Variation in the gene for muscle-specific AMP deaminase is associated with insulin clearance, a highly heritable trait
Variation in the gene for muscle-specific AMP deaminase is associated with insulin clearance, a highly heritable trait
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DOI：
10.2337/diabetes.54.4.1222
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发表时间：
2005-04-01
期刊：
影响因子：
7.7
通讯作者：
Rotter, JI
中科院分区：
文献类型：
--
作者：
Goodarzi, MO;Taylor, KD;Rotter, JI
在我们的社会中，胰岛素抵抗综合征的患病率不断上升，需要更好地了解胰岛素作用和代谢各个方面的遗传决定因素。我们评估了 403 名墨西哥裔美国人的胰岛素敏感性遗传性和胰岛素代谢清除率 (MCRI)，通过正常血糖-高胰岛素钳夹进行量化。我们测试了候选基因 AMP 脱氨酶 1 (AMPD1) 与胰岛素相关性状的关联，因为它编码的酶有可能影响胰岛素药效学的多个方面。通过将 AMP 转化为肌苷单磷酸，AMPD1 在调节细胞 AMP 水平方面发挥着重要作用。 AMP 激活 AMP 激酶，这是一种调节细胞能量和胰岛素作用的酶。我们确定九个 AMPD1 单核苷酸多态性 (SNP) 定义了两个单倍型块。研究发现，胰岛素清除率 (h(2) = 0.58) 比空腹胰岛素 (h(2) = 0.38) 或胰岛素敏感性 (h(2) = 0.44) 具有更高的遗传力。 MCRI 与 AMPD1 SNP 和单倍型相关。胰岛素清除率是一种高度遗传性状，AMPD1 基因（编码骨骼肌特异性蛋白）内的特定单倍型与胰岛素清除率的变化相关。我们假设骨骼肌中的胰岛素作用和胰岛素清除过程受到高度调节，并且 AMPD1 功能可能在这些现象中发挥重要作用。
The rising prevalence of the insulin resistance syndrome in our society necessitates a better understanding of the genetic determinants of all aspects of insulin action and metabolism. We evaluated the heritability of insulin sensitivity and the metabolic clearance rate of insulin (MCRI) as quantified by the euglycemic-hyperinsulinemic clamp in 403 Mexican Americans. We tested the candidate gene AMP deaminase 1 (AMPD1) for association with insulin-related traits because it codes for an enzyme that has the potential to influence multiple aspects of insulin pharmacodynamics. By converting AMP to inosine monophosphate, AMPD1 plays a major role in regulating cellular AMP levels; AMP activates AMP kinase, an enzyme that modulates cellular energy and insulin action. We determined that nine AMPD1 single nucleotide polymorphisms (SNPs) defined two haplotype blocks. Insulin clearance was found to have a higher heritability (h(2) = 0.58) than fasting insulin (h(2) = 0.38) or insulin sensitivity (h(2) = 0.44). The MCRI was associated with AMPD1 SNPs and haplotypes. Insulin clearance is a highly heritable trait, and specific haplotypes within the AMPD1 gene, which encodes a skeletal muscle-specific protein, are associated with variation in insulin clearance. We postulated that the processes of insulin action and insulin clearance in skeletal muscle are highly regulated and that AMPD1 function may play an important role in these phenomena.