BREAST CANCER LYMPHEDEMA: ROLE OF INSULIN RESISTANCE/FOXC2

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。假设：假设：1)对晚期乳腺癌幸存者的胰岛素敏感性进行定量评估，将表现出同侧手臂水肿和未表现出同侧手臂水肿的受试者平均划分，以及2)相对胰岛素抵抗（IR）的存在与乳腺癌相关淋巴水肿表达的相关性，将导致未来适当的风险分层和靶向治疗干预的阐述。此外，我们将对每位患者的FOXC2基因（包括未翻译的5'区）进行测序，以确定可能与IR和淋巴水肿风险相关的潜在多态性。实验设计：在初次访问时，每个研究对象将接受一般健康的临床评估，包括体格检查和评估上肢体积，通过四肢周长的卷尺测量来估计。将获得外周血样本用于FOXC2基因的分析。在第二次访问中，将进行胰岛素敏感性评估。胰岛素促进葡萄糖摄取的能力将通过原先描述的胰岛素抑制试验（IST）的修改来估计。禁食一夜后，将奥曲肽放入含有2.5% （w/v）人血清白蛋白的溶液中，通过哈佛输注泵以25 g/hr的速率给药，以抑制内源性胰岛素分泌。同时胰岛素和葡萄糖分别以25mU/m2/min和240mg /m2/min注入。在测试开始150分钟前每半小时抽血一次，然后在测试的最后30分钟内每10分钟抽血一次。在第三次（最后一次）就诊时，每位受试者将接受标准的口服葡萄糖耐量试验。禁食一夜后，给予75g口服葡萄糖负荷，随后在0,30,60,120和180分钟采集静脉血。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hypothesis: It is hypothesized that: 1) a quantitative assessment of insulin sensitivity in late breast cancer survivors, equally divided among subjects who display clinical evidence of ipsilateral arm edema and those that do not, and 2) correlation of the presence of relative insulin resistance (IR) to the expression of breast cancer-associated lymphedema, will lead to future elaboration of appropriate risk stratification and targeted therapeutic interventions. Additionally, we will sequence the FOXC2 gene, including the untranslated 5' region, in each patient to identify potential polymorphisms that might correlate both to the presence of IR and lymphedema risk. Experimental Design: In the initial visit, each study subject will undergo clinical assessment of general health, including a physical examination, and evaluation of upper extremity volume, estimated from tape measurements of limb circumference. A peripheral blood sample will be obtained for analysis of the FOXC2 gene. In the second visit, assessment of insulin sensitivity will be performed. The ability of insulin to promote glucose uptake will be estimated by a modification of the insulin suppression test (IST) as originally described. After an overnight fast, octreotide in a solution containing 2.5% (w/v) human serum albumin will be administered at a rate of 25 ¿g/hr by a Harvard infusion pump, to suppress endogenous insulin secretion. Simultaneously, insulin and glucose will be infused at 25mU/m2/min and 240 mg/m2/min, respectively. Blood will be sampled every half hour until 150 min into the test, and then every ten min in the last 30 min of the test. In the third (last) visit, each subject will undergo a standard oral glucose tolerance test. After an overnight fast, a 75 g oral glucose load will be administered, with subsequent venous blood collection at times 0, 30, 60, 120, and 180 min.