胰岛素样生长因子2 mRNA结合蛋白2（IGF2BP2）的rs11705701 G>A多态性与内脏脂肪组织中IGF2BP2的mRNA和蛋白质水平相关——与2型糖尿病易感性存在关联。
The rs11705701 G>A polymorphism of IGF2BP2 is associated with IGF2BP2 mRNA and protein levels in the visceral adipose tissue - a link to type 2 diabetes susceptibility.
作者信息
Chistiakov Dimitry A, Nikitin Alexey G, Smetanina Svetlana A, Bel'chikova Larisa N, Suplotova Lyudmila A, Shestakova Marina V, Nosikov Valery V
机构信息
Pirogov Russian State Medical University, 117997 Moscow, Russia.
出版信息
Rev Diabet Stud. 2012 Summer-Fall;9(2-3):112-22. doi: 10.1900/RDS.2012.9.112. Epub 2012 Nov 15.
BACKGROUND
Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) regulates translation of IGF2, a growth factor that plays a key role in controlling fetal growth and organogenesis including adipogenesis and pancreatic development. In Caucasians, the rs4402960 G>T polymorphism of IGF2BP2 has been shown to predispose to type 2 diabetes (T2D) in multiple populations. In this study, we tested whether rs4402960 G>T and rs11705701 G>A contribute to the development of T2D in a Russian population.
METHODS
Both markers were genotyped in Russian diabetic (n = 1,470) and non-diabetic patients (n = 1,447) using a Taqman allele discrimination assay. The odds ratio (OR) for the risk of developing T2D was calculated using logistic regression assuming an additive genetic model adjusted for age, sex, HbA1c, hypertension, obesity, and body mass index (BMI). Multivariate linear regression analyses were used to test genotype-phenotype correlations, and adjusted for age, sex, hypertension, obesity, and BMI. Expression of IGF2BP2 in the visceral adipose tissue was quantified using real-time PCR. The content of IGF2BP2 protein and both its isoforms (p58 and p66) in the adipose tissue was measured using Western blot analysis.
RESULTS
There was no significant association between rs4402960 and T2D. Whereas, allele A of rs11705701 was associated with higher T2D risk (OR = 1.19, p < 0.001). Diabetic and non-diabetic carriers of genotype TT (rs4402960) had significantly increased HOMA-IR (p = 0.033 and p = 0.031, respectively). Non-diabetic patients homozygous for AA (rs11705701) had higher HOMA-IR (p = 0.04), lower HOMA-β (p = 0.012), and reduced 2-h insulin levels (p = 0.016). Non-obese individuals (diabetic and non-diabetic) homozygous for either AA (rs11705701) or TT (rs4402960) had higher levels of IGF2BP2 mRNA in the adipose tissue than other IGF2BP2 variants. Also, allele A of rs11705701 was associated with reduced amounts of the short isoform (p58) and increased levels of the long isoform (p66) of the IGF2BP2 protein in adipose tissue of non-obese diabetic and non-diabetic subjects.
CONCLUSIONS
IGF2BP2 genetic variants contribute to insulin resistance in Russian T2D patients. The short protein isoform p58 of IGF2BP2 is likely to play an anti-diabetogenic role in non-obese individuals.
背景
胰岛素样生长因子2信使核糖核酸结合蛋白2（IGF2BP2）调节IGF2的翻译，IGF2是一种生长因子，在控制胎儿生长和器官发生（包括脂肪生成和胰腺发育）中起关键作用。在高加索人群中，IGF2BP2的rs4402960 G>T多态性已被证明在多个人群中易患2型糖尿病（T2D）。在本研究中，我们测试了rs4402960 G>T和rs11705701 G>A是否与俄罗斯人群中T2D的发生有关。
方法
使用Taqman等位基因鉴别分析对俄罗斯糖尿病患者（n = 1470）和非糖尿病患者（n = 1447）的这两个标记进行基因分型。使用逻辑回归计算发生T2D风险的比值比（OR），假设采用年龄、性别、糖化血红蛋白、高血压、肥胖和体重指数（BMI）调整后的加性遗传模型。使用多变量线性回归分析测试基因型与表型的相关性，并对年龄、性别、高血压、肥胖和BMI进行调整。使用实时聚合酶链反应对内脏脂肪组织中IGF2BP2的表达进行定量。使用蛋白质免疫印迹分析测量脂肪组织中IGF2BP2蛋白及其两种异构体（p58和p66）的含量。
结果
rs4402960与T2D之间无显著关联。然而，rs11705701的A等位基因与更高的T2D风险相关（OR = 1.19，p < 0.001）。基因型TT（rs4402960）的糖尿病和非糖尿病携带者的稳态模型评估胰岛素抵抗（HOMA-IR）显著增加（分别为p = 0.033和p = 0.031）。AA（rs11705701）纯合的非糖尿病患者的HOMA-IR更高（p = 0.04），HOMA-β更低（p = 0.012），2小时胰岛素水平降低（p = 0.016）。AA（rs11705701）或TT（rs4402960）纯合的非肥胖个体（糖尿病和非糖尿病）的脂肪组织中IGF2BP2信使核糖核酸水平高于其他IGF2BP2变体。此外，rs11705701的A等位基因与非肥胖糖尿病和非糖尿病受试者脂肪组织中IGF2BP2蛋白的短异构体（p58）含量减少和长异构体（p66）水平增加相关。
结论
IGF2BP2基因变异在俄罗斯T2D患者中导致胰岛素抵抗。IGF2BP2的短蛋白异构体p58可能在非肥胖个体中发挥抗糖尿病作用。
Zotero 插件