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)一直被认为是一种慢性自身免疫引起的疾病 破坏产生胰岛素的胰腺β细胞。在大量智力进步的同时， 我们对T1D的自然历史的了解，在复杂的生理系列中仍然存在重大差距 启动β细胞自身免疫的免疫和代谢事件，刺激功能性β细胞团的丧失， 并最终发展为临床糖尿病。有一级亲属(FDR)患有T1D的人增加了约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)作为追踪疾病进展的生物标记物，这些生物标记物对 菲尔德。然而，在T1D进展中仍然存在显著的异质性，并且更多的生物标志物 T1D风险是迫切需要的。该小组的研究表明，来自器官捐赠者的胰腺重量 T1D显著降低，包括在糖尿病发作时，并提供了使用 胰腺重量/体重或BMI(相对胰腺体积，RPV)，以使受试者的性别和年龄正常化。 然而，在T1D发病机制方面，单一AAB+组也观察到胰腺大小缩小 供者与自身抗体阴性(AAB-)对照供者。随后，一项试点横断面DP3试验 在NIH-NIDDK TrialNet(TN)受试者中，使用磁共振成像(MRI)来量化RPV 在FDR中与对照组和新发T1D患者(病程1年)进行比较。令人惊讶的是，削减 在没有AAB的FDR中观察到RPV(AAB-)，在有单个和多个FDR的FDR中RPV进一步降低 AAB+。我们假设，较小的胰腺大小预示着T1D风险和胰腺的下降 随着时间的推移，体型大小可以预测糖尿病的进展。这一假设将在四个TrialNet中心进行测试 在富兰克林·罗斯福的研究对象中。为了验证我们的假设，我们将：目标1：量化胰腺体积(PV)和形态 FDR受试者按AAB状态和PV纵向变化进行检验。目标2：将PV和形态联系起来 带有β的替代标记--细胞功能和质量。目标3：将PV和形态与代理相关 腺泡功能的标志物。目的4：对胰腺大小的遗传决定因素进行SNP分析。这个 这些研究的成功完成将有助于扩大胰腺MRI在 了解T1D病理生理学。非对比剂胰腺MRI在儿童和儿童中是安全和容易执行的 可能会增加生物标记物，告知T1D风险预测，并可能导致进展。内分泌-外分泌 相互作用是新的，有望为糖尿病的发病机制提供新的理解。早些时候 确定T1D进展的最高风险受试者预计将对预防产生重大影响 策略及其成功应用之前，功能性β细胞团的丧失是不可逆转的。

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