DFU Clinical Research Unit

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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.