Studying Progression and Regression of Beta Cell Dysfunction in Type 2 Diabetes

描述(由申请人提供) 摘要：2型糖尿病(T2 DM)影响着大约2580万美国人，每年在美国消耗超过2100亿美元的医疗费用。T2 DM是一种多基因慢性疾病，涉及胰岛素抵抗和�细胞功能障碍。然而，只有40%-50%的胰岛素抵抗患者进展为T2 DM。进展者的关键缺陷是�细胞无法通过适当的高胰岛素血症来补偿胰岛素抵抗，变得功能失调，最终死亡。因此，�细胞功能障碍是从代谢障碍发展到疾病状态的关键一步。T2 DM的另一个大问题是T2 DM是否可逆。减肥手术已经被证明可以在很高比例的严重肥胖的T2 DM患者中诱导缓解。更多数据表明，减肥手术后�细胞功能有所改善。然而，环境和遗传因素如何影响�细胞功能障碍的进展和消退在很大程度上是未知的。因此，迫切需要建立新的模型来研究T2 DM患者�细胞功能障碍的进展和消退。人类诱导多能干细胞(HiPSCs)为研究人类疾病的遗传因素提供了新的系统，也为总结疾病的细胞病理学提供了一个平台。然而，HiPSCs还没有成功地用于慢性病的建模。在这里，我们建议使用人源化的小鼠模型来研究环境和遗传因素在T2 DM患者�细胞功能障碍进展和消退中的作用。通过与纽约器官捐赠网络的合作，我们收集了健康捐赠者、被诊断为胰岛素抵抗的捐赠者或被诊断为2型糖尿病的捐赠者的胰岛。我们使用两种方法来创造人性化的小鼠。一种是直接使用初级患者的胰岛。另一项是从患者的胰岛建立IPSCs，并使用IPSCs衍生的内分泌前体细胞创造人源化的小鼠。这项拟议的研究真正具有创新性，因为它建立了一个模型，利用IPSCs来研究一种受环境和遗传因素影响的慢性疾病。与以前使用患者群体或动物模型进行的研究相比，人源化的小鼠模型具有几个优势。首先，使用患者胰岛或来自患者特有的IPSCs的葡萄糖反应细胞的模型，这些细胞携带患者的遗传缺陷。其次，人源化小鼠模型中的环境因素可以得到严格控制。最后，含有患者特异性IPSC来源群体的人源化小鼠提供了一个实时监测�细胞功能障碍从代偿到功能障碍，最后是细胞凋亡的过程的平台。我们将利用这些人源化的小鼠模型来研究环境和遗传因素对�细胞功能障碍进展和消退的速度和动态的影响，并确定T2 DM的�细胞功能障碍进展的临界点。这项拟议的研究具有很高的影响，因为我们将学习如何预防或治疗T2 DM。

DESCRIPTION (Provided by the applicant) Abstract: Type 2 diabetes mellitus (T2DM) affects approximately 25.8 million Americans and consumes more than $210 billion dollars in United States health care costs every year. T2DM is a polygenetic and chronic disease, involving insulin resistance and � cell dysfunction. However, only 40-50% of individuals with insulin resistance progress to T2DM. The pivotal defect in those who progress is that � cells fail to compensate for the insulin resistance with appropriate hyperinsulinemia, become dysfunctional and, eventually, die. Thus, � cell dysfunction is a key step in the progression from metabolic impairments to a disease state. Another big question in T2DM is whether T2DM is reversible. Bariatric surgery has been shown to induce remission in a high proportion of severely obese patients with T2DM. Additional data suggested � cell function improves after bariatric surgery. However, how environmental and genetic factors affect the progression and regression of � cell dysfunction is largely unknown. Thus, there is a strong need to establish novel models to study the progression and regression of � cell dysfunction in T2DM. Human induced pluripotent stem cells (hiPSCs), provide new systems to study the genetic factors in human diseases, as well as a platform to recapitulate the cellular pathology in the diseases. However, hiPSCs have not yet been successfully used to model chronic diseases. Here, we propose to use humanized mouse models to study the role of the environmental and genetic factors in the progression and regression of � cell dysfunction in T2DM. By collaborating with New York Organ Donation Network, we collect islets from healthy donors, donors diagnosed with insulin resistance or donors diagnosed with T2DM. We use two approaches to create humanized mice. One is to directly use the primary patient islets. The other one is to establish iPSCs from patient islets and create humanized mice using iPSCs-derived endocrine progenitors. The proposed study is truly innovative because it establishes a model to use iPSCs to study a chronic disease affected by both environmental and genetic factors. Compare to the previous studies using patient population or animal models, the humanized mouse models have several advantages. Firstly, the models using patient islets or glucose-responding cells derived from patient-specific iPSCs, which carry the genetic defects of patients. Secondly, the environmental factors in a humanized mice model can be tightly controlled. Finally, humanized mice containing patient-specific iPSC-derived population provide a platform to real time monitor the progression of � cell dysfunction from compensation to dysfunction, and finally apoptosis. We will use these humanized mouse models to study the effect of environmental and genetic factors on the rate and dynamic of the progression and regression of � cell dysfunction, and identify the ""tipping point"" of the progression of � cell dysfunction of T2DM. The proposed study has high impact because we will learn how to prevent or treat T2DM.