The Role of Cytokine Signaling in Arsenic Induced Insulin Resistance

细胞因子信号传导在砷诱导的胰岛素抵抗中的作用

• 批准号: 8008640
• 负责人: Ingrid Druwe
• 金额: $ 4.14万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2011-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8008640
• 关键词: Accounting; Adipocytes; Affect; Aging; Area; Arsenic; Biochemical; Bladder; Blood Glucose; Cancerous; Cardiovascular Diseases; Cells; Chronic; Cytokine Signaling; Defect; Development; Diabetes Mellitus; Diagnosis; Disease; Environmental Risk Factor; Epidemiologic Studies; Exposure to; Family history of; Human; Hypertension; Ingestion; Insulin; Insulin Resistance; Interleukin-6; Kidney; Knowledge; Link; Lung; Malignant neoplasm of liver; Metals; Minerals; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Population; Production; Risk Factors; Role; Skin; Soil; Time; United States; Weather; blood glucose regulation; cytokine; drinking water; ground water; neurotrophic factor; public health relevance; response; toxicant

DESCRIPTION (provided by applicant): Arsenic is a naturally occuring metal that has contaminated the ground water of Western, Midwestern and Northeastern areas of the United States, largely as a result of minerals dissolving from weathered rocks and soils. Arsenic has been recognized as a human toxicant since ancient times and has been linked to the development of skin, kidney, lung, bladder, and liver cancers. Additionally, a variety of non-cancerous conditions such as hypertension, cardiovascular disease and diabetes mellitus have been associated with chronic ingestion of low levels of arsenic. The majority of arsenic-associated diabetes mellitus studies have focused on epidemiological studies of exposed populations, yet little is known about the biochemical mechanisms that maybe aberrantly affected by chronic exposure to low levels of arsenic. Our group has been able to show that exposure to arsenic in drinking water as low as 10 ppb (0.13 5M) could produce hyperinsulemia in C57Bl/6 mice. Additional studies performed by our group in mature adipocytes show an increase in secretion of cytokines, such as IL-6 and curiosly NT-3, in response to low level arsenic exposure (50 ppb). To our knowledge this is the first evidence that the neurotrophin, NT-3, can be secreted by 3T3-L1 adipocytes in response to arsenic exposure. For this reason, the objective of this application is to define the and characterize mechanism(s) by which NT-3 is being secreted by arsenic exposure and the downstream consequences it produces. Hence, our central hypothesis is that chronic exposure to low levels of arsenic results in insulin-resistance and hyperinsulimia in insulin-responsive cells due to arsenic-induced cytokine secretion. PUBLIC HEALTH RELEVANCE: Diabetes is a group of diseases that are characterized by high levels of blood glucose resulting from defects in insulin production or from insulin-resistance. The number of diagnosed cases of the disease have more than doubled over the past ten years and amongst these, Type 2 diabetes accounts for 90-95%. Risk factors associcated with Type 2 diabetes include aging, obesity, family history as well as exposure to environmental factors such as arsenic. Knowledge of how arsenic interrupts normal blood-glucose regulation will help to elucidate the etiological factors behind the progression of Type 2 diabetes mellitus.

描述(申请人提供)：砷是一种天然存在的金属，已经污染了美国西部、中西部和东北部地区的地下水，主要是由于矿物从风化的岩石和土壤中溶解而成。砷自古以来就被认为是一种人类毒物，并与皮肤癌、肾癌、肺癌、膀胱癌和肝癌的发生有关。此外，高血压、心血管疾病和糖尿病等各种非癌症疾病都与长期摄入低水平的砷有关。大多数与砷相关的糖尿病研究都集中在暴露人群的流行病学研究上，但对长期接触低水平砷可能会异常影响的生化机制知之甚少。我们的小组已经能够证明，暴露在低至10 ppb(0.135米)的饮用水中的砷可以在C57BL/6小鼠中产生高胰岛素血症。我们小组在成熟脂肪细胞上进行的其他研究表明，低水平的砷暴露(50ppb)会增加细胞因子的分泌，如IL-6和NT-3。据我们所知，这是第一个证据表明神经营养因子NT-3可以由3T3-L1脂肪细胞对砷暴露做出反应。因此，本申请的目的是定义和表征暴露于砷中的NT-3的分泌机制(S)及其产生的下游后果。因此，我们的中心假设是，长期暴露于低水平的砷会导致胰岛素反应细胞的胰岛素抵抗和高胰岛素血症，这是由于砷诱导的细胞因子分泌。 公共卫生相关性：糖尿病是一组疾病，其特征是由于胰岛素产生缺陷或胰岛素抵抗而导致的高血糖水平。在过去的十年里，确诊的糖尿病病例数量增加了一倍多，其中，2型糖尿病占90%-95%。与2型糖尿病相关的风险因素包括年龄、肥胖、家族史以及接触环境因素，如砷。了解砷如何干扰正常的血糖调节将有助于阐明2型糖尿病进展背后的病因。