PC1 IN INSULIN RESISTANT HUMANS

描述(改编自申请人的摘要)：首席调查员 初步研究指出，患有严重胰岛素抵抗的患者 表达了一种称为PC-1的特定表面蛋白的数量增加。 随后的纯化和部分测序导致了对 PC-1为核苷酸焦磷酸酶/碱性磷酸酶。一个曲面 功能不确定但可能参与循环的胞外酶 多种细胞类型的核苷酸磷酸盐。酶活性已开启 蛋白质的胞外区域，它只有一个跨膜 结构域和短的细胞内尾巴。这种蛋白质以同源二聚体的形式存在。 由染色体6q22-q23区域编码。在成纤维细胞中 先证者和患者胰岛素受体和2的酪氨酸自动磷酸化 据报道，脱氧葡萄糖摄取对胰岛素的反应比 对照组和先证者S细胞中PC-1含量大约升高 10倍。随后对9名NIDDM患者的成纤维细胞进行的研究表明， PC-1含量范围广泛，但其中7例水平升高。 PC-1在几个成纤维细胞系中的过表达(约10倍)导致 抑制胰岛素刺激的受体自身磷酸化。这一效果 EGF或IGF-1受体均未见表达。这些研究发表在 成纤维细胞在人类肌肉和脂肪中的进一步初步研究 探讨PC-1含量与胰岛素抵抗的关系。 基于在健康对照和肥胖个体中观察到的相关性 PI假设PC-1可能参与了胰岛素抵抗。 至少某些形式的NIDDM是由于受体自身磷酸化受损所致。 他建议研究体内胰岛素敏感性之间的关系 (最小模型)和用胰岛素测量的体外胰岛素敏感性 刺激葡萄糖转运和激活受体酪氨酸激酶。 研究将在非糖尿病患者中进行，患者范围广泛 胰岛素敏感性和肥胖个体。还将寻求相关性。 脂肪细胞和成纤维细胞的胰岛素敏感性与PC-1含量的关系 这些纸巾中。然后，PI将确定PC-1和 体内观察到的受体酪氨酸激酶的损伤持续存在于培养的 细胞(成纤维细胞和肌肉)。最后，PI和合作者将 解决是否在体内采取干预措施改善胰岛素敏感性(体重 减少和运动)改变PC-1表达和酪氨酸激酶活性 在人类身上。

DESCRIPTION (Adapted from applicant's abstract): The Principal Investigator noted in preliminary studies that a patient with severe insulin resistance expressed increased amounts of a specific surface protein called PC-1. Subsequent purification and partial sequencing led to the identification of PC-1 as nucleotide pyrophosphatase/alkaline phosphatase. A surface ectoenzyme of uncertain function but perhaps involved in recycling of nucleotide phosphates by multiple cell types. The enzymatic activity is on the extracellular domain of the protein which has a single membrane spanning domain and a short intracellular tail. This protein exists as a homodimer is coded for by chromosomal region 6q22-q23. In fibroblasts from the proband patient tyrosine auto-phosphorylation of the insulin receptor and 2 deoxyglucose uptake were reported less responsive to insulin compared with controls and PC-1 content in the proband s cell were elevated approximately 10-fold. Subsequent studies in fibroblasts from 9 NIDDM subjects showed a wide range of PC-1 content but levels were elevated in 7 of 9. Overexpression (approx 10 fold) of PC-1 in several fibroblasts lines led to diminished insulin-stimulated receptor auto-phosphorylation. This effect was not seen with either the EGF or IGF-1 receptor. These studies in fibroblasts led to further preliminary studies in human muscle and adipose exploring the relationship between PC-1 content and insulin resistance. Based on the correlations observed in healthy controls and obese individuals the PI hypothesizes that PC-1 may be involved in the insulin resistance in at least some forms of NIDDM due to impaired receptor auto-phosphorylation. He proposes to examine the relationship between in vivo insulin sensitivity (minimal model) and in vitro insulin sensitivity as measured by insulin stimulation of glucose transport and activation of receptor tyrosine kinase. Studies will be done in non-diabetic individuals with a wide range of insulin sensitivity and obese individuals. Correlations will also be sought between insulin sensitivity in adipocytes and fibroblasts and PC-1 content of these tissues. The PI will then determine increases in PC-1 and impairments in receptor tyrosine kinase observed in vivo persist in cultured cells (fibroblasts and muscle) . Finally, the PI and collaborators will address whether interventions to improve insulin sensitivity in vivo (weight reduction and exercise) alter PC-1 expression and tyrosine kinase activity in humans.