The Role of Cytokine Signaling in Arsenic Induced Insulin Resistance

描述（由申请人提供）：砷是一种天然存在的金属，已污染了美国西部、中西部和东北部地区的地下水，主要是由于风化岩石和土壤中溶解的矿物质。砷自古以来就被认为是一种人类毒物，与皮肤癌、肾癌、肺癌、膀胱癌和肝癌的发生有关。此外，各种非癌性疾病，如高血压、心血管疾病和糖尿病，都与长期摄入低水平的砷有关。大多数砷相关性糖尿病的研究都集中在暴露人群的流行病学研究，但很少有人知道的生化机制，可能异常影响慢性暴露于低水平的砷。我们的小组已经能够表明，暴露于饮用水中的砷低至10 ppb（0.13 5 M）可以产生高胰岛素血症的C57 Bl/6小鼠。我们小组在成熟脂肪细胞中进行的其他研究表明，低水平砷暴露（50 ppb）会增加细胞因子（如IL-6和NT-3）的分泌。据我们所知，这是第一个证据表明，神经营养因子，NT-3，可以分泌的3 T3-L1脂肪细胞在砷暴露。出于这个原因，本申请的目的是定义和表征通过砷暴露分泌NT-3的机制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导致胰岛素抵抗和胰岛素敏感细胞由于砷诱导的细胞因子分泌的hyperinsulimia。 公共卫生相关性：糖尿病是一组疾病，其特征在于由胰岛素产生缺陷或胰岛素抵抗引起的高血糖水平。在过去的十年中，这种疾病的诊断病例数量增加了一倍多，其中，2型糖尿病占90- 95%。与2型糖尿病相关的危险因素包括衰老、肥胖、家族史以及暴露于砷等环境因素。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学因素。

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.