Indiana University clinical Center for acute pancreatitis and diabetes clinical research network

项目摘要/摘要 胰源性糖尿病，或3c型糖尿病(T3cDM)，是急性胰腺炎(AP)的已知并发症。 最近的数据表明，T3cDM比以前认识到的更常见，并表现出一系列 缺陷包括1型和2型糖尿病的特征重叠。目前，在多大程度上 AP后会发生免疫激活、β细胞功能障碍和胰岛素抵抗。 这些表型的影像相关性还没有被描述出来。为了解决这些知识差距，我们 已经组建了一个多学科的团队，在胰腺炎和外分泌病理生理学，糖尿病， 印第安纳大学医学院的β细胞生物学、糖尿病遗传学和胰腺成像。这些Iu 临床中心将与1型糖尿病急性胰腺炎联盟的其他成员合作，测试 假设T3cDM包含代谢和潜在免疫学的异质组合 由不同的潜在病理生理决定的表型。我们提出了以下具体目标 (Sa)实现本框架协议的目标。SA#1：对性格强健的成年人进行观察性研究 与AP合作，以解决自身抗体阳性糖尿病自然病史和发病率方面的知识差距 (AAB+)、糖耐量受损(IGT)/空腹血糖受损(IFG)以及随后发生的糖尿病 美联社注册参与者的纵向特征将是强调识别遗传、免疫学、 AAB+、IGT/IFG或T3cDM发生的代谢和临床危险因素。我们将使用最先进的 免疫学表型和胰腺β细胞功能的测定以确定其生理基础 急性胰腺炎后T3cDM的代谢紊乱。同时，将开发一个生物库，用于进行 翻译、机制和生物标志物调查及辅助研究。SA#2：的成像形态 急性胰腺炎后糖尿病患者的胰腺(即将进行)研究旨在利用新的定量方法 磁共振成像技术作为一种非侵入性生物标志物来识别有风险的患者 急性胰腺炎后T3cDM的发展。这项纵向研究将评估胰腺实质的形态和 AAB+、正常血糖、糖耐量减低和糖尿病患者急性胰腺炎后的病理生理改变。成像表型将 与SA#1中确立的代谢、遗传和免疫表型相关。SA#3：执行 一项嵌套病例对照研究，使用最先进的技术来定义潜在的病理生理学 AAB+AP相关代谢功能障碍患者亚组的内分泌和外分泌功能 相对于那些血糖正常的人。我们将进行详细的代谢表型分析来评估胰岛 细胞反应(即β和α细胞功能)与精氨酸增强的高血糖钳夹平行 测量功能性β细胞质量的方法学，以及定义内窥镜评估之间的关系 AAB+T3cDM患者外分泌和内分泌功能受损。我们将利用25名AAB+和IGT或 T3cDM，并将结果与SA#1自身抗体阴性的25名血糖正常的个体的结果进行比较。

PROJECT SUMMARY / ABSTRACT Pancreatogenic diabetes, or type 3c diabetes (T3cDM), is a known complication of acute pancreatitis (AP). Recent data suggest that T3cDM occurs more commonly than previously recognized and exhibits a spectrum of defects including features that overlap aspects of both type 1 and type 2 diabetes. At present, the extent to which immune activation, β cell dysfunction, and insulin resistance occur following AP and the genetic, metabolic and imaging correlates of these phenotypes have not been characterized. To address these knowledge gaps, we have assembled a multidisciplinary team with expertise in pancreatitis and exocrine pathophysiology, diabetes, β cell biology, diabetes genetics, and pancreatic imaging at the Indiana University School of Medicine. The IU Clinical Center will work with other members of the Type 1 Diabetes in Acute Pancreatitis Consortium to test the hypothesis that T3cDM encompasses a heterogeneous combination of metabolic and potentially immunologic phenotypes that are determined by distinct underlying pathophysiologies. We propose the following specific aims (SA) to meet the goals of this RFA. SA #1: To perform an observational study of robustly characterized adults with AP in order to address knowledge gaps in the natural history and incidence of autoantibody-positive diabetes (AAb+), impaired glucose tolerance (IGT)/impaired fasting glucose (IFG), and diabetes occurring subsequent to AP. Enrolled participants will be longitudinally characterized with emphasis on identifying genetic, immunological, metabolic, and clinical risk factors for the development of AAb+, IGT/IFG, or T3cDM. We will use state-of-the-art immunologic phenotyping and measurements of pancreatic β cell function to define the physiologic basis for metabolic dysregulation in T3cDM after AP. In tandem, a biorepository will be developed for undertaking translational, mechanistic and biomarker investigations and ancillary studies. SA#2: The Imaging Morphology of Pancreas in Diabetic Patients following Acute Pancreatitis (IMMINENT) study aims to utilize novel quantitative magnetic resonance imaging techniques as a non-invasive biomarker to identify patients at risk for the development of post-AP T3cDM. This longitudinal study will evaluate pancreatic parenchymal morphologic and pathophysiologic changes following AP in AAb+, euglycemic, IGT and DM individuals. Imaging phenotypes will be correlated with the metabolic, genetic and immunological phenotypes established in SA#1. SA#3: To perform a nested case control study using state-of-the-art techniques to define the underlying pathophysiology of endocrine and exocrine function in the subgroup of AAb+ individuals with AP-associated metabolic dysfunction relative to those who remain normoglycemic. We will undertake detailed metabolic phenotyping to evaluate islet cell responses (i.e. β and alpha cell function) in parallel with arginine-augmented hyperglycemic clamp methodology to measure functional β cell mass, and endoscopic assessment to define the relationship between impaired exocrine and endocrine function in AAb+ T3cDM. We will utilize 25 individuals with AAb+ and IGT or T3cDM and compare findings to results in 25 normoglycemic individuals with negative autoantibodies from SA#1.