TIME OF ONSET OF NON-INSULIN-DEPENDENT DIABETES-MELLITUS AND GENETIC-VARIATION IN THE BETA(3)-ADRENERGIC-RECEPTOR GENE
TIME OF ONSET OF NON-INSULIN-DEPENDENT DIABETES-MELLITUS AND GENETIC-VARIATION IN THE BETA(3)-ADRENERGIC-RECEPTOR GENE
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DOI：
10.1056/nejm199508103330603
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发表时间：
1995-08-10
影响因子：
158.5
通讯作者：
SHULDINER, AR
中科院分区：
文献类型：
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作者：
WALSTON, J;SILVER, K;SHULDINER, AR
背景β（3）-肾上腺素能受体在内脏脂肪组织中表达，并被认为有助于调节静息代谢率和脂解。为了研究β 3肾上腺素能受体基因突变是否使患者易患肥胖和非胰岛素依赖型糖尿病（NIDDM），我们通过单链构象多态性分析和双脱氧序列分析研究了10名皮马印第安人的β 3肾上腺素能受体基因。对642名Pima受试者（390名NIDDM患者和252名非NIDDM患者）进行了关联研究。在β（3）-肾上腺素能受体基因中发现了一个错义突变，导致受体第一个胞内环中色氨酸被精氨酸（Trp 64 Arg）取代。在美国，这种突变在皮马印第安人中的等位基因频率为0.31，在62名墨西哥裔美国人中为0.13，在49名黑人中为0.12，在48名白人中为0.08。在Pimas中，Trp 64 Arg突变的频率在非糖尿病和糖尿病受试者中相似。然而，在突变纯合子受试者中，NIDDM发病时的平均（+/-SD）年龄（36+/-10岁）显著低于Trp 64 Arg杂合子（40+/-10岁）或正常纯合子（41 +/- 11岁; P = 0.02）。此外，携带该突变的受试者倾向于具有较低的调整后的静息代谢率（协方差分析P = 0.14）。Trp 64 Arg β（3）-肾上腺素能受体突变纯合子Pima受试者NIDDM发病较早，静息代谢率较低。该突变可能通过改变脂肪组织能量代谢平衡而加速NIDDM的发病。
Background. The beta(3)-adrenergic receptor is expressed in visceral adipose tissue and is thought to contribute to the regulation of the resting metabolic rate and lipolysis.Methods. To investigate whether mutations in the gene for the beta(3)-adrenergic receptor predispose patients to obesity and non-insulin-dependent diabetes mellitus (NIDDM), we studied this gene in 10 Pima Indians by analysis of single-stranded conformational polymorphisms and dideoxy sequence analysis. Association studies were performed in 642 Pima subjects (390 with NIDDM and 252 without NIDDM).Results. A missense mutation was identified in the gene for the beta(3)-adrenergic receptor that results in the replacement of tryptophan by arginine (Trp64Arg) in the first intracellular loop of the receptor. This mutation was detected with allelic frequencies of 0.31 in Pima Indians, 0.13 in 62 Mexican Americans, 0.12 in 49 blacks, and 0.08 in 48 whites in the United States. Among Pimas, the frequency of the Trp64Arg mutation was similar in nondiabetic and diabetic subjects. However, in subjects homozygous for the mutation the mean (+/-SD) age at the onset of NIDDM was significantly lower (36+/-10 years) than in Trp64Arg heterozygotes (40+/-10 years) or normal homozygotes (41 +/- 11 years; P = 0.02). Furthermore, subjects with the mutation tended to have a lower adjusted resting metabolic rate (P = 0.14 by analysis of covariance).Conclusions. Pima subjects homozygous for the Trp64Arg beta(3)-adrenergic-receptor mutation have an earlier onset of NIDDM and tend to have a lower resting metabolic rate. This mutation may accelerate the onset of NIDDM by altering the balance of energy metabolism invisceral adipose tissue.