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

描述（由申请人提供）：胰腺细胞分泌胰岛素，胰岛素是一种肽激素，促进骨骼肌对碳水化合物和其他营养物质的吸收和储存，同时抑制肝脏的葡萄糖外排。糖尿病是由于胰岛素供应不足以满足组织胰岛素需求引起的，最近的研究表明，1型和2型糖尿病都与β细胞数量减少有关，这是由于增殖减少和细胞凋亡增加造成的。此外，在分离或移植过程中β细胞对凋亡和坏死的易感性阻碍了利用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维持个体健康细胞群的策略至关重要。噻唑烷二酮类（TZDs）是一类新型的口服降糖药，它通过激活过氧化物酶体增殖物激活受体γ (PPAR γ)来改善胰岛素敏感性，PPAR γ是脂肪细胞分化的关键转录介质。虽然TZDs的分子作用机制尚不明确，但其作用可能与上调脂肪细胞特异性分泌分子脂联素（AcrpSO）有关。过去几年的许多临床报告和遗传学研究表明，在人类和动物的代谢功能障碍（如肥胖和胰岛素抵抗）中，这种脂肪因子的循环水平降低。脂联素缺乏、转基因脂联素过量产生和药理学脂联素处理动物模型的表型支持脂联素在维持葡萄糖和脂质稳态中的有益作用。总的来说，这些研究表明脂联素可能具有有效的抗炎特性，这也可能对β细胞凋亡起保护作用。事实上，脂联素和TZDs在体内都对β细胞有保护作用。本研究拟在体内评价脂联素和PPAR γ对β细胞存活和增殖的影响。使用转基因小鼠（脂联素敲除、脂联素转基因、PPAR β细胞敲除）或外源性脂联素或PPAR γ配体管理，我将在NOD小鼠（一种常用的自身免疫性糖尿病模型）以及我们最近表征的PANIC- ATTAC小鼠中研究脂联素和PPAR γ对β细胞凋亡和增殖的影响。PANIC ATTAC小鼠提供了独特的机会来评估细胞特异性和可滴定诱导凋亡后的β细胞再生。

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.