Association of type 2 diabetes candidate polymorphisms in KCNQ1 with incretin and insulin secretion.
Association of type 2 diabetes candidate polymorphisms in KCNQ1 with incretin and insulin secretion.
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DOI：
10.2337/db08-1589
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发表时间：
2009-07
期刊：
影响因子：
7.7
通讯作者：
Fritsche A
中科院分区：
文献类型：
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作者：
Müssig K;Staiger H;Machicao F;Kirchhoff K;Guthoff M;Schäfer SA;Kantartzis K;Silbernagel G;Stefan N;Holst JJ;Gallwitz B;Häring HU;Fritsche A
KCNQ 1基因多态性与2型糖尿病相关这种联系似乎是由β细胞功能改变介导的。为了研究潜在的机制，我们研究了四个KCNQ 1单核苷酸多态性（SNP）对不同刺激下胰岛素分泌的影响。我们对1,578名2型糖尿病风险增加的非糖尿病受试者进行了rs 151290、rs 2237892、rs 2237895和rs 2237897基因分型。所有参与者均接受口服葡萄糖耐量试验（OGTT）;在170名参与者中测量胰高血糖素样肽（GLP）-1和胃抑制肽分泌。在519名参与者中，进行了高胰岛素-正葡萄糖钳夹，在314名参与者中进行了静脉内葡萄糖耐量试验（IVGTT），在102名受试者中进行了高血糖钳夹联合GLP-1和精氨酸刺激。在显性模型中，rs 151290与OGTT期间30分钟C肽水平、第一时相胰岛素分泌和调整后的胰岛素生成指数名义上相关（所有P ≤ 0.01）。rs 2237892、rs 2237895和rs 2237897与OGTT衍生的胰岛素分泌指数名义上相关（均P < 0.05）。在静脉内葡萄糖或GLP-1给药期间，没有SNP与β细胞功能相关。然而，rs 151290与显性模型中调整后的葡萄糖刺激的胃抑制多肽和GLP-1增加相关（分别为P = 0.0042和P = 0.0198）。其他SNPs与基础或刺激的肠促胰岛素水平之间未检测到相关性（所有P均≥ 0.05）。KCNQ 1的常见遗传变异与2型糖尿病风险增加的德国人群口服葡萄糖负荷后的胰岛素分泌相关口服和静脉注射葡萄糖之间的差异似乎不是由肠促胰岛素信号的改变来解释的，而很可能是由肠促胰岛素分泌的变化来解释的。
KCNQ1 gene polymorphisms are associated with type 2 diabetes. This linkage appears to be mediated by altered β-cell function. In an attempt to study underlying mechanisms, we examined the effect of four KCNQ1 single nucleotide polymorphisms (SNPs) on insulin secretion upon different stimuli. We genotyped 1,578 nondiabetic subjects at increased risk of type 2 diabetes for rs151290, rs2237892, rs2237895, and rs2237897. All participants underwent an oral glucose tolerance test (OGTT); glucagon-like peptide (GLP)-1 and gastric inhibitory peptide secretion was measured in 170 participants. In 519 participants, a hyperinsulinemic-euglycemic clamp was performed, in 314 participants an intravenous glucose tolerance test (IVGTT), and in 102 subjects a hyperglycemic clamp combined with GLP-1 and arginine stimuli. rs151290 was nominally associated with 30-min C-peptide levels during OGTT, first-phase insulin secretion, and insulinogenic index after adjustment in the dominant model (all P ≤ 0.01). rs2237892, rs2237895, and rs2237897 were nominally associated with OGTT-derived insulin secretion indexes (all P < 0.05). No SNPs were associated with β-cell function during intravenous glucose or GLP-1 administration. However, rs151290 was associated with glucose-stimulated gastric inhibitory polypeptide and GLP-1 increase after adjustment in the dominant model (P = 0.0042 and P = 0.0198, respectively). No associations were detected between the other SNPs and basal or stimulated incretin levels (all P ≥ 0.05). Common genetic variation in KCNQ1 is associated with insulin secretion upon oral glucose load in a German population at increased risk of type 2 diabetes. The discrepancy between orally and intravenously administered glucose seems to be explained not by altered incretin signaling but most likely by changes in incretin secretion.