Increased Recovery Rates of Phosphocreatine and Inorganic Phosphate after Isometric Contraction in Oxidative Muscle Fibers and Elevated Hepatic Insulin Resistance in Homozygous Carriers of the A-allele of FTO rs9939609
Increased Recovery Rates of Phosphocreatine and Inorganic Phosphate after Isometric Contraction in Oxidative Muscle Fibers and Elevated Hepatic Insulin Resistance in Homozygous Carriers of the A-allele of FTO rs9939609
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DOI：
10.1210/jc.2008-1592
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发表时间：
2009-02-01
影响因子：
5.8
通讯作者：
Vaag, Allan
中科院分区：
文献类型：
--
作者：
Grunnet, Louise G.;Brons, Charlotte;Vaag, Allan
目的：最近的研究确定了FTO（脂肪量和肥胖相关）基因的rs 9939609 A等位基因与肥胖和2型糖尿病相关。我们研究了A等位基因在调节肥胖和2型糖尿病发病机制中涉及的外周器官功能中的作用。方法：46名年轻男性接受了高胰岛素正葡萄糖钳夹术，切除骨骼肌活检，静脉葡萄糖耐量试验，（31）磷磁共振波谱，并在呼吸室中测量24小时全身代谢。结果：FTO rs 9939609 A等位基因与空腹血糖和血浆胰岛素升高、肝胰岛素抵抗以及主要I型肌肉运动后磷酸肌酸和无机磷酸盐恢复半衰期缩短相关。这些关系-除了空腹胰岛素-在校正体脂百分比后仍然显着。危险等位基因与脂肪分布、外周胰岛素敏感性、胰岛素分泌、24小时能量消耗、葡萄糖和脂肪氧化无关。FTO基因型并没有影响FTO的mRNA表达或一组关键的核或骨骼肌编码的基因在rest.Conclusion：提高能源效率和潜在的增加线粒体耦合所建议的更快的恢复率磷酸肌酸和无机磷酸盐在氧化肌纤维可能有助于肥胖和2型糖尿病的风险增加的FTO A风险等位基因的纯合子携带者。肝脏胰岛素抵抗可能是导致与FTO表型相关的空腹血糖轻度升高的关键代谢缺陷。（临床内分泌代谢杂志94：596-602，2009）
Objective: Recent studies identified the rs9939609 A-allele of the FTO ( fat mass and obesity associated) gene as being associated with obesity and type 2 diabetes. We studied the role of the A-allele in the regulation of peripheral organ functions involved in the pathogenesis of obesity and type 2 diabetes.Methods: Forty-six young men underwent a hyperinsulinemic euglycemic clamp with excision of skeletal muscle biopsies, an iv glucose tolerance test, (31)phosphorous magnetic resonance spectroscopy, and 24-h whole body metabolism was measured in a respiratory chamber.Results: The FTO rs9939609 A-allele was associated with elevated fasting blood glucose and plasma insulin, hepatic insulin resistance, and shorter recovery half-times of phosphocreatine and inorganic phosphate after exercise in a primarily type I muscle. These relationships-except for fasting insulin-remained significant after correction for body fat percentage. The risk allele was not associated with fat distribution, peripheral insulin sensitivity, insulin secretion, 24-h energy expenditure, or glucose and fat oxidation. The FTO genotype did not influence the mRNA expression of FTO or a set of key nuclear or mitochondrially encoded genes in skeletal muscle during rest.Conclusion: Increased energy efficiency-and potentially increased mitochondrial coupling-as suggested by faster recovery rates of phosphocreatine and inorganic phosphate in oxidative muscle fibers may contribute to the increased risk of obesity and type 2 diabetes in homozygous carriers of the FTO A-risk allele. Hepatic insulin resistance may represent the key metabolic defect responsible for mild elevations of fasting blood glucose associated with the FTO phenotype. (J Clin Endocrinol Metab 94: 596-602, 2009)