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，1 型糖尿病 (T1D) 一直被认为是一种由慢性自身免疫性疾病引起的疾病 破坏产生胰岛素的胰腺β细胞。虽然大量的智力进步已经得到改善 我们对 T1D 自然史的理解，在一系列复杂的生理学过程中仍然存在重大差距 引发 β 细胞自身免疫的免疫和代谢事件，刺激功能性 β 细胞质量的损失， 并最终导致临床糖尿病。一级亲属 (FDR) 患有 1 型糖尿病的人的患病率增加了约 15 倍 T1D 的终生风险。重要的是，自然历史研究已经为胰岛相关自身抗体的使用提供了信息 （AAb）作为跟踪明显疾病进展的生物标志物，这些生物标志物对于 场地。尽管如此，T1D 进展仍然存在显着的异质性，并且其他生物标志物 T1D 风险亟待解决。该小组的研究表明，器官捐献者的胰腺重量 T1D 显着减少，包括糖尿病发病时，并使用以下比率提供了重要数据： 胰腺重量除以体重或 BMI（相对胰腺体积，RPV），以标准化受试者的性别和年龄。 然而，就 T1D 发病机制而言，更深远的是，在单一 AAb+ 中也观察到胰腺大小的减小 供者与自身抗体阴性（AAb-）对照供者进行比较。随后，进行了一项横断面 DP3 试点试验 在 NIH-NIDDK TrialNet (TN) 受试者中使用磁共振成像 (MRI) 量化 RPV 完成 与对照组和新发 T1D 患者（病程 < 1 年）相比，FDR 的变化。引人注目的是，减少 在没有 AAb (AAb-) 的 FDR 中观察到 RPV 的增加，而使用单一和多重抗体的 FDR 的 RPV 进一步降低 AAb+。我们假设较小的胰腺尺寸预示着 T1D 风险和胰腺功能下降 随着时间的推移，大小可以预测糖尿病的进展。该假设将在四个 TrialNet 中心进行测试 在罗斯福主题中。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 受试者的 AAb 状态和 PV 纵向变化测试。目标 2：关联 PV 和形态 具有 β 细胞功能和质量的替代标记。目标 3：将 PV 和形态与替代物相关联 腺泡功能的标志物。目标 4：对胰腺大小的遗传决定因素进行 SNP 分析。这 这些研究的成功完成将有助于扩大胰腺 MRI 的预后用途 了解 T1D 病理生理学。非造影胰腺 MRI 安全且易于在儿童和儿童中进行 可以添加到生物标志物中，以告知 T1D 风险预测和潜在的进展情况。内分泌-外分泌 相互作用是新颖的，有望提供对糖尿病发病机制的新认识。早些时候 识别 T1D 进展风险最高的受试者预计将显着影响预防 在功能性 β 细胞质量丧失不可逆转之前，采取策略并成功应用。

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