Kose Hiroyuki, Bando Yoshimi, Izumi Keisuke, Yamada Takahisa, Matsumoto Kozo
Division for Animal Research Resources, Institute of Health Biosciences, The University of Tokushima Graduate School, Kuramoto-cho, Tokushima, 770-8503, Japan.
Mamm Genome. 2007 Aug;18(8):609-15. doi: 10.1007/s00335-007-9031-7. Epub 2007 Aug 21.
Glucose homeostasis is believed to be regulated by multiple genetic components, in addition to numerous external factors. It is therefore crucial to dissect and understand what roles each causative gene plays in maintaining proper glucose metabolism. In OLETF (Otsuka Long-Evans Tokushima Fatty) rat, a model of polygenic type 2 diabetes, at least 14 quantitative trait loci (QTLs) influencing plasma glucose levels were identified. In congenic strains some of the OLETF allelic variants were shown to increase glucose levels. In this study the focus was on two of the hyperglycemic loci, Nidd1/of and Nidd2/of. Congenic rats possessing OLETF genome fragment at either locus showed similar levels of mild hyperglycemia. A newly established double congenic rat showed a further aggravation of hyperglycemia. The Nidd1/of locus was also shown to function in the reduction of plasma leptin levels and fat weights, while the Nidd2/of locus led to increased plasma insulin and fat weights. Interestingly, both plasma leptin and fat weights reverted to the control levels in the double congenic rat. These results indicate that there is an epistatic interaction between the two loci. However, it is unlikely that the abnormal level of enhanced glucose homeostasis is mediated, at least not directly, by leptin or fat mass.
除了众多外部因素外，葡萄糖稳态被认为受多种遗传成分调控。因此，剖析并了解每个致病基因在维持正常葡萄糖代谢中所起的作用至关重要。在多基因2型糖尿病模型OLETF（大冢长- Evans德岛肥胖）大鼠中，已鉴定出至少14个影响血糖水平的数量性状基因座（QTL）。在近交系中，一些OLETF等位基因变体显示会升高血糖水平。在本研究中，重点关注两个高血糖基因座Nidd1/of和Nidd2/of。在任一基因座上拥有OLETF基因组片段的近交系大鼠表现出相似程度的轻度高血糖。新建立的双近交系大鼠高血糖进一步加重。Nidd1/of基因座还显示出具有降低血浆瘦素水平和脂肪重量的作用，而Nidd2/of基因座则导致血浆胰岛素和脂肪重量增加。有趣的是，在双近交系大鼠中，血浆瘦素和脂肪重量均恢复到对照水平。这些结果表明这两个基因座之间存在上位性相互作用。然而，增强的葡萄糖稳态异常水平不太可能至少不是直接由瘦素或脂肪量介导的。
