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

印第安纳大学急性胰腺炎和糖尿病临床中心临床研究网络

• 批准号: 10265585
• 负责人: Carmella Evans-Molina
• 金额: $ 27.85万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-17 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10265585
• 关键词: 3-Dimensional; Address; Adult; Affect; Alpha Cell; Ancillary Study; Arginine; Artificial Intelligence; Autoantibodies; Beta Cell; Biological; Biological Markers; Cell Death; Cell physiology; Cellular Stress; Cellular biology; Clinical; Clinical Research; Closure by clamp; Complication; Data; Defect; Development; Diabetes Mellitus; Diabetes autoantibodies; Diffusion Magnetic Resonance Imaging; Disease; Duodenum; Endocrine; Enrollment; Epidemiology; Etiology; Evolution; Exhibits; Exocrine pancreas; Exocrine pancreatic insufficiency; Extracellular Matrix; Fatty acid glycerol esters; Functional disorder; Genetic; Genomic DNA; Glucagon; Glucose; Glucose Intolerance; Goals; Health; Hyperglycemia; Image; Imaging Techniques; Immune; Immunologics; Impaired fasting glycaemia; Impairment; Incidence; Indiana; Individual; Infiltration; Insulin; Insulin Resistance; Insulin deficiency; Insulin-Dependent Diabetes Mellitus; Investigation; Islet Cell; Knowledge; Liquid substance; Longitudinal Studies; Magnetic Resonance; Magnetic Resonance Elastography; Magnetic Resonance Imaging; Measurement; Measures; Meta-Analysis; Metabolic; Metabolic dysfunction; Methodology; Monitor; Morphology; Motion; Natural History; Nested Case-Control Study; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Observational Study; Pancreas; Pancreatic Function Tests; Pancreatitis; Participant; Patients; Perfusion; Phenotype; Physiological; Plasma; Population; Relaxation; Reporting; Research Personnel; Risk; Risk Factors; Risk Marker; Secretin; Signal Transduction; Structure of beta Cell of islet; Subgroup; Techniques; Testing; Texture; Time; Tissues; Universities; Urine; Work; acute pancreatitis; biobank; biomarker development; clinical center; clinical phenotype; clinical risk; contrast enhanced; diabetes mellitus genetics; diabetic patient; endocrine pancreas development; extracellular; genetic analysis; glucose tolerance; immune activation; impaired glucose tolerance; insulin secretion; insulin sensitivity; islet autoimmunity; islet cell antibody; medical schools; member; metabolic imaging; metabolic phenotype; multidisciplinary; non-diabetic; novel; pancreas imaging; polygenic risk score; prospective; radiomics; repository; response

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.

项目总结/摘要 胰源性糖尿病或3c型糖尿病（T3 cDM）是急性胰腺炎（AP）的已知并发症。 最近的数据表明，T3 cDM比以前认识到的更常见，并表现出一系列的 缺陷包括与1型和2型糖尿病重叠的特征。目前， AP后发生免疫激活、β细胞功能障碍和胰岛素抵抗， 这些表型的成像相关性尚未被表征。为了弥补这些知识差距，我们 组建了一个多学科团队，在胰腺炎和外分泌病理生理学，糖尿病， 印第安纳州大学医学院的β细胞生物学、糖尿病遗传学和胰腺成像。的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， 假设T3 cDM包括代谢和潜在免疫的异质性组合 由不同的潜在病理生理学决定的表型。我们提出以下具体目标 (SA)以实现RFA的目标。SA #1：对特征明确的成人进行观察性研究 以解决自身抗体阳性糖尿病自然史和发病率方面的知识空白 (AAb+）、葡萄糖耐量受损（IGT）/空腹血糖受损（IFG）和糖尿病发生后， AP.将对入组的受试者进行纵向表征，重点是识别遗传、免疫学、 AAb+、IGT/IFG或T3 cDM发生的代谢和临床风险因素。我们将使用最先进的 免疫表型和胰腺β细胞功能的测量，以确定 AP后T3 cDM的代谢失调。同时，将开发一个生物储存库， 翻译、机制和生物标志物研究和辅助研究。SA#2：成像形态学 急性胰腺炎后糖尿病患者的胰腺（IMMINENT）研究旨在利用新的定量 磁共振成像技术作为一种非侵入性生物标志物，以确定患者的风险， AP后T3 cDM的发展。这项纵向研究将评估胰腺实质形态学和 AAb+、血糖正常、IGT和DM个体AP后的病理生理变化。成像表型将 与SA#1中建立的代谢、遗传和免疫表型相关。SA#3：执行 一项巢式病例对照研究，使用最先进的技术来定义 AP相关代谢功能障碍AAb+个体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， 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，以及确定 AAb+ T3 cDM的外分泌和内分泌功能受损。我们将使用25名AAb+和IGT患者，或 T3 cDM，并将结果与25名SA#1自身抗体阴性的血糖正常个体的结果进行比较。