Gene variants in the novel type 2 diabetes loci CDC123/CAMK1D, THADA, ADAMTS9, BCL11A, and MTNR1B affect different aspects of pancreatic beta-cell function.
Gene variants in the novel type 2 diabetes loci CDC123/CAMK1D, THADA, ADAMTS9, BCL11A, and MTNR1B affect different aspects of pancreatic beta-cell function.
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新型2型糖尿病基因座CDC123/CAMK1D，THADA，ADAMTS9，BCL11A和MTNR1B中的基因变体会影响胰腺β细胞功能的不同方面。
DOI：
10.2337/db09-1048
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发表时间：
2010-01
期刊：
影响因子：
7.7
通讯作者：
't Hart LM
中科院分区：
文献类型：
--
作者：
Simonis-Bik AM;Nijpels G;van Haeften TW;Houwing-Duistermaat JJ;Boomsma DI;Reiling E;van Hove EC;Diamant M;Kramer MH;Heine RJ;Maassen JA;Slagboom PE;Willemsen G;Dekker JM;Eekhoff EM;de Geus EJ;'t Hart LM
最近，来自全基因组关联研究的荟萃分析结果已经产生了一些新的2型糖尿病基因座。然而，关于它们对胰岛素分泌和胰岛素敏感性的影响，已经发表了相互矛盾的结果。在这项研究中，我们使用三种不同刺激的高血糖钳来测试这些新位点与β细胞功能的各种测量之间的关联。在这项研究中，336名参与者，180名糖耐量正常，156名糖耐量受损，接受了2小时的高血糖钳夹。在一个子集中，我们还评估了延长钳夹期间对胰高血糖素样肽(GLP)-1和精氨酸的反应（n = 123）。所有受试者均对JAZF1、CDC123/CAMK1D、TSPAN8/LGR5、THADA、ADAMTS9、NOTCH2/ADAMS30、DCD、VEGFA、BCL11A、HNF1B、WFS1和MTNR1B基因变异进行基因分型。CDC123/CAMK1D、ADAMTS9、BCL11A和MTNR1B的基因变异影响胰岛素对葡萄糖反应的各个方面（均P < 6.9 × 10−3）。THADA基因变异与β细胞对GLP-1和精氨酸的反应降低相关（P均< 1.6 × 10−3），表明β细胞质量降低可能是致病机制。值得注意的是，我们还注意到MTNR1B携带者对GLP-1的胰岛素反应增加的趋势（P = 0.03），这可能提供新的治疗可能性。其他7个位点与β细胞功能没有明显的关联。糖尿病风险等位基因CDC123/CAMK1D、THADA、ADAMTS9、BCL11A和MTNR1B与β细胞功能的各个特定方面相关。这些发现表明，这些不同的基因变异可能对胰腺β细胞的功能产生明显的影响。
Recently, results from a meta-analysis of genome-wide association studies have yielded a number of novel type 2 diabetes loci. However, conflicting results have been published regarding their effects on insulin secretion and insulin sensitivity. In this study we used hyperglycemic clamps with three different stimuli to test associations between these novel loci and various measures of β-cell function. For this study, 336 participants, 180 normal glucose tolerant and 156 impaired glucose tolerant, underwent a 2-h hyperglycemic clamp. In a subset we also assessed the response to glucagon-like peptide (GLP)-1 and arginine during an extended clamp (n = 123). All subjects were genotyped for gene variants in JAZF1, CDC123/CAMK1D, TSPAN8/LGR5, THADA, ADAMTS9, NOTCH2/ADAMS30, DCD, VEGFA, BCL11A, HNF1B, WFS1, and MTNR1B. Gene variants in CDC123/CAMK1D, ADAMTS9, BCL11A, and MTNR1B affected various aspects of the insulin response to glucose (all P < 6.9 × 10−3). The THADA gene variant was associated with lower β-cell response to GLP-1 and arginine (both P < 1.6 × 10−3), suggesting lower β-cell mass as a possible pathogenic mechanism. Remarkably, we also noted a trend toward an increased insulin response to GLP-1 in carriers of MTNR1B (P = 0.03), which may offer new therapeutic possibilities. The other seven loci were not detectably associated with β-cell function. Diabetes risk alleles in CDC123/CAMK1D, THADA, ADAMTS9, BCL11A, and MTNR1B are associated with various specific aspects of β-cell function. These findings point to a clear diversity in the impact that these various gene variants may have on (dys)function of pancreatic β-cells.