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引起的疾病

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