Beta cell dysfunction as an acute and a post acute sequelae of COVID19

PROJECT SUMMARY Beta cell dysfunction and death are significant pathologies underlying the development of Type 2 diabetes. Our long-term goal is to identify molecular mechanisms restrict beta cell function and survival. During the SARS- CoV2-driven COVID19 pandemic, there are reports of adult COVID19+ patients presenting with diabetic ketoacidosis in emergency rooms. 25% of new-onset type 1 diabetes (T1D) patients presenting with diabetic ketoacidosis in the T1D Exchange registry are COVID19+. Our group has reported a significant increase in the number of new-onset type 2 diabetes patients presenting in diabetic ketoacidosis. This suggests that the pathogenesis of COVID19 may have acute and specific effects on pancreatic beta cell function. One of the barriers to understanding how SARS-CoV2 infection may affect beta cell function and survival in patients is the limited number of physiologically relevant animal models to study. We have capitalized on unique access the pancreas of SCV2-innoculated animals to model and understand how the infection may affect beta cell function and survival. Our preliminary data that shows: (1) SARS-CoV2 directly infects beta cells, (2) SARS-CoV2 infection causes dramatic morphological changes in islet, (3) SARS-CoV2 infection shifts beta cell metabolism to glycolytic profile, and (4) SARS-CoV2 infection results in decreased in beta cell function and survival. The objective of this proposal is to define the mechanisms that drive the post-acute consequences of COVID19-mediated beta cell injury in vivo. There is controversy in the literature regarding if SARS-CoV2 directly infects beta cells and affects beta cell function and survival or if the disruption of glucose homeostasis in patients is secondary. We hypothesize that SARS-CoV2 infection reprograms cellular metabolism and induces necroptosis, thus leaving hosts susceptible to beta cell dysfunction acutely and as a post-acute sequelae of COVID19. These highly innovative experiments capitalize on a unique and clinically relevant model system and employs cutting edge techniques to assess how beta cell survival and metabolism are affected by SARS-CoV2 infection. These experiments will provide critical mechanistic insight to the underpinnings of the emerging clinical phenotype of acute hyperglycemia, diabetic ketoacidosis, and potentially lifelong diabetes that may afflict a significant number of patients who have recovered from COVID19.