PC1 IN INSULIN RESISTANT HUMANS

描述（改编自申请人摘要）：主要研究者 在初步研究中指出， 一种叫做PC-1的特殊表面蛋白的表达量增加。 随后的纯化和部分测序导致鉴定了 PC-1作为核苷酸焦磷酸酶/碱性磷酸酶。的表面 一种功能不确定的胞外酶，但可能与细胞的再循环有关。 核苷酸磷酸盐由多种细胞类型。酶的活性是 具有单跨膜的蛋白质的细胞外结构域 结构域和短的胞内尾。这种蛋白质以同源二聚体的形式存在 由染色体区域6 q22-q23编码。成纤维细胞中均 先证者患者胰岛素受体酪氨酸自身磷酸化，2 脱氧葡萄糖摄取对胰岛素的反应较低， 对照组和先证者细胞中PC-1含量升高， 十倍随后对9名NIDDM受试者的成纤维细胞进行的研究显示， PC-1含量范围广泛，但9例中有7例的水平升高。 PC-1在几个成纤维细胞系中的过表达（约10倍）导致了 减少胰岛素刺激的受体自身磷酸化。这种效果 EGF和IGF-1受体均未表达。这些研究 成纤维细胞导致了对人类肌肉和脂肪的进一步初步研究 探讨PC-1含量与胰岛素抵抗的关系。 基于在健康对照组和肥胖个体中观察到的相关性， PI推测PC-1可能参与了胰岛素抵抗， 至少某些形式的NIDDM是由于受损的受体自身磷酸化。 他建议研究体内胰岛素敏感性与 （最小模型）和体外胰岛素敏感性，通过胰岛素敏感性测定 刺激葡萄糖转运和激活受体酪氨酸激酶。 研究将在非糖尿病个体中进行， 胰岛素敏感性和肥胖个体。也将寻求相关性 脂肪细胞和成纤维细胞胰岛素敏感性与PC-1含量之间的关系 这些组织。然后PI将确定PC-1的增加， 在体内观察到的受体酪氨酸激酶的损伤在培养的 细胞（成纤维细胞和肌肉）。最后，PI和合作者将 解决是否干预以改善体内胰岛素敏感性（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.