Stoehr J P, Nadler S T, Schueler K L, Rabaglia M E, Yandell B S, Metz S A, Attie A D
Department of Biochemistry, University of Wisconsin-Madison, USA.
Diabetes. 2000 Nov;49(11):1946-54. doi: 10.2337/diabetes.49.11.1946.
Nonlinear interactions between obesity and genetic risk factors are thought to determine susceptibility to type 2 diabetes. We used genetic obesity as a tool to uncover latent differences in diabetes susceptibility between two mouse strains, C57BL/6J (B6) and BTBR. Although both BTBR and B6 lean mice are euglycemic and glucose tolerant, lean BTBR x B6 F1 male mice are profoundly insulin resistant. We hypothesized that the genetic determinants of the insulin resistance syndrome might also predispose genetically obese mice to severe diabetes. Introgressing the ob allele into BTBR revealed large differences in diabetes susceptibility between the strain backgrounds. In a population of F2-ob/ob mice segregating for BTBR and B6 alleles, we observed large variation in pancreatic compensation for the underlying insulin resistance. We also detected two loci that substantially modify diabetes severity, and a third locus that strongly links to fasting plasma insulin levels. Amplification of the genetic signal from these latent diabetes susceptibility alleles in F2-ob/ob mice permitted discovery of an interaction between the two loci that substantially increased the risk of severe type 2 diabetes.
肥胖与遗传风险因素之间的非线性相互作用被认为决定了对2型糖尿病的易感性。我们将遗传性肥胖作为一种工具，来揭示两种小鼠品系C57BL/6J（B6）和BTBR在糖尿病易感性方面的潜在差异。尽管BTBR和B6瘦小鼠的血糖和葡萄糖耐受性均正常，但瘦的BTBR×B6 F1雄性小鼠却具有严重的胰岛素抵抗。我们推测，胰岛素抵抗综合征的遗传决定因素可能也会使遗传性肥胖小鼠易患严重糖尿病。将ob等位基因导入BTBR后发现，品系背景之间在糖尿病易感性方面存在很大差异。在一个分离BTBR和B6等位基因的F2-ob/ob小鼠群体中，我们观察到胰腺对潜在胰岛素抵抗的代偿存在很大差异。我们还检测到两个显著改变糖尿病严重程度的基因座，以及一个与空腹血浆胰岛素水平密切相关的第三个基因座。对F2-ob/ob小鼠中这些潜在糖尿病易感性等位基因的遗传信号进行放大，使得我们发现了两个基因座之间的相互作用，这种相互作用大幅增加了患严重2型糖尿病的风险。
