Pancreas Volume in Preclinical Type 1 Diabetes

临床前 1 型糖尿病的胰腺体积

• 批准号: 8644494
• 负责人: MARTHA CAMPBELL-THOMPSON
• 金额: $ 139.85万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8644494
• 关键词: Adult; Age; Age-Years; Atrophic; Autoantibodies; Autoimmune Process; Autoimmunity; Beta Cell; Biological Assay; Biological Markers; Biometry; Blinded; C-Peptide; Cell physiology; Childhood; Clinical; Clinical Endocrinology; Clinical Trials; Complement; Complex; Control Groups; Cross-Sectional Studies; Data; Diabetes Mellitus; Diagnosis; Disease; Disease Progression; Endocrinology; Event; Exocrine pancreas; Faculty; First Degree Relative; Florida; Funding; Future; Gender; Genotype; Glucose; Glutamate Decarboxylase; Glycosylated hemoglobin A; Growth Factor; Image; Immunologics; Immunology; Individual; Inflammation; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention Trial; Laboratories; Life; Longitudinal Studies; Magnetic Resonance Imaging; Measurement; Measures; Metabolic; Methodology; Methods; Monitor; Morphology; Natural History; Onset of illness; Organ Donor; Outcome; Pancreas; Pancreatitis; Participant; Pathogenesis; Pathology; Pathway interactions; Patients; Persons; Physiological; Pilot Projects; Prevention; Preventive Intervention; Radiology Specialty; Recruitment Activity; Reproducibility; Research; Research Personnel; Resolution; Risk; Sensitivity and Specificity; Series; Serum; Structure of beta Cell of islet; Surrogate Markers; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Trypsinogen; Ultrasonography; United States National Institutes of Health; Universities; Visit; Weight; base; clinical care; cost; diabetes risk; disorder risk; fasting glucose; functional loss; high risk; imaging modality; innovation; insulin dependent diabetes mellitus onset; pancreas imaging; pre-clinical; prognostic; public health relevance; radiologist; tool

DESCRIPTION (provided by applicant): For decades, type 1 diabetes (T1D) has been considered a disorder resulting from the autoimmune destruction of insulin producing pancreatic beta cells. What is often less appreciated, but is in fact equally well established, is the generalized atrophy of the pancreas in new onset T1D as well as in those with established disease. Recent studies by the applicants demonstrated that pancreas weight from organ donors with T1D was significantly reduced. However, and more profound, reductions in pancreas weight were also observed in organ donors with only single diabetes-related autoantibodies. These findings underscore that changes in pancreas weight may represent an early event in the pathogenesis of T1D and raise the intriguing idea that pancreatic volume may serve as a long desired "biomarker" for understanding both disease prediction as well as progression. This application seeks funding for a pilot study to determine whether noninvasive estimations of pancreas volume can be used as a prognostic tool in monitoring autoantibody positive, first-degree relatives of patients with T1D. We hypothesize that T1D is associated with progressive pancreatic atrophy that correlates with functional beta cell mass. We propose to examine pancreas volume in four study groups: controls (age and gender matched to autoantibody positive participants), single autoantibody positive participants, multiple autoantibody positive participants, and recent onset T1D patients. Subjects will be recruited through the NIH TrialNet "Pathway to Prevention" studies and the Pediatric and Adult Endocrinology units at the University of Florida Diabetes Center. Specific aims include: 1) Utilize noninvasive radiological imaging to determine pancreas volume in control subjects, subjects at increased risk for T1D (single and multiple autoantibody positive groups), and subjects with new onset T1D. Pancreas volume will be assessed by two noninvasive radiological methods, ultrasound (US) and magnetic resonance imaging (MRI). 2) Correlate pancreas volume with beta cell function and autoimmunity. This aim seeks to determine if biomarkers of beta cell function (fasting glucose, C-peptide and HbA1c) and T1D risk (autoantibodies) correlate with pancreas volume. 3) Correlate pancreas volume with T cell function subsets and HLA. This final aim seeks to determine whether T cell subset functional studies and HLA types can be utilized to explain variance in pancreatic volume amongst controls, at risk subjects, and subjects with new onset T1D. Innovative aspects of this proposal include application of a highly accessible, noninvasive, and relatively low cost imaging method to assess T1D pathogenesis and the combination of faculty in immunology, pathology, clinical endocrinology (pediatric and adult endocrinology), biostatistics, and radiology to form a highly interactive and complementary research team. If pancreatic volume could be monitored over time and one is able to identify a specific loss of functional beta cell mass which coincides with a certain threshold of pancreas volume, pancreas volume could represent a major complement to other biomarkers used for clinical prevention and intervention trials for patients at risk for T1D. As well, monitoring pancreatic volume over time could function as an accurate, noninvasive, and simple surrogate marker for disease progression, allowing timely and guided clinical care.

描述(申请人提供)：几十年来，1型糖尿病(T1D)一直被认为是一种由于产生胰岛素的胰岛β细胞的自身免疫破坏而引起的疾病。新发的T1D患者和既往疾病患者的胰腺普遍萎缩，这一点通常不太被认识到，但实际上同样得到了很好的证实。申请者最近的研究表明，患有T1D的器官捐赠者的胰腺重量显著减轻。然而，更深刻的是，只有一种糖尿病相关自身抗体的器官捐赠者也观察到胰腺重量的减轻。这些发现强调，胰腺重量的变化可能代表了T1D发病机制中的早期事件，并提出了一个有趣的想法，即胰腺体积可能是理解疾病预测和进展的长期理想的“生物标志物”。这项申请寻求资金用于一项先导性研究，以确定对胰腺体积的非侵入性估计是否可以用作监测自身抗体阳性的T1D患者的一级亲属的预后工具。我们假设T1D与进行性胰腺萎缩有关，而进行性胰腺萎缩与功能性β细胞团相关。我们建议在四个研究组中检测胰腺体积：对照组(年龄和性别与自身抗体阳性的参与者匹配)、单一自身抗体阳性的参与者、多个自身抗体阳性的参与者以及新近发病的T1D患者。受试者将通过NIH TrialNet“预防之路”研究以及佛罗里达大学糖尿病中心的儿科和成人内分泌科招募。具体目标包括：1)利用 非侵入性放射成像以确定对照受试者、T1D高危受试者(单一和多个自身抗体阳性组)和新发T1D受试者的胰腺体积。胰腺体积将通过两种非侵入性放射学方法进行评估，即超声(US)和磁共振成像(MRI)。2)胰腺体积与胰岛β细胞功能和自身免疫相关。这一目标旨在确定β细胞功能的生物标记物(空腹血糖、C肽和HbA1c)和T1D风险(自身抗体)是否与胰腺体积相关。3)胰腺体积与T细胞功能亚群及人类白细胞抗原相关。最终目的是确定T细胞亚群功能研究和人类白细胞抗原分型是否可以用来解释对照组、高危受试者和新发T1D受试者之间胰腺体积的差异。这项建议的创新方面包括应用一种高度可访问、非侵入性和相对低成本的成像方法来评估T1D的发病机制，并将免疫学、病理学、临床内分泌学(儿童和成人内分泌学)、生物统计学和放射学的教职员工结合起来，组成一个高度互动和互补的研究团队。如果可以随着时间的推移监测胰腺体积，并且能够识别与某个胰腺体积阈值一致的特定的功能性β细胞质量损失，那么胰腺体积可能是对其他用于T1D风险患者临床预防和干预试验的生物标志物的主要补充。此外，随着时间的推移监测胰腺体积可以作为疾病进展的准确、非侵入性和简单的替代标记物，允许及时和指导临床护理。

项目成果

Pancreatic duct hyperplasia/dysplasia in type 1 diabetes and pancreatic weight in individuals with and without diabetes. Reply to Kobayashi T, Aida K, Fukui T et al [letter] and Saisho Y [letter].

1 型糖尿病中的胰管增生/发育不良以及患有和不患有糖尿病的个体的胰腺重量。

• DOI: 10.1007/s00125-016-3889-4
• 发表时间: 2016
• 期刊: Diabetologia
• 影响因子: 8.2
• 作者: Campbell-Thompson,MarthaL;Schatz,DesmondA;Kaddis,JohnS;Atkinson,MarkA
• 通讯作者: Atkinson,MarkA

New insight on human type 1 diabetes biology: nPOD and nPOD-transplantation.

• DOI: 10.1007/s11892-014-0530-0
• 发表时间: 2014-10
• 期刊: CURRENT DIABETES REPORTS
• 影响因子: 4.2
• 作者: Pugliese, Alberto;Vendrame, Francesco;Reijonen, Helena;Atkinson, Mark A.;Campbell-Thompson, Martha;Burke, George W.
• 通讯作者: Burke, George W.

Abnormalities of the Exocrine Pancreas in Type 1 Diabetes.

• DOI: 10.1007/s11892-015-0653-y
• 发表时间: 2015-10
• 期刊: CURRENT DIABETES REPORTS
• 影响因子: 4.2
• 作者: Campbell-Thompson, Martha;Rodriguez-Calvo, Teresa;Battaglia, Manuela
• 通讯作者: Battaglia, Manuela