Role of Human Resistin in Insulin Resistance

糖尿病是美国发病和死亡的主要原因。2型糖尿病，最常见的 形式，与肥胖有关，其特征是对胰岛素作用的抵抗。虽然 2型糖尿病的发病机制复杂且有争议，但现在很清楚，2型糖尿病是一种慢性疾病。 炎症状态，且炎症调节葡萄糖代谢。我们是第一个描述小说的人 一种叫做β-淀粉样蛋白的分泌蛋白，它会加剧胰岛素抵抗。在小鼠中，Leptin是脂肪细胞特异性的， 组成型表达，但人的巨噬细胞主要由巨噬细胞产生，并由 炎性刺激流行病学和遗传学证据支持抵抗素在人类糖尿病中的作用， 心血管疾病，我们已经证明，巨噬细胞来源的人的cardiovascular足够， 加剧饮食引起的胰岛素抵抗。然而，炎症诱导的炎症反应的代谢效应， 不知道。我们现在已经建立了一个创新的人源化的小鼠模型， 小鼠BcN表达低循环水平的BcN，其随着高脂肪饮食而增加，并且在暴露于 内毒素具体目的1是确定人源化的Bptin表达对肥胖的影响， 炎症相关的胰岛素抵抗。我们假设人源化的cDNAn表达诱导 胰岛素抵抗是慢性有害的，但保护性低血糖，并将评估这一点，使用 通过葡萄糖和胰岛素钳夹研究探索的创新炎症模型。具体目标二是 确定人源化的Ignorn表达对心血管疾病的影响。我们假设 人源化表达的HSP 12蛋白将加重心力衰竭，并将在适当的模型中测试这一点。 具体目标3是确定Bcln表达的种属特异性和细胞特异性的机制， 一种创新的表观基因组发现方法将解决这一重要问题。总的来说，拟议的研究 将解决关键问题的作用，作为一个链接之间的炎症，胰岛素抵抗， 和心脏代谢疾病，以及干预这些毁灭性疾病的潜在目标。这些 这些研究对我们这个代谢性疾病猖獗的社会具有重要意义。 相关性（参见说明）： 糖尿病是美国发病和死亡的主要原因。2型糖尿病，最常见的 糖尿病的一种形式，与肥胖有关，其特征是对胰岛素作用的抵抗。 了解胰岛素抵抗的机制对于寻找新的治疗方法至关重要。我们决定 胰岛素抵抗的作用，它加剧胰岛素抵抗，是由人类炎症引起的。抵抗素 可能是新疗法的目标，可以阻止我们社会中代谢疾病的流行。

Diabetes is a leading cause of morbidity and death in the United States. Type 2 diabetes, the most common form, is associated with obesity and characterized by resistance to the actions of insulin. Although the underiying mechanisms are complex and controversial, it is now clear that type 2 diabetes is a chronic inflammatory state, and that inflammation modulates glucose metabolism. We were first to describe a novel secreted protein called resistin that exacerbates insulin resistance. In mice, resistin is adipocyte-specific and expressed constitutively, but human resistin is produced predominantly by macrophages and induced by nflammatory stimuli. Epidemiologic and genetic evidence supports a role for resistin in human diabetes and cardiovascular disease, and we have demonstrated that macrophage-derived human resistin is sufficient to exacerbate diet-induced insulin resistance. However, the metabolic effects of inflammation-induced resistin are not known. We now have established an innovative humanized resistin model in which mice lacking mouse resistin express low circulating levels of resistin that increase with high fat diet and after exposure to endotoxin. Specific Aim 1 is to determine the impact of humanized resistin expression on obesity- and inflammation-associated insulin resistance. We hypothesize that humanized resistin expression induces insulin resistance that is chronically deleterious but protective hypoglycemia, and will evaluate this using innovative models of inflammation interrogated by glucose and insulin clamp studies. Specific Aim 2 is to determine the effects of humanized resistin expression on cardiovascular disease. We hypothesize that the humanized expression of resistin will exacerbate heart failure, and will test this in appropriate models. Specific Aim 3 is to detennine the mechanism of species- and cell-specificity of resistin expression, applying an innovative epigenomic discovery approach will to this important problem. Together, the proposed studies will address critical questions about the role of resistin as a link between inflammation, insulin resistance, and cardiometabolic diseases, and a potential target for intervention in these devastating diseases. These studies have important implications for our society in which metabolic diseases are rampant. RELEVANCE (See instructions): Diabetes is a leading cause of morbidity and death in the United States. Type 2 diabetes, the most common form of diabetes, is associated with obesity and characterized by resistance to the actions of insulin. Understanding the mechanism of insulin resistance is critical to finding new therapies. We are determining the role of resistin, which exacerbates insulin resistance and is induced by inflammation in humans. Resistin may be a target for novel therapies that stem the tide of the epidemic of metabolic disease in our society.