Chr 11NSY and NSY mice. None of the four congenic strains showed insulin resistance. Genes on mouse Chr 11 could explain glucose intolerance, impaired insulin secretion, insulin resistance in NSY mice under sucrose administration. Congenic mapping with high sucrose environment localized susceptibility genes for type 2 diabetes associated with impaired insulin secretion in the middle segment (26.0–63.4 Mb) of Chr 11. Gene(s) that decrease white adipose tissue were mapped to the distal segment of Chr 11. The identification of diabetogenic gene on Chr 11 in the future study will facilitate precision medicine in type 2 diabetes by controlling specific environments in targeted subjects with susceptible genotypes.

中文翻译：

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高蔗糖环境下小鼠11号染色体上的2型糖尿病易感基因。

遗传因素和环境因素均会导致2型糖尿病的发展。我们使用从动物2型糖尿病模型建立的清醒小鼠来鉴定在特定环境下有助于2型糖尿病发展的易感基因。我们先前在C3H的遗传背景下建立了名古屋-柴田-Yasuda（NSY）小鼠的糖尿病致病性Chr 11或14的清毒株（C3H-Chr 11NSY和C3H-Chr 14NSY）老鼠。为了寻找在特定环境下促成2型糖尿病的基因，我们首先研究了蔗糖的施用是否会使纯菌株中2型糖尿病的相关性状恶化。我们通过在蔗糖管理下建立具有不同区段的NSY衍生Chr 11的同系菌株来解剖Chr 11上的基因座。在C3H-Chr 11NSY小鼠中，给予蔗糖10周会使高血糖，胰岛素抵抗和胰岛素分泌受损，这与含蔗糖的NSY小鼠相当。在C3H-Chr 14NSY小鼠中，给予蔗糖可引起葡萄糖耐量下降，但不会引起胰岛素抵抗和胰岛素分泌受损。为了剖析Chr 11上存在的蔗糖诱导的2型糖尿病基因，我们在C3H小鼠中构建了四个具有不同NSY衍生Chr 11片段的新型同系菌株（R1，R2，R3和R4）。与C3H-Chr 11NSY小鼠相比，R2小鼠表现出明显的葡萄糖耐受不良和胰岛素分泌受损。R3和R4小鼠还显示出胰岛素分泌受损。R4小鼠的白色脂肪组织显着减少，与亲本C3H-Chr 11NSY和NSY小鼠的方向相反。四个同系菌株均未显示胰岛素抵抗。小鼠Chr 11上的基因可以解释在蔗糖管理下NSY小鼠中的葡萄糖耐受不良，胰岛素分泌受损和胰岛素抵抗。用高蔗糖环境进行的同基因作图定位了Chr 11中段（26.0-63.4 Mb）中与胰岛素分泌受损有关的2型糖尿病的易感基因，将减少白色脂肪组织的基因定位到Chr 11的远端。在未来的研究中，在Chr 11上鉴定致糖尿病基因将通过控制具有易感基因型的目标受试者的特定环境，促进2型糖尿病的精确医学。蔗糖管理下NSY小鼠的胰岛素抵抗。用高蔗糖环境进行的同基因作图定位了Chr 11中段（26.0-63.4 Mb）中与胰岛素分泌受损有关的2型糖尿病的易感基因，将减少白色脂肪组织的基因定位到Chr 11的远端。在未来的研究中，在Chr 11上鉴定致糖尿病基因将通过控制具有易感基因型的目标受试者的特定环境，促进2型糖尿病的精确医学。蔗糖管理下NSY小鼠的胰岛素抵抗。用高蔗糖环境进行的同基因作图定位了Chr 11中段（26.0-63.4 Mb）中与胰岛素分泌受损有关的2型糖尿病的易感基因，将减少白色脂肪组织的基因定位到Chr 11的远端。在未来的研究中，在Chr 11上鉴定致糖尿病基因将通过控制具有易感基因型的目标受试者的特定环境，促进2型糖尿病的精确医学。