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

基本信息

批准号：
9914371
负责人：
BRIAN G ENGELHARDT
金额：
$ 39.5万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-15 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9914371
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 Preventive Intervention 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

项目摘要

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.

项目概要/摘要同种异体造血细胞移植 (HCT) 接受者代表了一个确定的人群，其中大约 50% 的患者会出现新发的移植后糖尿病 (PTDM)，其中糖尿病的发展使死亡风险增加 3 倍糖尿病前期的传播。当胰腺 β 细胞无法满足葡萄糖所需的胰岛素需求时，就会发生高血糖 IL-33/血清 STimulation-2 (ST2) 信号传导丧失和 ST2+ 调节性 T 细胞耗竭。内脏脂肪组织中的 Tregs 通过增加 Th1 介导的炎症而恶化 β 细胞耗竭在一组 HCT 接受者中，我们证明 PTDM 的发展是其特征是：1) 移植前空腹 C 肽水平升高；2) 胰岛反应受损； HCT 后高血糖和 GLP-1 随着 β 细胞胰岛素分泌和 α 细胞抑制减弱而降低， 3) 移植后血清可溶性 ST2 (sST2) 水平升高，这是一种隔离 IL-33 的诱饵受体。我们发现，在 PTDM 中，最初的 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、以下目标将测试 PTDM 期间的胰岛细胞和 ST2 调节。确定在匹配的相关供体 (MRD) HCT 之前或之后是否可以检测到胰岛细胞生理学的变化在开发新发 PTDM 患者时，我们将使用高血糖钳直接测量胰岛素。 MRD HCT 之前和之后 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) 的发展评估 α 细胞失调、葡萄糖诱导的胰高血糖素。将在高血糖钳夹和 2 次口服葡萄糖耐量测试期间测量抑制有或没有 GLP-1 输注 (Subaim 1B) 在目标 2 中，我们将定义 IL-33/ST2 轴在其中的作用。通过测量脂肪和血浆中 IL-33 和 sST2 的水平来检测 PTDM 期间的免疫/胰岛细胞失调，将在体外评估 ST2 表达对循环 Tregs 和 Th1 细胞的影响。确定 T 细胞增殖或炎性细胞因子的产生在患有以下疾病的患者之间是否存在差异：没有 PTDM 或 IL-33 是否直接降低人胰岛胰岛素分泌和活力是高度的。在 HCT 幸存者中普遍存在，但其病因、病理生理学和最佳治疗尚不清楚。通过研究 PTDM 的生理学和免疫学，该提案将揭示两者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转化为治疗性临床试验来测试预防和治疗 PTDM 的药物干预。