A cluster of three single nucleotide polymorphisms in the 3′-untranslated region of human glycoprotein PC-1 gene stabilizes PC-1 mRNA and is associated with increased PC-1 protein content and insulin resistance-related abnormalities
A cluster of three single nucleotide polymorphisms in the 3′-untranslated region of human glycoprotein PC-1 gene stabilizes PC-1 mRNA and is associated with increased PC-1 protein content and insulin resistance-related abnormalities
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DOI：
10.2337/diabetes.50.8.1952
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发表时间：
2001-08-01
期刊：
影响因子：
7.7
通讯作者：
Trischitta, V
中科院分区：
文献类型：
--
作者：
Frittitta, L;Ercolino, T;Trischitta, V
糖蛋白PC-1抑制胰岛素信号传导，并且当过表达时，在人胰岛素抵抗中起作用。PC-1过表达的机制尚不清楚。我们在PC-1基因的3 ' -非翻译区发现了一种单倍型，它可能调节PC-1的表达，并增加胰岛素抵抗的风险。来自西西里，意大利的携带“P”单倍型的个体（即，G2897 A、G2906 C和C2948 T）具有较高的胰岛素抵抗风险（P < 0.01），在口服葡萄糖耐量试验中具有较高的血糖和胰岛素水平（P < 0.05），以及较高的胆固醇、HDL胆固醇和收缩压水平。骨骼肌和培养的皮肤成纤维细胞中PC-1蛋白含量也高于对照组（P < 0.05-0.01）。在用P或野生型cDNA转染的CHO细胞中，用P转染的细胞的特异性PC-1 mRNA半衰期增加（t/2 = 3.73 +/- 1.0 vs. 1.57 +/- 0.2 h; P < 0.01）。在不同种族的人群中（加尔加诺，意大利东海岸），2型糖尿病患者（最可能的临床结果，胰岛素抵抗）的P单倍型频率高于健康对照受试者（7.8 vs. 1.5%，P < 0.01），从而复制了在西西里岛人中观察到的P等位基因与胰岛素抵抗相关异常之间的关联。总之，我们已经确定了PC-1过表达的一个可能的分子机制，赋予胰岛素抵抗相关异常的风险增加。
Glycoprotein PC-1 inhibits insulin signaling and, when overexpressed, plays a role in human insulin resistance. Mechanisms of PC-1 overexpression are unknown. We have identified a haplotype in the 3 ' -untranslated region of the PC-1 gene that may modulate PC-1 expression and confer an increased risk for insulin resistance. Individuals from Sicily, Italy, carrying the "P" haplotype (i.e., a cluster of three single nucleotide polymorphisms: G2897A, G2906C, and C2948T) were at higher risk (P < 0.01) for insulin resistance and had higher (P < 0.05) levels of plasma glucose and insulin during an oral glucose tolerance test and higher levels of cholesterol, HDL cholesterol, and systolic blood pressure. They also had higher (P < 0.05-0.01) PC-1 protein content in both skeletal muscle and cultured skin fibroblasts. In CHO cells transfected with either P or wild-type cDNA, specific PC-1 mRNA half-life was increased for those transfected with P (t/2 = 3.73 +/- 1.0 vs. 1.57 +/- 0.2 h; P < 0.01). In a population of different ethnicity (Gargano, East Coast Italy), patients with type 2 diabetes (the most likely clinical outcome,of insulin resistance) had a higher P haplotype frequency than healthy control subjects (7.8 vs. 1.5%, P < 0.01), thus replicating the association between the P allele and the insulin resistance-related abnormalities observed among Sicilians. In conclusion, we have identified a possible molecular mechanism for PC-1 overexpression that confers an increased risk for insulin resistance-related abnormalities.