Understanding pancreatic endocrine and exocrine loss in pre-type 1 diabetes

了解 1 型糖尿病前期的胰腺内分泌和外分泌丧失

• 批准号: 10461979
• 负责人: MARTHA CAMPBELL-THOMPSON
• 金额: $ 64.11万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10461979
• 关键词: Abdomen; Acinar Cell; Acute; Affect; Age; Area Under Curve; Arginine; Autoantibodies; Autoimmunity; Beta Cell; Biological Markers; Blinded; Body Size; Body Weight; Body mass index; C-Peptide; Cell physiology; Child; Chronic; Clinical; Complex; Custom; DNA; Data; Diabetes Mellitus; Disease; Disease Progression; Early identification; Endocrine; Enrollment; Event; Fasting; First Degree Relative; Florida; Functional disorder; Funding; Genetic Determinism; Genotype; Glucose; Glycosylated hemoglobin A; Heterogeneity; Hyperglycemia; Image; Immunologics; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Islets of Langerhans; Learning; Lipase; Longitudinal Studies; MRI Scans; Magnetic Resonance Imaging; Measures; Metabolic; Morphology; Multicenter Studies; National Institute of Diabetes and Digestive and Kidney Diseases; Natural History; OGTT; Organ Donor; Organ Size; Organ Weight; Pancreas; Patients; Persons; Phenotype; Physiological; Prevention strategy; Radiology Specialty; Research Institute; Risk; Sampling; Secretory Cell; Series; Serum; Structure of beta Cell of islet; Surrogate Markers; Testing; Time; Trypsinogen; United States National Institutes of Health; Universities; Weight; autoimmune pathogenesis; diabetes pathogenesis; diabetes risk; disorder risk; functional loss; genetic analysis; high risk; improved; insulin dependent diabetes mellitus onset; islet; islet cell antibody; lifetime risk; novel; prognostic value; progression risk; radiologist; response; sex

For decades, type 1 diabetes (T1D) has been considered a disorder resulting from chronic autoimmune destruction of insulin-producing pancreatic β-cells. While a broad number of intellectual advances have improved our understanding of the natural history of T1D, significant gaps remain in the complex series of physiological events, both immunologic and metabolic, that initiate β-cell autoimmunity, spur the loss of functional β-cell mass, and culminate in clinical diabetes. People with a first-degree relative (FDR) with T1D have ~15-fold increased lifetime risk of T1D. Importantly, natural history studies have informed the use of islet-associated autoantibodies (AAb) as biomarkers to track progression to overt disease, and these biomarkers were transformative for the field. Nevertheless, there remains significant heterogeneity in T1D progression, and additional biomarkers of T1D risk are urgently needed. Studies by this group demonstrated that pancreas weights from organ donors with T1D were significantly reduced, including at diabetes onset, and provided essential data using the ratio of pancreas weight to body weight or BMI (relative pancreas volume, RPV) to normalize for subjects’ sex and age. Yet more profound in terms of T1D pathogenesis, reductions in pancreas size were also observed in single AAb+ donors compared to autoantibody-negative (AAb-) control donors. Subsequently, a pilot cross-sectional DP3 trial in NIH-NIDDK TrialNet (TN) subjects was completed using magnetic resonance imaging (MRI) to quantify RPV in FDR in comparison to controls and patients with recent-onset T1D (< 1-year duration). Strikingly, a reduction in RPV was observed in FDR without AAb (AAb-) with further reductions in RPV for FDR with single and multiple AAb+. We hypothesize that a smaller pancreas size is predictive of T1D risk and a decline in pancreas size over time is predictive for diabetes progression. This hypothesis will be tested at four TrialNet centers in FDR subjects. To test our hypothesis, we will: Aim 1: Quantify pancreas volume (PV) and morphology in FDR subjects by AAb status and test for longitudinal changes in PV. Aim 2: Correlate PV and morphology with surrogate markers of β-cell function and mass. Aim 3: Correlate PV and morphology with surrogate markers of acinar function. Aim 4: Perform SNP analyses for genetic determinants of pancreas size. The successful completion of these studies will serve to expand the prognostic utility of pancreas MRI in understanding T1D pathophysiology. Non-contrast pancreas MRI is safe and readily performed in children and could add to biomarkers informing T1D risk predication, and potentially, progression. Endocrine-exocrine interactions are novel and are expected to provide a new understanding of diabetes pathogenesis. Earlier identification of subjects at highest risk for T1D progression is expected to significantly impact prevention strategies and their successful application before the loss of functional β-cell mass is irreversible.

几十年来，慢性自身免疫性产生的1型糖尿病（T1D）被认为是一种疾病 胰岛素产生的胰腺β细胞的破坏。虽然大量的智力进步已经提高 我们对T1D自然历史的理解，在复杂的一系列生理系列中仍然存在明显的差距 启动β细胞自身免疫性的免疫学和代谢的事件刺激了功能性β细胞质量的丧失， 并在临床糖尿病中达到高潮。具有T1D一级亲戚（FDR）的人增加了约15倍 终身风险T1D。重要的是，自然史研究已告知使用与胰岛相关的自身抗体 （AAB）作为追踪到明显疾病进展的生物标志物，这些生物标志物是变化的 场地。然而，T1D进展中仍然存在明显的异质性，以及其他的生物标志物 迫切需要T1D风险。该小组的研究表明，来自器官捐献者的胰腺具有 T1D显着降低，包括在糖尿病发作时，并使用比率提供了必要的数据 胰腺体重或体重的重量或BMI（相对胰腺体积，RPV）以适应受试者的性别和年龄。 在T1D发病机理方面，在单个AAB+中也观察到了胰腺大小的减少。 与自身抗体阴性（AAB-）对照供体相比。随后，试点横截面DP3试验 在NIH-NIDDK试验网（TN）中，使用磁共振成像（MRI）来量化RPV 与对照组和最近发作T1D的患者相比，FDR（<1年）。令人惊讶的是，减少了 在没有AAB（AAB-）的FDR中观察到在RPV中，对于单个和多个的RPV，RPV进一步降低 AAB+。我们假设较小的胰腺大小可以预测T1D风险和胰腺下降 随着时间的流逝，大小可以预测糖尿病的进展。该假设将在四个试验网中心进行检验 在FDR主题中。为了检验我们的假设，我们将：目标1：量化胰腺体积（PV）和形态 FDR受试者通过AAB状态并测试PV的纵向变化。目标2：关联光伏和形态 具有β细胞功能和质量的替代标记。目标3：将光伏和形态与替代物相关联 腺泡功能的标记。 AIM 4：对胰腺大小的遗传确定剂进行SNP分析。这 这些研究的成功完成将有助于扩大胰腺MRI的预后效用 了解T1D病理生理学。非对比度胰腺MRI是安全的，在儿童中很容易执行 可能会增加为T1D风险鉴定的生物标志物，并可能进展。内分泌 - 分泌 相互作用是新颖的，有望提供对糖尿病发病机理的新理解。较早 预计对T1D进展风险最高风险的受试者的识别有望显着影响预防 在功能性β细胞质量损失之前的策略及其成功应用是不可逆的。

项目成果

Type 1 Diabetes: A Disorder of the Exocrine and Endocrine Pancreas.

1 型糖尿病：胰腺外分泌和内分泌疾病。

• DOI: 10.33696/immunology.5.177
• 发表时间: 2023
• 期刊: Journal of cellular immunology
• 作者: Bruggeman,BrittanyS;Schatz,DesmondA
• 通讯作者: Schatz,DesmondA

Standard Operating Procedures for Biospecimen Collection, Processing, and Storage: From the Type 1 Diabetes in Acute Pancreatitis Consortium.

• DOI: 10.1097/mpa.0000000000002077
• 发表时间: 2022-07-01
• 期刊: PANCREAS
• 影响因子: 2.9
• 作者: Wasserfall, Clive;Dyer, Anne-Marie;Speake, Cate;Andersen, Dana K.;Baab, Kendall Thomas;Bellin, Melena D.;Broach, James R.;Campbell-Thompson, Martha;Chinchilli, Vernon M.;Lee, Peter J.;Park, Walter G.;Pratley, Richard E.;Saloman, Jami L.;Sims, Emily K.;Tang, Gong;Yadav, Dhiraj;Yazici, Cemal;Conwell, Darwin L.
• 通讯作者: Conwell, Darwin L.

Substance Use Affects Type 1 Diabetes Pancreas Pathology: Implications for Future Studies.

• DOI: 10.3389/fendo.2021.778912
• 发表时间: 2021
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2
• 作者: Bruggeman BS;Campbell-Thompson M;Filipp SL;Gurka MJ;Atkinson MA;Schatz DA;Jacobsen LM
• 通讯作者: Jacobsen LM