GHR exon 3 polymorphism:: Association with type 2 diabetes mellitus and metabolic disorder
GHR exon 3 polymorphism:: Association with type 2 diabetes mellitus and metabolic disorder
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DOI：
10.1016/j.ghir.2007.04.005
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发表时间：
2007-10-01
影响因子：
1.4
通讯作者：
Brismar, K.
中科院分区：
文献类型：
--
作者：
Strawbridge, R. J.;Karvestedt, L.;Brismar, K.
通过生长激素受体（GHR）的生长激素（GH）信号传导形成GH-IGF-1轴的主要部分，其对于控制代谢和生长至关重要。GHR的两种常见变体的区别在于存在（全长或GHR（fl））或不存在外显子3（外显子3缺失或GHR（d3）），其功能未知。然而，在GHR（d3）变异体携带者中观察到对GH治疗的不同反应，从而获得更高的生长速率。本研究对糖耐量正常（NGT）、糖耐量受损（IGT）和2型糖尿病（T2 DM）患者的GHR基因进行了研究，分别从NGT（n = 158）、IGT（n = 116）和T2 DM（n = 194）患者的血样中提取DNA。第1组中的T2 DM受试者（n = 39）为新诊断，而第2组中的T2 DM受试者（n = 155）的平均病程为7年。第1组还包括NGT和IGT受试者。通过标准PCR和凝胶电泳进行基因分型。观察到T2 DM和NGT之间存在显著差异（p < 0.0001），T2 DM中GHR（d3）的频率显著较低（3.6%，NGT中为17%）。两组具有至少一个GHR（d3）等位基因的T2 DM受试者的BMI均显著较高。在T2 DM的较大亚组中，GHR（d3）与较高的CRP水平以及年龄调整的IGF-1相关，具有较高的C肽分泌和受损的脂质水平的趋势，表明与GHR（fl/fl）T2 DM受试者相比时具有代谢紊乱的表型。然而，当其他因素导致明显的T2 DM时，GHR（d3）等位基因赋予指示代谢紊乱的表型。这项研究支持了这两个GHR等位基因通过其包含或排除外显子3而在功能上不同的假设。爱思唯尔有限公司出版
Growth hormone (GH) signaling via the growth hormone receptor (GHR) forms a major part of the GH-IGF-1 axis, which is crucial for controlling metabolism and anabolism. Two common variants of the GHR differ by the presence (full length or GHR(fl)) or absence of exon 3 (exon 3 deleted or GHR(d3)) the function of which is unknown. However, differential response to GH treatment has been observed with carriers of the GHR(d3) variant conferring a greater growth rate. This study investigates these GHR variants in subjects with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT), including Type 2 diabetes mellitus (T2DM).DNA was extracted from blood samples from subjects with NGT (n = 158), IGT (n = 116) and T2DM (n = 194). The T2DM subjects in set 1 (n = 39) were newly diagnosed, whilst those in set 2 (n = 155) had a mean duration of 7 years. Set 1 also included NGT and IGT subjects. Genotyping by standard PCR and gel electrophoresis were carried out. A significant difference was observed between T2DM and NGT (p < 0.0001) with a significantly lower frequency of GHR(d3) in T2DM (3.6% compared to 17% in NGT). Both sets of T2DM subjects with at least one GHR(d3) allele had significantly higher BMI. In the larger subset of T2DM, GHR(d3) was associated with higher CRP levels as well as age adjusted IGF-1, with a trend of higher C-peptide secretion and impaired lipid levels, indicating a phenotype with metabolic disorder when compared to the GHR(fl/fl) T2DM subjects.In conclusion, homozygosity for the GHR(d3) allele appears to be preventive of T2DM. However, when other factors cause overt T2DM, the GHR(d3) allele confers a phenotype indicative of metabolic disorder. This study supports the hypothesis that the two GHR alleles by their inclusion or exclusion of exon 3 are functionally different. Published by Elsevier Ltd.