Synergistic Roles of Adiponectin & PPARgamma in Beta-Cell Survival/Proliferation

描述(申请人提供)：胰岛β细胞分泌胰岛素，这是一种促进碳水化合物和其他营养物质在骨骼肌中的吸收和储存，同时抑制葡萄糖从肝脏流出的多肽激素。糖尿病的原因是胰岛素供应不足以满足组织对胰岛素的需求，最近的研究表明，1型和2型糖尿病都与由于增殖减少和细胞凋亡增加而导致的β细胞质量减少有关。此外，在分离或移植过程中，β细胞对凋亡和坏死的敏感性阻碍了将胰岛移植作为治疗这些疾病的尝试。了解控制β细胞存活的调控信号对于制定策略以维持个体中健康的细胞种群至关重要。噻唑烷二酮类(TZDS)是一类新型口服降糖药物，通过激活脂肪细胞分化的关键转录介质--过氧化体增殖物激活受体-γ(PPAR-Gamma)来改善胰岛素敏感性。尽管TZDS的分子作用机制仍不确定，但它们的作用可能涉及脂肪细胞特异性分泌分子脂联素(AcrpSO)的上调。过去几年的许多临床报告和遗传学研究表明，在代谢功能障碍中，这种脂肪因子的循环水平降低，例如人类和动物的肥胖和胰岛素抵抗。脂联素缺乏、转基因脂联素过度生产和药物治疗的动物模型的表型支持脂联素在维持糖和脂平衡方面的有益作用。总而言之，这些研究表明，脂联素可能具有强大的抗炎特性，这可能也对β细胞凋亡起到保护作用。事实上，脂联素和TZDS对体内的β细胞都有保护作用。这项建议将评估脂联素和PPARγ对体内β细胞存活和增殖的影响。使用转基因小鼠(脂联素基因敲除、脂联素转基因、PPARβ细胞敲除)或注射外源性脂联素或PPARγ配体I，将检测脂联素和PPARγ对NOD小鼠(一种常用的自身免疫性糖尿病模型)以及我们最近描述的Panic-ATTAC小鼠β细胞凋亡和增殖的影响。恐慌的ATTAC小鼠提供了独特的机会，在细胞特异性和可滴定的诱导细胞凋亡后评估β细胞的再生。

DESCRIPTION (provided by applicant): Pancreatic beta cells secrete insulin, a peptide hormone that promotes the uptake and storage of carbohydrates and other nutrients in skeletal muscle while simultaneously repressing glucose efflux from the liver. Diabetes mellitus results from insulin availability that is insufficient to meet tissue insulin needs, and recent studies suggest that both the type 1and type 2 forms of the disease are associated with decreased beta cell mass resulting from decreased proliferation and increased apoptosis. Moreover, the susceptibility of beta cells to both apoptosis and necrosis during isolation or transplantation has hindered attempts to utilize islet transplantation as a treatment for these diseases. Understanding the regulatory signals governing beta cell survival is critical for devising strategies to maintain a healthy population of cells in individuals. Thiazolidinediones (TZDs) are a novel class of oral antidiabetic agents which improves insulin sensitivity through activation of peroxisome proliferator-activated receptor-gamma (PPAR gamma), a critical transcriptional mediator of adipocyte differentiation. Although there remains uncertainty about the molecular mechanism of action of TZDs, their effects likely involve upregulation of the adipocyte-specific secretory molecule adiponectin (AcrpSO). Many clinical reports and genetic studies over the past few years demonstrate decreased circulating levels of this adipokine in metabolic dysfunction, such as obesity and insulin resistance in both humans and animals. The phenotypes of adiponectin-deficient, transgenic adiponectin overproducing, and pharmacologic adiponectin treated animal models support a beneficial role of adiponectin in the maintenance of glucose and lipid homeostasis. Collectively, these studies suggest that adiponectin may have potent anti-inflammatory properties, which may also play a protective role on beta cell apoptosis. Indeed, adiponectin and TZDs both have protective effects on the beta cell in vivo. This proposal will evaluate the effects of adiponectin and PPAR gamma on beta cell survival and proliferation in vivo. Using genetically modified mice (adiponectin knockouts, adiponectin transgenic, PPARgamma beta cell knockout) or administration of exogenous adiponectin or PPAR gamma ligand I will examine the effects of adiponectin and PPAR gamma on beta cell apoptosis and proliferation in the NOD mouse (a commonly used model for autoimmune diabetes) as well as our recently characterized PANIC- ATTAC mouse. The PANIC ATTAC mouse allows the unique opportunity to evaluate beta cell regeneration following the cell specific and titratable induction of apoptosis.