Recessive mutations in the cancer gene Ataxia Telangiectasia Mutated (ATM), at a locus previously associated with metformin response, cause dysglycaemia and insulin resistance.
Recessive mutations in the cancer gene Ataxia Telangiectasia Mutated (ATM), at a locus previously associated with metformin response, cause dysglycaemia and insulin resistance.
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DOI：
10.1111/dme.13037
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发表时间：
2016-03
期刊：
影响因子：
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通讯作者：
Pearson ER
中科院分区：
文献类型：
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作者：
Connelly PJ;Smith N;Chadwick R;Exley AR;Shneerson JM;Pearson ER
研究未确诊糖尿病的共济失调毛细血管扩张症患者的葡萄糖和胰岛素代谢。在患有共济失调毛细血管扩张症的参与者（n = 10）和对照组（n = 10）中进行标准口服葡萄糖耐量试验。进行连续葡萄糖和胰岛素测量，以允许对葡萄糖-胰岛素稳态以及胰岛素分泌和敏感性指数进行队列比较。在口服葡萄糖耐量试验期间，（6.75 vs 4.93 mmol/l; P = 0.029），胰岛素浓度（285.6 vs 148.5 pmol/l; P = 0.043），葡萄糖曲线下面积增加共济失调毛细血管扩张症患者的胰岛素曲线下面积（37，720 pmol/l/min vs 18，080 pmol/l/min; P = 0.03）和胰岛素曲线下面积增量（314 vs 161 mmol/l/min; P = 0.036）均高于对照组。两组间空腹血糖、胰岛素浓度或胰岛素生成指数测量值无显著差异（0.94 vs 0.95; P = 0.95）。反映全身胰岛素敏感性的Matsuda指数在共济失调毛细血管扩张症受试者中（5.96 vs 11.03; P = 0.019）低于对照受试者。共济失调毛细血管扩张症突变（ATM）导致共济失调毛细血管扩张症的突变与无糖尿病参与者的高血糖和低胰岛素敏感性相关。这表明ATM在葡萄糖和胰岛素代谢途径中的作用。在2011年的一项全基因组关联研究中，我们的研究小组将共济失调毛细血管扩张症突变（ATM）确定为与二甲双胍的血药反应相关的潜在候选基因。在这项研究中，我们调查ATM在碳水化合物代谢中的作用，通过对该基因隐性突变的参与者进行口服葡萄糖耐量试验，导致共济失调毛细血管扩张症，以及健康对照组。我们发现共济失调毛细血管扩张症与高血糖和胰岛素敏感性降低有关。这些结果表明ATM在葡萄糖和胰岛素代谢途径中具有重要作用。
To investigate glucose and insulin metabolism in participants with ataxia telangiectasia in the absence of a diagnosis of diabetes. A standard oral glucose tolerance test was performed in participants with ataxia telangiectasia (n = 10) and in a control cohort (n = 10). Serial glucose and insulin measurements were taken to permit cohort comparisons of glucose‐insulin homeostasis and indices of insulin secretion and sensitivity. During the oral glucose tolerance test, the 2‐h glucose (6.75 vs 4.93 mmol/l; P = 0.029), insulin concentrations (285.6 vs 148.5 pmol/l; P = 0.043), incremental area under the curve for glucose (314 vs 161 mmol/l/min; P = 0.036) and incremental area under the curve for insulin (37,720 vs 18,080 pmol/l/min; P = 0.03) were higher in participants with ataxia telangiectasia than in the controls. There were no significant differences between groups in fasting glucose, insulin concentrations or insulinogenic index measurement (0.94 vs 0.95; P = 0.95). The Matsuda index, reflecting whole‐body insulin sensitivity, was lower in participants with ataxia telangiectasia (5.96 vs 11.03; P = 0.019) than in control subjects. Mutations in Ataxia Telangiectasia Mutated (ATM) that cause ataxia telangiectasia are associated with elevated glycaemia and low insulin sensitivity in participants without diabetes. This indicates a role of ATM in glucose and insulin metabolic pathways. In a genome‐wide association study in 2011, our group identified Ataxia Telangiectasia Mutated (ATM) as a potential candidate gene associated with glycaemic response to metformin. In this study, we investigate the role of ATM in carbohydrate metabolism by performing an oral glucose tolerance test in participants with recessive mutations in this gene, causing the condition ataxia telangiectasia, and healthy control subjects. We show that ataxia telangiectasia is associated with elevated glycaemia and decreased insulin sensitivity. These results indicate a significant role of ATM in glucose and insulin metabolic pathways.