The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men
The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men
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DOI：
10.1007/s00125-009-1307-x
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发表时间：
2009-07-01
期刊：
影响因子：
8.2
通讯作者：
Vaag, A. A.
中科院分区：
文献类型：
--
作者：
Pilgaard, K.;Jensen, C. B.;Vaag, A. A.
我们研究了TCF 7 L2基因携带者患2型糖尿病风险增高的生理、代谢和激素机制，对81名丹麦健康青年男性进行了TCF 7 L2基因rs7903146分型，并进行了各种β细胞试验，包括：24小时血糖、胰岛素和胰高血糖素曲线; OGTT;混合餐试验; IVGTT;共输注胰高血糖素样肽（GLP）-1或葡萄糖依赖性促胰岛素多肽（GIP）的高血糖钳夹;和一个正常的高胰岛素钳夹结合葡萄糖示踪剂输注研究肝脏和外周胰岛素的作用。混合餐试验期间胰岛素浓度（p < 0.05）和相对于葡萄糖的胰岛素分泌减少（β指数：p < 0.003），但在IVGTT期间则不然。在7 mmol/l高血糖钳夹期间，GLP-1（p = 0.03）和GIP（p = 0.07）的晚期促胰岛素作用降低进一步支持了这一点。混合餐试验期间GLP-1和GIP的分泌正常。尽管肝葡萄糖生成增加，但T等位基因携带者24 h胰高血糖素浓度显著降低（p < 0.02），表明α细胞功能改变。肝葡萄糖生成增加和肠促胰岛素激素促胰岛素作用降低导致TCF 7 L2 rs7903146风险T等位基因携带者2型糖尿病风险增加。
We studied the physiological, metabolic and hormonal mechanisms underlying the elevated risk of type 2 diabetes in carriers of TCF7L2 gene.We undertook genotyping of 81 healthy young Danish men for rs7903146 of TCF7L2 and carried out various beta cell tests including: 24 h glucose, insulin and glucagon profiles; OGTT; mixed meal test; IVGTT; hyperglycaemic clamp with co-infusion of glucagon-like peptide (GLP)-1 or glucose-dependent insulinotropic polypeptide (GIP); and a euglycaemic-hyperinsulinaemic clamp combined with glucose tracer infusion to study hepatic and peripheral insulin action.Carriers of the T allele were characterised by reduced 24 h insulin concentrations (p < 0.05) and reduced insulin secretion relative to glucose during a mixed meal test (beta index: p < 0.003), but not during an IVGTT. This was further supported by reduced late-phase insulinotropic action of GLP-1 (p = 0.03) and GIP (p = 0.07) during a 7 mmol/l hyperglycaemic clamp. Secretion of GLP-1 and GIP during the mixed meal test was normal. Despite elevated hepatic glucose production, carriers of the T allele had significantly reduced 24 h glucagon concentrations (p < 0.02) suggesting altered alpha cell function.Elevated hepatic glucose production and reduced insulinotropic effect of incretin hormones contribute to an increased risk of type 2 diabetes in carriers of the rs7903146 risk T allele of TCF7L2.