Insulin-degrading enzyme identified as a candidate diabetes susceptibility gene in GK rats
Insulin-degrading enzyme identified as a candidate diabetes susceptibility gene in GK rats
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DOI：
10.1093/hmg/9.14.2149
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发表时间：
2000-09-01
影响因子：
3.5
通讯作者：
Galli, J
中科院分区：
文献类型：
--
作者：
Fakhrai-Rad, H;Nikoshkov, A;Galli, J
糖尿病 GK 大鼠的遗传分析揭示了几个糖尿病易感位点，通过将 GK 等位基因转移到血糖正常的 F344 大鼠的基因组上，已为主要糖尿病位点 Niddm1 建立了同源品系，Niddm1 被解剖成两个亚位点，在同源品系 Niddm1b 和 Niddm1i 中物理分离，每个亚位点具有 至少一种疾病易感基因。在这里，我们通过该基因座的新同源亚系的遗传和病理生理学特征将 Niddm1b 定位到 1 cM，编码胰岛素降解酶 (Ide) 的基因位于该 1 cM 区域，GK 等位基因中鉴定的两个氨基酸取代（H18R 和 A890V）使转染细胞中的胰岛素降解活性降低了 31%。然而，当单独研究 H18R 和 A890V 变体时，没有观察到任何影响，这表明这两种变体对胰岛素降解具有协同作用。在细胞裂解物中没有观察到对胰岛素降解的影响，表明该影响与受体介导的胰岛素内化有关。具有 Ide GK 等位基因的同源大鼠表现出餐后高血糖、脂肪细胞中的脂肪生成减少、胰岛素刺激的葡萄糖跨膜摄取减弱以及离体肌肉中的胰岛素降解减少。对其他大鼠品系的分析表明，功能失调的 Ide 等位基因是 GK 所独有的。这些数据表明 Ide 在 GK 糖尿病表型中发挥重要作用。
Genetic analysis of the diabetic GK rat has revealed several diabetes susceptibility loci, Congenic strains have been established for the major diabetes locus, Niddm1, by transfer of GK alleles onto the genome of the normoglycemic F344 rat, Niddm1 was dissected into two subloci, physically separated in the congenic strains Niddm1b and Niddm1i, each with at least one disease susceptibility gene. Here we have mapped Niddm1b to 1 cM by genetic and pathophysiological characterization of new congenic substrains for the locus, The gene encoding insulin-degrading enzyme (Ide) was located to this 1 cM region, and the two amino acid substitutions (H18R and A890V) identified in the GK allele reduced insulin-degrading activity by 31% in transfected cells. However, when the H18R and A890V variants were studied separately, no effects were observed, demonstrating a synergistic effect of the two variants on insulin degradation. No effect on insulin degradation was observed in cell lysates, indicating that the effect is coupled to receptor-mediated internalization of insulin, Congenic rats with the Ide GK allele displayed post-prandial hyperglycemia, reduced lipogenesis in fat cells, blunted insulin-stimulated glucose transmembrane uptake and reduced insulin degradation in isolated muscle. Analysis of additional rat strains demonstrated that the dysfunctional Ide allele was unique to GK. These data point to an important role for Ide in the diabetic phenotype in GK.