Inflammation, metabolic disorders and incident type 2 diabetes

Type 2 diabetes (T2D) is a major health threat of our era and has become a health priority worldwide. Emerging evidence suggests that T2D is a main post-COVID-19 metabolic sequela, further exacerbating its epidemic. Inflammation and metabolic disorders are two hallmarks of T2D, and both have been shown to heighten the risk of incident diabetes. However, there are significant heterogeneities in the risks of incident diabetes with exposure to each of them. Notably, accumulated evidence suggests a closely intertwined biological process between them. It is unknown whether elevated inflammation could interact with metabolic disorders acting on diabetogenesis and explain the diabetic risk heterogeneity in metabolic disorders. Furthermore, different levels of inflammation have distinct sources. Low-grade systemic inflammation commonly results from metabolic disorders, whereas highgrade inflammation is indicative of an acute phase response, mainly initiated from acute infectious processes and acute stress. Currently, mainstream knowledge excludes highgrade inflammation for addressing the risk of cardiometabolic diseases and has seldom linked it to the pathophysiology of diabetes. Nonetheless, the alarmingly high incidence of T2D postacute SARS-CoV-2 infections has awakened a need to link infectious diseases to the development of T2D. This thesis aims to provide data-based epidemiological insights into the combined effect of different sources and levels of inflammation with a wide range of metabolic disorders on the development of diabetes and specifically considers the potential interactive effects between them. This thesis is composed of nine chapters: an overview of the thesis (Chapter 1); a comprehensive literature review (Chapter 2); six results chapters (Chapters 3–8); and a final chapter with a general discussion of the main findings and future directions (Chapter 9). The first chapter of the thesis includes an introduction and overview of the entire thesis. This is t