Increased nicotinamide nucleotide transhydrogenase levels predispose to insulin hypersecretion in a mouse strain susceptible to diabetes
Increased nicotinamide nucleotide transhydrogenase levels predispose to insulin hypersecretion in a mouse strain susceptible to diabetes
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DOI：
10.1007/s00125-007-0814-x
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发表时间：
2007-12-01
期刊：
影响因子：
8.2
通讯作者：
Andrikopoulos, S.
中科院分区：
文献类型：
--
作者：
Aston-Mourney, K.;Wong, N.;Andrikopoulos, S.
目的/假设 胰岛素分泌过多可能是进展为 2 型糖尿病的独立预测因子。识别影响胰岛素分泌过多的基因对于了解疾病进展非常重要。我们之前已经证明，易患糖尿病的 DBA/2 小鼠先天性地表现出高胰岛素分泌。我们研究了该模型，以绘制和鉴定负责该性状的基因。方法对 171 只 (C57BL/6 x DBA/2) x C57BL/6 回交小鼠进行静脉葡萄糖耐量测试，然后进行全基因组扫描。结果将数量性状基因座（指定为 hyperinsulin Production-1 (Hip1)）以 7.7 的比值对数映射到 13 号染色体上的区域。同源小鼠证实 Hip1 影响胰岛素分泌过多的特征。通过研究合适的重组近交系小鼠品系，Hip1位点进一步定位于2 Mb区间，其中仅包含9个基因。表达分析表明，从亲本菌株分离的胰岛中唯一差异表达的基因是Nnt，它编码线粒体质子泵、烟酰胺核苷酸转氢酶(NNT)。我们还在五种小鼠品系中发现 NNT 活性与第一相胰岛素分泌之间呈正相关（r(2)= 0.90，p< 0.01），强调了这种酶在 β 细胞功能中的重要性。此外，在这五种菌株中，只有那些具有高 NNT 活性的菌株在肥胖后会表现出严重的糖尿病。 结论/解释 胰岛素分泌过多与 Nnt 表达增加有关。我们认为，NNT 在 β 细胞功能中一定发挥着重要作用，并且它对 DBA/2 小鼠高胰岛素分泌能力的影响可能会使这些小鼠的 β 细胞容易衰竭。
Aims/ hypothesis Insulin hypersecretion may be an independent predictor of progression to type 2 diabetes. Identifying genes affecting insulin hypersecretion are important in understanding disease progression. We have previously shown that diabetes- susceptible DBA/ 2 mice congenitally display high insulin secretion. We studied this model to map and identify the gene(s) responsible for this trait.Methods Intravenous glucose tolerance tests followed by a genome- wide scan were performed on 171 (C57BL/ 6 x DBA/ 2) x C57BL/ 6 backcross mice.Results A quantitative trait locus, designated hyperinsulin production-1 (Hip1), was mapped with a logarithm of odds score of 7.7 to a region on chromosome 13. Production of congenic mice confirmed that Hip1 influenced the insulin hypersecretion trait. By studying appropriate recombinant inbred mouse strains, the Hip1 locus was further localised to a 2 Mb interval, which contained only nine genes. Expression analysis showed that the only gene differentially expressed in islets isolated from the parental strains was Nnt, which encodes the mitochondrial proton pump, nicotinamide nucleotide transhydrogenase (NNT). We also found in five mouse strains a positive correlation (r(2)= 0.90, p< 0.01) between NNT activity and first-phase insulin secretion, emphasising the importance of this enzyme in beta cell function. Furthermore, of these five strains, only those with high NNT activity are known to exhibit severe diabetes after becoming obese.Conclusions/interpretation Insulin hypersecretion is associated with increased Nnt expression. We suggest that NNT must play an important role in beta cell function and that its effect on the high insulin secretory capacity of the DBA/2 mouse may predispose beta cells of these mice to failure.