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: 10226911
• 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/10226911
• 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; Cells; Child; Chronic; Clinical; Complex; Custom; DNA; Data; Data Analyses; 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; 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; 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; pancreas imaging; prognostic value; 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（T1 D）一直被认为是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。虽然大量的知识进步已经改善， 我们对T1 D自然史的理解，在复杂的生理学系列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细胞群的丧失， 最终导致临床糖尿病。一级亲属（FDR）患有T1 D的人， T1 D的终身风险重要的是，自然史研究已经告知胰岛相关自身抗体的使用 (AAb)作为生物标志物来跟踪疾病的进展，这些生物标志物对于 领域尽管如此，T1 D进展仍存在显著异质性，并且T1 D进展的其他生物标志物 T1 D风险是迫切需要的。该小组的研究表明， T1 D显著降低，包括在糖尿病发作时，并使用以下比率提供基本数据： 胰腺重量与体重或BMI（相对胰腺体积，RPV）的比值，以使受试者的性别和年龄标准化。 然而，在T1 D发病机制方面更深刻的是，在单一AAb+中也观察到胰腺大小的减小。 与自身抗体阴性（AAb-）对照供体相比。随后，一项试点横断面DP 3试验 在NIH-NIDDK TrialNet（TN）受试者中，使用磁共振成像（MRI）完成RPV定量 与对照组和近期发作的T1 D患者（持续时间< 1年）相比，FDR中。令人惊讶的是， 在无AAb（AAb-）的FDR中观察到RPV的降低，而在单次和多次AAb AAb+。我们假设较小的胰腺大小预示着T1 D风险和胰腺功能下降。 随时间变化的大小可预测糖尿病的进展。这一假设将在四个TrialNet中心进行检验 罗斯福主题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， 按AAb状态和PV纵向变化检验列出的FDR受试者。目的2：将PV和形态学相关联 与β细胞功能和质量的替代标志物。目的3：将PV和形态学与替代物相关联 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。的 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T1 D病理生理学。非对比胰腺MRI是安全的，容易在儿童中进行， 可以添加到生物标志物告知T1 D风险预测，并可能，进展。内分泌-外分泌 这些相互作用是新颖的，并有望提供对糖尿病发病机制的新理解。早些时候 预计识别T1 D进展风险最高的受试者将显著影响预防 在功能性β细胞团的损失不可逆转之前，这些策略及其成功应用。