Clee Susanne M, Nadler Samuel T, Attie Alan D
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
Am J Ther. 2005 Nov-Dec;12(6):491-8. doi: 10.1097/01.mjt.0000178781.89789.25.
The BTBR mouse strain harbors alleles promoting insulin resistance. When made genetically obese (ob/ob), these mice develop severe type 2 diabetes (fasting glucose >400 mg/dL). By contrast, C57BL/6 ob/ob mice are able to compensate for the obesity-induced insulin resistance by increasing pancreatic insulin secretion and thus maintain only slightly elevated plasma glucose levels (<250 mg/dL). Islet insulin secretory responses to glucose are undiminished in the remaining islets of BTBR ob/ob mice. A genome-wide linkage analysis identified 3 major loci influencing plasma glucose and/or insulin levels in an F2ob/ob sample derived from the 2 strains. A locus on chromosome 2 affects insulin sensitivity and is independent of obesity. Loci on chromosomes 16 and 19 affect fasting glucose and insulin levels and likely affect beta-cell mass or function. Analysis of mRNA expression patterns revealed a reduction in lipogenic gene expression in adipose tissue associated with obesity. Conversely, hepatic lipogenic gene expression increases in obese mice, but to a much greater extent in the diabetes-resistant C57BL/6 strain. We propose that hepatic lipogenic capacity affects susceptibility to obesity-induced diabetes.
BTBR小鼠品系携带促进胰岛素抵抗的等位基因。当这些小鼠发生基因性肥胖（ob/ob）时，会发展为严重的2型糖尿病（空腹血糖>400mg/dL）。相比之下，C57BL/6 ob/ob小鼠能够通过增加胰腺胰岛素分泌来代偿肥胖诱导的胰岛素抵抗，因此仅维持轻度升高的血糖水平（<250mg/dL）。BTBR ob/ob小鼠剩余胰岛对葡萄糖的胰岛素分泌反应并未减弱。全基因组连锁分析在源自这两个品系的F2 ob/ob样本中确定了3个影响血糖和/或胰岛素水平的主要基因座。2号染色体上的一个基因座影响胰岛素敏感性，且独立于肥胖因素。16号和19号染色体上的基因座影响空腹血糖和胰岛素水平，可能影响β细胞质量或功能。对mRNA表达模式的分析显示，与肥胖相关的脂肪组织中脂肪生成基因表达减少。相反，肥胖小鼠肝脏中脂肪生成基因表达增加，但在抗糖尿病的C57BL/6品系中增加幅度更大。我们认为肝脏脂肪生成能力影响对肥胖诱导糖尿病的易感性。
