University of Minnesota Clinical Center for the Study of Acute Pancreatitis and Diabetes

摘要 有急性胰腺炎（AP）病史的患者患糖尿病（DM）的风险较高， 影响AP后约四分之一的患者。临床风险因素知之甚少，导致 AP后DM的发展尚不清楚。我们建议研究的风险和机制， AP后DM的发展;具体而言，我们将研究β细胞自身免疫的贡献， 胰岛素分泌和AP后对DM的胰岛素抵抗。 在1型糖尿病（T1 DM）中，胰岛素缺乏是由胰岛的靶向自身免疫破坏引起的 β细胞;这种自身免疫性是由遗传易感性中未知的环境暴露引发的。 个体我们假设AP期间组织损伤与炎症环境的改变相结合激活了 AP相关DM患者亚组中的β细胞自身免疫（T1 DM）。我们的初步数据 提示复发性AP或慢性胰腺炎患者β细胞自身免疫信号增加， DM.我们假设AP后发生DM的患者胰岛素分泌减少（由于 胰腺损伤）、胰岛素敏感性降低，并且一个子集将具有β细胞自身免疫性。 我们的总体目标是建立一个仔细分型的多中心纵向队列的成人诊断为 AP以确定DM的临床危险因素，定义AP-DM的代谢功能障碍，并确定 免疫学对AP-DM的贡献。明尼苏达大学临床中心的研究人员是 AP、DM和T1 DM免疫学领域，非常适合解决联盟目标。在 目标1，我们将在首次研究后0至3个月在整个联盟范围内识别、招募和入组成人（N=1250）。 急性胰腺炎发作的纵向研究，以提高我们对糖尿病进展的理解， AP.我们将确定AP后DM的临床危险因素。在目标2中，我们将定义 通过研究250例AP后患者（来自目标1）的混合餐耐量和频繁样本， 静脉内葡萄糖耐量试验，以测量胰岛素分泌和胰岛素敏感性。在目标3中，我们 通过确定β细胞自身免疫在疾病中的作用， AP后发生DM。我们将在整个队列中进行HLA分型和β细胞自身抗体检测， 目的1和评估T细胞和B细胞四聚体的细胞自身免疫性，在60名受试者的亚组中， DM和AAb状态。将使用单独的组织生物库来评价复发性AP中的胰岛浸润。 这项工作将有助于我们对胰源性糖尿病和T1 DM的理解。背景下 更好地定义疾病的病理生理机制对于改善治疗和 延缓或阻止糖尿病的进展。对于T1 DM，这项工作提供了一种更好地识别 胰岛β细胞作为引起自身免疫的自身反应性免疫细胞的关键触发物的重要作用。

Abstract Patients with a history of acute pancreatitis (AP) are at high risk for developing diabetes mellitus (DM), affecting about 1 in 4 patients after AP. Clinical risk factors are poorly understood, and mechanisms leading to development of DM after AP are unknown. We propose to study risk for and mechanisms underlying development of DM after AP; specifically we will study the contributions of beta cell autoimmunity, defects in insulin secretion, and insulin resistance to DM after AP. In type 1 diabetes mellitus (T1DM) insulin deficiency results from targeted autoimmune destruction of the islet β-cells; this autoimmunity is triggered by unknown environmental exposures in genetically susceptible individuals. We hypothesize that tissue injury combined with an altered inflammatory milieu during AP activates β-cell autoimmunity (T1DM) in a subset of patients with AP-related DM. Our preliminary data collectively suggests an increased signal of β-cell autoimmunity in patients with recurrent AP or chronic pancreatitis and DM. We hypothesize that patients who develop DM after AP will have reduced insulin secretion (due to pancreatic injury), reduced insulin sensitivity, and a subset will have β-cell autoimmunity. Our overall goal is to establish a carefully phenotyped multi-center longitudinal cohort of adults diagnosed with AP to determine clinical risk factors for DM, define metabolic dysfunction in AP-DM, and determine the immunologic contributions to AP-DM. The University of Minnesota-Clinical Center investigators are leaders in the fields of AP, DM, and T1DM immunology and are ideally suited to address the consortium objectives. In Aim 1, we will identify, recruit, and enroll adults (N=1250) consortium-wide at 0 to 3 months after a first episode of acute pancreatitis for a longitudinal study to advance our understanding of progression to DM after AP. We will determine clinical risk factors for DM after AP. In Aim 2, we will define mechanistic mechanisms of AP-related DM by studying 250 patients after AP (from Aim 1) with mixed meal tolerance and frequent sample intravenous glucose tolerance tests to measure insulin secretion and insulin sensitivity. In Aim 3, we will define immunologic mechanisms of disease by determining the contribution of β-cell autoimmunity in development of DM after AP. We will perform HLA-typing and β-cell autoantibodies in the entire cohort from Aim 1 and assess cellular autoimmunity with T-cell and B-cell tetramers in a subset of 60 subjects selected by DM and AAb status. A separate tissue biobank will be used to evaluate islet infiltrates in recurrent AP. This work will contribute significantly to both our understanding of pancreatogenic DM and T1DM. In the setting of AP, better defining the pathophysiologic mechanisms of disease is critical to improving treatment and delaying or preventing progression to DM. For T1DM, this work provides an avenue to better identify an important role for islet β-cells as a key trigger for the self-reactive immune cells causing autoimmunity.