DFU Clinical Research Unit

摘要 正在进行的新冠肺炎大流行对2型糖尿病(T2D)患者的影响不成比例，他们尤其 容易受到SARS-CoV-2引起的不良后果和并发症的影响。T2D患者有几个 增加他们易感性的共病：肥胖、慢性炎症和血管并发症，即， 糖尿病肾病(DKD)、糖尿病神经病变(DN)和心血管疾病(CVD)。T2D患者是 也容易患上细胞因子风暴综合症(Css)，这是一种由新冠肺炎引发的急性炎症状态。 Css释放一系列炎性细胞因子，导致危险的高血糖飙升和 维持细胞因子释放的恶性循环。然而，对于最初的css如何 发生在新冠肺炎病的发作叠加在慢性T2D炎症上造成不利 新冠肺炎T2D患者的预后以及最能预测临床病程的细胞因子是什么。 鉴于T2D的流行，高新冠肺炎感染率，以及缺乏治疗，存在着迫切的未得到满足的需求 识别风险因素和炎性生物标志物概况，预测最关键的新冠肺炎T2D 我们还迫切需要循证的指导方针来管理 第一波幸存者的并发症。我们的目标是建立满足以下要求的知识库 通过开发风险评估工具来为当前新冠肺炎T2D患者的管理提供信息来满足这一临床需求 并为未来的浪潮做好准备。我们的总体假设是，继发于SARS的急性炎症激增- CoV-2诱导的CS，增加急性不良结局的风险，加速慢性糖尿病的进展 并发症。我们将在一项正在进行的队列中测试这一假设，该队列中有大约500名重症新冠肺炎患者在 密歇根医学，其中208人患有T2D。称为密歇根医学新冠肺炎队列(M2C2，PI： 在入院时和整个住院过程中收集了临床数据和生物样本。我们的一个- 一年的短期目标是：(I)确定与M2C2住院结果相关的炎症信号， (Ii)M2C2深度表型参与者因慢性血管并发症(DKD， (Iii)评估M2C2患者3-6个月的心理社会结局 参与者。我们的具体目标是：1)确定与急性并发症有关的炎性生物标志物特征 在T2D M2C2患者中；b)通过T2D中的炎症生物标记物信号来定义出院后的临床过程 M2C2患者。我们提出的研究将通过生成基于知识的 管理当前和未来的急需且立即适用的临床指南所需的 新冠肺炎T2D患者。它还将建立一个信息丰富的生物标记物小组，与急性和 慢性T2D新冠肺炎的临床表型及新冠肺炎术后T2D患者的门诊管理 感染。迫切需要来自这项提案的数据，以根据我们的T2D人群的特殊情况来对待他们 脆弱性。

ABSTRACT The ongoing COVID-19 pandemic disproportionately affects type 2 diabetes (T2D) patients, who are especially susceptible to SARS-CoV-2-induced adverse outcomes and complications. T2D patients have several comorbidities that increases their vulnerability: obesity, chronic inflammation, and vascular complications, i.e., diabetic kidney disease (DKD), diabetic neuropathy (DN), and cardiovascular disease (CVD). T2D patients are also predisposed to the cytokine storm syndrome (CSS), an acute inflammation state triggered by COVID-19. CSS releases a cascade of inflammatory cytokines that causes dangerous hyperglycemic surges and perpetuates a vicious cycle of cytokine release. Yet, there is a critical knowledge gap on how the initial CSS that occurs with the onset of COVID-19 disease superimposes on chronic T2D inflammation to contribute to adverse outcomes and what are the cytokines that most strongly predict the clinical course in COVID-19 T2D patients. Given the T2D prevalence, high COVID-19 infection rate, and lack of therapies, there is an urgent unmet need to identify risk-factors and inflammatory biomarker profiles that predict the most critical incoming COVID-19 T2D cases to prepare us for the next pandemic wave.We also urgently need evidence-based guidelines for managing complications in survivors from the first wave. Our objective is to establish the knowledge base needed to meet this clinical need by developing risk-assessment tools to inform management of current COVID-19 T2D patients and prepare for future waves. Our overall hypothesis is that acute inflammatory surges, secondary to SARS- CoV-2-induced CSS, raise the risk of acute adverse outcomes and accelerate progression of chronic diabetic complications. We will test this hypothesis in an ongoing cohort of ~500 severe COVID-19 patients admitted at Michigan Medicine, of whom 208 have T2D. Known as the Michigan Medicine COVID-19 Cohort (M2C2, PI: Hayek), clinical data and biosamples were collected on admission and throughout the hospital course. Our one- year short term goals are to: (i) identify inflammatory signatures that correlate to inpatient outcomes in the M2C2, (ii) deeply phenotype M2C2 participants 3-6 months post-hospitalization for chronic vascular complications (DKD, DN, CVD), and longer term inflammatory signatures, (iii) assess the 3-6 month psychosocial outcomes of M2C2 participants. Our Specific Aims are:1) Identify an inflammatory biomarker signature linked to acute complications in T2D M2C2 patients; b) Define the post-discharge clinical course by inflammatory biomarker signatures in T2D M2C2 patients. Our proposed research will have immediate significant impact by generating the knowledge based required for much needed, and immediately applicable clinical guidelines for managing current and future COVID-19 T2D patients. It will also establish an informative biomarker panels that correlate with acute and chronic T2D COVID-19 clinical phenotypes and inform outpatient management of T2D patients post-COVID-19 infection. Data from this proposal are urgently needed to treat our T2D population in light of their particular vulnerability.