Ancillary Study Proposal for The Restoring Insulin Secretion (RISE) Study: Autoimmune Mechanisms for the Progressive Decline of Beta cell Function in Type 2 Diabetes (T2D)

 描述（由申请人提供）：免疫应答在肥胖、胰岛素抵抗和2型糖尿病（T2 D）发展中的关键作用已被公认为具有临床重要性的关键研究领域。我们在小型初步研究中观察到T2 D患者的胰岛自身免疫（胰岛自身抗体和/或胰岛特异性T细胞），并证明胰岛自身免疫与更严重的β细胞病变和β细胞功能更快速下降相关。我们假设“胰岛自身免疫是T2 D中β细胞功能下降的重要因素，并可能影响糖尿病治疗的疗效”。我们将在恢复胰岛素分泌（RISE）研究的框架内进行研究。RISE是一项由NIH支持的大型临床试验，旨在研究药物和手术干预对糖尿病前期β细胞功能的恢复和保护， 早期T2 D RISE研究的前瞻性设计提供了一个理想的机会，将我们的小型试点研究的结果扩展到T2 D和糖尿病前期患者的大型纵向随访种族多样性队列。到目前为止，使用内部资金，我们已经分析了74个基线血液样本和14个6个月样本的胰岛反应性T细胞从RISE研究受试者，并观察到细胞胰岛自身免疫的40%的RISE患者（初步数据）。这项提案的资助将使我们能够继续收集和分析胰岛自身免疫性RISE患者样本，并在我们的专家合作者的协助下开始研究与1型（T1 D）糖尿病中确定的β细胞功能下降相关的其他免疫机制（循环微小RNA，外周免疫特征（免疫表型和细胞因子），高亲和力胰岛自身抗体，和β细胞死亡（未甲基化INS DNA）），以及胰岛自身免疫对RISE干预的影响。我们对RISE受试者的访问，我们在使用本辅助研究中概述的经验证的测定方面的熟练程度，以及我们合作者的专家协助，使我们处于独特的位置，以完成我们提出的研究。这项辅助研究的结果可能对我们理解与T2 D相关的β细胞功能障碍的病理生理学产生重大影响，并可能导致识别对T2 D患者有益的基于免疫的治疗。

 DESCRIPTION (provided by applicant): The key role that immune responses play in obesity, development of insulin resistance and type 2 diabetes (T2D) has been acknowledged as a critical area of research with clinical importance. We have observed in small pilot studies, islet autoimmunity (islet autoantibodies and/or islet specific T cells) in T2D patients and have demonstrated islet autoimmunity to be associated with a more severe beta (β)-cell lesion, and a more rapid decline in β-cell function. We hypothesize that "Islet autoimmunity is an important contributor to the β-cell functional decline in T2D and may impact the efficacy of diabetes therapies". We will perform our investigations within the framework of The Restoring Insulin Secretion (RISE) study. RISE is a large NIH supported clinical trial investigating medical and surgical interventions for the restoration and preservation of β-cell function in pre-diabetes and early T2D. The prospective design of the RISE study provides an ideal opportunity to extend the results of our small pilot studies into a large longitudinally followed ethnically diverse cohort o T2D and pre-diabetes patients. To date, using internal funds, we have analyzed 74 baseline blood samples and 14 6-month samples for islet reactive T cells from RISE study subjects and have observed cellular islet autoimmunity in 40% of RISE patients (preliminary data). Funding of this proposal will allow us to continue collection and analysis of RISE patient samples for islet autoimmunity and begin investigating, with the assistance of our expert collaborators, additional immunological mechanisms associated with β-cell functional decline identified in Type 1 (T1D) diabetes (circulating microRNA, peripheral immune signatures (immune phenotypes and cytokines), high affinity islet autoantibodies, and β cell death (unmethylated INS DNA)) in the pathophysiology of T2D, and the impact of islet autoimmunity on the RISE interventions. Our access to RISE subjects, our proficiency in the use of the validated assays outlined in this ancillary study, and the expert assistance of our collaborators puts us in a unique position to accomplish our proposed research. The results of this ancillary study are likely to have a major impact on our understanding of the pathophysiology of the β-cell dysfunction associated with T2D and may result in identification of immune based therapies beneficial for T2D patients.