Insulin-Like Growth Factor Axis and Type 2 Diabetes

描述（由申请人提供）：2型糖尿病是一种日益严重的公共卫生问题，影响约2000万美国人，通常与胰岛素抵抗有关。胰岛素样生长因子I（insulin-like growth factor，IGF I）与胰岛素具有结构上的同源性，越来越多的证据表明IGF I及其结合蛋白（IGFBPs）可能在正常的葡萄糖稳态中发挥重要作用。外源性IGF-I给药可改善人类胰岛素敏感性，包括2型糖尿病患者。然而，据我们所知，只有一项小型研究前瞻性地研究了IGF-I与葡萄糖耐受不良风险之间的关系，并报告高IGF-I水平与葡萄糖耐量受损（IGT）和2型糖尿病风险降低相关。虽然这项研究提供了重要的初始数据，但由于样本量小（44例IGT和7例2型糖尿病）和未能测量“游离”IGF-I（可能是IGF-I的生物利用度更高的形式）以及IGFBP-2和IGFBP-3（两种最丰富的IGF结合蛋白），因此受到限制。我们在妇女健康倡议观察性研究（WHI-OS）和心血管健康研究（CHS）中进行的两项试点研究表明，测量所有主要IGFBPs可能具有重要意义。在WHI-OS中，IGFBP-3与空腹血糖受损和2型糖尿病的患病率具有统计学显著性正相关，在CHS中，观察到与2型糖尿病具有边缘统计学显著性的类似相关性（未测量IGFBP-2）。此外，IGF-I还可以具有抗炎作用，其可以降低与胰岛素抵抗和发展2型糖尿病的风险相关的炎症因子的水平。然而，IGF-I及其结合蛋白与炎症因子和脂肪因子的相互关系还不清楚。本申请提出了第一项大型前瞻性研究，以评估基线时总IGF-I、游离IGF-I、IGFBP- 1、IGFBP-2和IGFBP-3的空腹血浆水平与2型糖尿病发病风险之间的相关性。具体来说，拟议的研究将建立在现有的嵌套病例对照研究的几个生物标志物，包括炎症标志物和脂肪因子，和2型糖尿病的风险（900例事件和900个单独匹配的对照），在护士的健康研究（NHS），一个大的队列的妇女年龄在30-55岁的招聘。大样本量、长期随访和高质量协变量数据是该NHS辅助研究的优势。这项研究还提供了一个独特的和具有成本效益的机会，调查IGF-I及其结合蛋白与炎症标志物和脂肪因子的相互关系。如果IGF-轴和2型糖尿病之间存在关联，IGF-轴的相关组分可能被开发为新的治疗干预的靶点，以延迟或预防高危个体中的2型糖尿病。公共卫生相关性：2型糖尿病是一个日益严重的公共卫生问题，影响到约2000万美国人。这项研究将是第一个大型前瞻性研究，以评估胰岛素样生长因子（IGF）轴和2型糖尿病风险的关联。IGF-轴可能在2型糖尿病及其相关疾病的病因学中发挥作用，也可能为其预防提供新的治疗靶点。

DESCRIPTION (provided by applicant): Type 2 diabetes is an increasing public health problem affecting ~20 million Americans and is commonly associated with insulin resistance. The insulin-like growth factor (IGF)-I shares structural homology with insulin and increasing evidence indicates that IGF-I and its binding proteins (IGFBPs) may play an important role in normal glucose homeostasis. Exogenous IGF-I administration improves insulin sensitivity in humans, including patients with type 2 diabetes. However, to our knowledge, only one small study has prospectively investigated the association between IGF-I and the risk of developing glucose intolerance and reported that high IGF-I levels were associated with reduced risk of impaired glucose tolerance (IGT) and type 2 diabetes. Although this study provided important initial data, it was limited by its small sample size (44 incident cases of IGT and 7 of type 2 diabetes) and failure to measure `free' IGF-I (possibly the more bioavailable form of IGF-I), as well as IGFBP-2 and IGFBP-3, the two most abundant IGF-binding proteins. The possible importance of measuring all major IGFBPs was suggested in two pilot studies that we conducted within the Women's Health Initiative Observational Study (WHI-OS) and the Cardiovascular Health Study (CHS). In the WHI-OS, IGFBP-3 had a statistically significant positive association with prevalence of impaired fasting glucose and type 2 diabetes, and in the CHS a similar association with type 2 diabetes of borderline statistical significance was observed (IGFBP-2 was not measured). Further, IGF-I may also have anti- inflammatory effects that may lower levels of inflammatory factors associated with insulin resistance and the risk of developing type 2 diabetes. However, the inter-relationships of IGF-I and its binding proteins with inflammatory factors and adipokines are not well understood. This application proposes the first large prospective study to evaluate the associations between fasting plasma levels of total IGF-I, free IGF-I, IGFBP- 1, IGFBP-2 and IGFBP-3 at baseline and risk of incident type 2 diabetes. Specifically, the proposed study will build upon an existing nested case-control investigation of several biomarkers, including inflammatory markers and adipokines, and the risk of type 2 diabetes (900 incident cases and 900 individually matched controls), within the Nurse's Health Study (NHS), a large cohort of women aged 30-55 years at recruitment. The large sample size, long-term follow-up and high quality covariate data, are advantages of this NHS ancillary study. The proposed study also provides a unique and cost-effective opportunity to investigate the inter-relationships of IGF-I and its binding proteins with inflammatory markers and adipokines. If an association between the IGF- axis and type 2 diabetes exists, the relevant components of the IGF-axis could potentially be exploited as targets for novel therapeutic interventions to delay or prevent type 2 diabetes among high-risk individuals. PUBLIC HEALTH RELEVANCE: Type 2 diabetes is an increasing public health problem affecting ~20 million Americans. The proposed study will be the first large prospective study to evaluate the association of the insulin-like growth factor (IGF)-axis and risk of type 2 diabetes. The IGF-axis may potentially play a role in the etiology of type 2 diabetes and its related conditions and may also provide a novel therapeutic target for its prevention.