Islet Cell and ST2 Axis Dysregulation in Post-Transplant Diabetes Mellitus

移植后糖尿病中的胰岛细胞和 ST2 轴失调

• 批准号: 10394803
• 负责人: James Matthew Luther
• 金额: $ 39.5万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394803
• 关键词: Adipose tissue; Affect; Allogenic; Alpha Cell; Animal Model; Beta Cell; C-Peptide; Cardiovascular Diseases; Caring; Cell physiology; Cellular Stress; Clinical; Closure by clamp; Collaborations; Data; Development; Diabetes Mellitus; Disease; Endocrine; Failure; Fasting; Financial compensation; Functional disorder; Funding; Glucagon; Glucose; Hematological Disease; Human; Hyperglycemia; Iatrogenesis; Immune; Immunology; Immunosuppression; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Infrastructure; Infusion procedures; Insulin; Insulin Resistance; Intervention; Islet Cell; Measures; Mediating; Mentored Patient-Oriented Research Career Development Award; Metabolic; Metabolism; Methods; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Outcome; Patients; Pharmacology; Physicians; Physiology; Plasma; Population; Prediabetes syndrome; Preparation; Prevention; Procedures; Production; Publishing; Regulation; Regulatory T-Lymphocyte; Research Methodology; Rest; Risk; Role; Scientist; Secretory Cell; Serum; Signal Pathway; Signal Transduction; Stress; Structure of beta Cell of islet; T-Cell Proliferation; T-Lymphocyte; Testing; Th1 Cells; Therapeutic Clinical Trial; Therapeutic Intervention; Tissues; Training; Translating; Transplant Recipients; Transplantation; United States; Visceral; Work; base; blood glucose regulation; cohort; cytokine; euglycemia; exhaustion; glucagon-like peptide 1; glucose metabolism; hematopoietic cell transplantation; high risk; hormonal signals; hyperglucagonemia; immunoregulation; improved; insulin secretion; islet; mortality risk; new therapeutic target; novel; post-transplant; prevent; programs; prospective; receptor; response; screening; side effect; transplant survivor

Project Summary/Abstract Allogeneic hematopoietic cell transplant (HCT) recipients represent a defined population in which approximately 50% of patients will develop new-onset post-transplant diabetes mellitus (PTDM) and in whom the development of diabetes increases the risk of death 3-fold. The propagation of pre-diabetes to frank hyperglycemia occurs when pancreatic β-cells can no longer meet the insulin demand needed for glucose homeostasis. Loss of IL-33/serum STimulation-2 (ST2) signaling and depletion of ST2+ regulatory T cells (Tregs) in visceral adipose tissue exacerbates β-cell exhaustion by increasing both Th1-mediated inflammation and insulin resistance. In a cohort of HCT recipients, we demonstrated that PTDM development was characterized by: 1) elevated fasting C-peptide levels prior to transplant; 2) impaired islet response to hyperglycemia and GLP-1 after HCT with decreased β-cell insulin secretion and blunted α-cell suppression, and 3) increased post-transplant serum levels of soluble ST2 (sST2), a decoy receptor which sequesters IL-33. We hypothesize that in PTDM, initial β-cell compensation progresses to exhaustion during the course of HCT, which coincides with increased tissue demand for insulin due to changes in IL-33 signaling, inflammation, and/or hyperglucagonemia. The following aims will test islet cell and ST2 regulation during PTDM. Aim 1. To determine if changes in islet cell physiology are detectable before or after matched related donor (MRD) HCT in patients developing new-onset PTDM. Utilizing a hyperglycemic clamp, we will directly measure insulin secretory capacity before and 90 days after MRD HCT to determine the timing and role of β-cell dysfunction in the development of new-onset PTDM (Subaim 1A). To assess α-cell dysregulation, glucose-induced glucagon suppression will be measured during a hyperglycemic clamp and during 2 oral glucose tolerance tests either with or without GLP-1 infusion (Subaim 1B). In Aim 2 we will define the role of the IL-33/ST2 axis in immune/islet cell dysregulation during PTDM by measuring adipose and plasma levels of IL-33 and sST2 and quantifying ST2 expression on circulating Tregs and Th1 cells. IL-33 effects will be assessed in vitro to determine whether T cell proliferation or inflammatory cytokine production differs among patients with or without PTDM or whether IL-33 directly decreases human islet insulin secretion and viability. PTDM is highly prevalent in HCT survivors, however the cause, pathophysiology, and optimal management are unclear. By studying the physiology and immunology of PTDM, this proposal will uncover new connections between metabolic complications and immune regulation while simultaneously identifying novel targets for intervention. Longer term, data from these mechanistic studies will be translated into therapeutic clinical trials to test pharmacologic interventions for the prevention and treatment of PTDM.

项目总结/摘要 异基因造血细胞移植（HCT）接受者代表一个定义的群体，其中 大约50%的患者将发展为新发移植后糖尿病（PTDM）， 糖尿病的发展使死亡风险增加3倍。糖尿病前期对弗兰克的传播 当胰腺β细胞不能再满足葡萄糖所需的胰岛素需求时，发生高血糖症 体内平衡IL-33/血清STimulation-2（ST 2）信号传导的丧失和ST 2+调节性T细胞的耗竭 内脏脂肪组织中的THP通过增加Th 1介导的炎症和THP介导的炎症， 和胰岛素抵抗。在一组HCT接受者中，我们证明PTDM的发展是 其特征在于：1）移植前空腹C肽水平升高; 2）胰岛对 HCT后高血糖和GLP-1，β细胞胰岛素分泌减少，α细胞抑制减弱， 和3）增加的移植后可溶性ST 2（sST 2）血清水平，可溶性ST 2是一种螯合IL-33的诱饵受体。 我们假设在PTDM中，初始β细胞代偿在HCT过程中进展到衰竭， 这与由于IL-33信号传导，炎症， 和/或高胰高血糖素血症。以下目的将测试PTDM期间的胰岛细胞和ST 2调节。目标1。到 确定在匹配的相关供体（MRD）HCT之前或之后是否可检测到胰岛细胞生理学的变化 新发PTDM的患者。利用高血糖钳夹，我们将直接测量胰岛素 MRD HCT前和MRD HCT后90天的分泌能力，以确定β细胞功能障碍的时间和作用， 新发PTDM（Subaim 1A）的发生。为了评估α细胞失调，葡萄糖诱导的胰高血糖素 将在高血糖钳夹期间和2次口服葡萄糖耐量试验期间测量抑制， 联合或不联合GLP-1输注（Subaim 1B）。在目标2中，我们将定义IL-33/ST 2轴在以下中的作用： 通过测量脂肪和血浆IL-33和sST 2水平， 定量ST 2在循环T细胞和Th 1细胞上的表达。将在体外评估IL-33的作用， 确定T细胞增殖或炎性细胞因子的产生是否在患有或 没有PTDM或IL-33是否直接降低人胰岛胰岛素分泌和活力。PTDM高度 在HCT幸存者中普遍存在，然而病因、病理生理学和最佳管理尚不清楚。通过 通过研究PTDM的生理学和免疫学，这项提案将揭示PTDM与糖尿病之间的新联系。 代谢并发症和免疫调节，同时确定新的干预目标。 从长远来看，这些机制研究的数据将被转化为治疗性临床试验， 预防和治疗PTDM的药物干预。

项目成果

New-onset post-transplant diabetes mellitus after haploidentical hematopoietic cell transplant with post-transplant cyclophosphamide.

• DOI: 10.1002/jha2.70
• 发表时间: 2020-11
• 期刊: EJHaem
• 作者: Mangan BL;Patel D;Chen H;Gatwood KS;Byrne MT;Sengsayadeth S;Goodman S;Dholaria B;Kassim AA;Jagasia M;Chinratanalab W;Culos KA;Engelhardt BG
• 通讯作者: Engelhardt BG