PROJECT ABSTRACT American Indians and Alaska Natives (Native Americans) have suffered disproportionately during the COVID- 19 pandemic with higher rates of infection, hospitalization and mortality from COVID-19 compared to Non- Hispanic Whites. Native Americans also suffer disproportionately from diabetes with nearly 3 times the prevalence and 2.3 times the diabetes-related death rate of Non-Hispanic Whites. Growing evidence suggests that COVID-19 infection increases the risk of developing diabetes. Large cohort studies have reported a ~50% increased risk of developing diabetes following COVID-19 infection compared to matched or historic controls without known COVID-19 infection. While these studies offer important insight into the magnitude of risk of new onset diabetes following COVID-19 infection, existing studies were not inclusive of some of the highest risk populations because they studied US veterans, commercially insured patients enrolled in large US health insurance plans, and communities outside the US. Little is known how this risk varies across diverse populations within the US. Understanding the epidemiologic links between COVID-19 infection and diabetes in Native Americans is critical to address health disparities in a population that faces a disproportionate burden of both COVID-19 and diabetes. To measure the association between COVID-19 infection and diabetes risk in Native Americans we will conduct a series of analyses using two distinct data sources: 1) a large, nationally representative clinical database available through Indian Health Service and 2) the Alaska Diabetes Registry with linked electronic health record data from the Alaska Tribal Health System. Aim 1 will measure the association between COVID-19 infection and risk of incident diabetes in Native Americans via a matched, retrospective cohort study using national data from the Indian Health Service. Aim 2 will compare the clinical presentation of incident diabetes cases at diabetes onset and compare clinical progression over the 6 months following diagnosis by antecedent COVID-19 infection status in a retrospective cohort of individuals using nationwide data from Indian Health Service as well as the comprehensive Alaska Diabetes Registry maintained by the Alaska Native Tribal Health Consortium. The proposed studies will provide a comprehensive epidemiologic assessment of the COVID-19-diabetes association in Native Americans, including a nationwide description of COVID-19 infection-related diabetes risk and a deep dive into the clinical presentation of incident diabetes cases. This knowledge will support the continued efforts of Tribal, Federal, State, and community entities to mitigate the impacts of the COVID-19 pandemic in Native Americans and further efforts to address the COVID-19 and diabetes health disparities faced by this population.