Genetic analysis of the molecular basis of insulin resistance both in animal models and in humans.

SHR是人类胰岛素抵抗综合征（IRS）的遗传模型。IRS相关表型的数量性状基因座（QTL）已被定位到大鼠染色体（Chrs）3，4和12上的区域。有趣的是，多个QIL已被证明聚集在Chr 3或4上的单个区域周围。在来自美国NIH的SHR品系中，已在位于Chr 4-QTL区域内的Cd 36中鉴定出缺失突变。然而，在原始SHR品系的Cd 36中不存在该突变，并且在NIH的育种过程中被引入。SHR品系之间的比较表明，Cd 36突变不太可能是SHR胰岛素抵抗表型的主要原因。高血压，减少肥胖和胰岛素抵抗在SHR的QTL，以及候选基因（KAT-1）位点，已被定位到一个重叠区域的近端的大鼠Chr 3。我们已经在来自所有检查的SHR菌株的KAT-1中发现了一个功能性错义突变。KAT-1的人同源物与人Chr 9 q22的染色体定位，其中糖尿病、高血压和肥胖症先前已被关联，保证了对人中KAT-1同源物的进一步研究。

SHR is a genetic model of human insulin resistance syndrome (IRS). Quantitative trait loci (QTLs) for IRS-related phenotypes have been mapped to the regions on rat chromosomes (Chrs) 3, 4 and 12. Interestingly, multiple QILs have been shown to cluster around a single region on either Chr 3 or 4. In SHR strains derived from the NIH, USA, a deletional mutation has been identified in the Cd36 located within the Chr 4-QTL region. The mutation was, however, absent in the Cd36 of the original SHR strains and was shown to be introduced during breeding at the NIH. Comparison between SHR strains indicated that the Cd36 mutation is unlikely to be a major cause of insulin resistance phenotypes in SHR. QTLs for hypertension, reduced adiposity and insulin resistance in SHR, as well as a candidate gene (KAT-1) locus, have been mapped to an overlapping region of the proximal end of rat Chr 3. We have identified a functional missense mutation in the KAT-1 derived from all SHR strains examined. The chromosomal localization of the human homologue of KAT-1 to human Chr 9q22, where diabetes, hypertension and obesity have previously been linked, warrants further investigation of the homologue of KAT-i in humans.