Role of the transcription factor sox4 in insulin secretion and impaired glucose tolerance.
Role of the transcription factor sox4 in insulin secretion and impaired glucose tolerance.
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转录因子SOX4在胰岛素分泌和葡萄糖耐量受损中的作用。
DOI：
10.2337/db07-0337
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发表时间：
2008-08
期刊：
影响因子：
7.7
通讯作者：
Cox, Roger D.
中科院分区：
文献类型：
--
作者：
Goldsworthy, Michelle;Hugill, Alison;Freeman, Helen;Horner, Emma;Shimomura, Kenju;Bogani, Debora;Pieles, Guido;Mijat, Vesna;Arkell, Ruth;Bhattacharya, Shoumo;Ashcroft, Frances M.;Cox, Roger D.
目的：鉴定、定位、克隆和功能验证糖耐量和胰岛素分泌受损的新型小鼠模型。研究设计和方法-胰岛素受体单倍体不足和相关的轻度胰岛素抵抗已被用于敏化N-乙基-N-亚硝脲(ENU)筛查，以确定导致糖耐量受损和糖尿病的新突变。新的糖耐量受损4(IGT4)模型是通过腹腔葡萄糖耐量试验和回交后代确认的表型遗传来选择的。表型的分离与基因信息相关，以定位基因的位置和对突变的候选进行测序。用另一个ENU等位基因和小干扰RNA沉默检测SRY相关高迁移率族(HMG)-盒4(Sox4)基因在胰岛素瘤细胞胰岛素分泌中的功能。结果：我们描述了转录因子Sox4高度保守的HMG盒中的两个常染色体显性等位基因突变。SOX4基因突变以前与胰腺发育有关，成年小鼠的SOX4突变会导致胰岛素分泌缺陷，表现出与胰岛素受体+/−诱导的胰岛素抵抗相关的糖耐量受损。INS1和Min6细胞中Sox4转录本的消除导致了葡萄糖刺激的胰岛素释放的取消，类似于观察到的关键代谢酶葡萄糖激酶的沉默。经处理的细胞内钙测量表明，这种缺陷存在于ATP敏感K+通道(KATP通道)下游和钙内流。结论：IGT4代表了一种新的胰岛素抵抗和胰岛素分泌缺陷的双基因模型。Sox4基因在KATP通道下游的成年β细胞的胰岛素分泌中起作用。
OBJECTIVES— To identify, map, clone, and functionally validate a novel mouse model for impaired glucose tolerance and insulin secretion. RESEARCH DESIGN AND METHODS— Haploinsufficiency of the insulin receptor and associated mild insulin resistance has been used to sensitize an N-ethyl-N-nitrosourea (ENU) screen to identify novel mutations resulting in impaired glucose tolerance and diabetes. The new impaired glucose tolerance 4 (IGT4) model was selected using an intraperitoneal glucose tolerance test and inheritance of the phenotype confirmed by generation of backcross progeny. Segregation of the phenotype was correlated with genotype information to map the location of the gene and candidates sequenced for mutations. The function of the SRY-related high mobility group (HMG)-box 4 (Sox4) gene in insulin secretion was tested using another ENU allele and by small interfering RNA silencing in insulinoma cells. RESULTS— We describe two allelic autosomal dominant mutations in the highly conserved HMG box of the transcription factor Sox4. Previously associated with pancreas development, Sox4 mutations in the adult mouse result in an insulin secretory defect, which exhibits impaired glucose tolerance in association with insulin receptor+/−–induced insulin resistance. Elimination of the Sox4 transcript in INS1 and Min6 cells resulted in the abolition of glucose-stimulated insulin release similar to that observed for silencing of the key metabolic enzyme glucokinase. Intracellular calcium measurements in treated cells indicate that this defect lies downstream of the ATP-sensitive K+ channel (KATP channel) and calcium influx. CONCLUSIONS— IGT4 represents a novel digenic model of insulin resistance coupled with an insulin secretory defect. The Sox4 gene has a role in insulin secretion in the adult β-cell downstream of the KATP channel.
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影响因子：
2.5
作者：
Lioubinski, O;Müller, M;Sander, M
通讯作者：
Sander, M
DOI：
10.1073/pnas.0500584102
发表时间：
2005-08-30
影响因子：
11.1
作者：
Bogani, D;Willoughby, C;Arkell, RM
通讯作者：
Arkell, RM
影响因子：
30.8
作者：
Coghill, EL;Hugill, A;Brown, SDM
通讯作者：
Brown, SDM
影响因子：
29
作者：
Freeman, H;Shimomura, K;Ashcroft, FM
通讯作者：
Ashcroft, FM
影响因子：
7.7
作者：
Martinez, Sara C.;Cras-Meneur, Corentin;Permutt, M. Alan
通讯作者：
Permutt, M. Alan