Abstract
Type 2 diabetes mellitus (T2D) is a growing health problem, but little is known about its early disease stages, its effects on biological processes or the transition to clinical T2D. To understand the earliest stages of T2D better, we obtained samples from 106 healthy individuals and individuals with prediabetes over approximately four years and performed deep profiling of transcriptomes, metabolomes, cytokines, and proteomes, as well as changes in the microbiome. This rich longitudinal data set revealed many insights: first, healthy profiles are distinct among individuals while displaying diverse patterns of intra- and/or inter-personal variability. Second, extensive host and microbial changes occur during respiratory viral infections and immunization, and immunization triggers potentially protective responses that are distinct from responses to respiratory viral infections. Moreover, during respiratory viral infections, insulin-resistant participants respond differently than insulin-sensitive participants. Third, global co-association analyses among the thousands of profiled molecules reveal specific host–microbe interactions that differ between insulin-resistant and insulin-sensitive individuals. Last, we identified early personal molecular signatures in one individual that preceded the onset of T2D, including the inflammation markers interleukin-1 receptor agonist (IL-1RA) and high-sensitivity C-reactive protein (CRP) paired with xenobiotic-induced immune signalling. Our study reveals insights into pathways and responses that differ between glucose-dysregulated and healthy individuals during health and disease and provides an open-access data resource to enable further research into healthy, prediabetic and T2D states.
Highlights
Type 2 diabetes mellitus (T2D) is a growing health problem, but little is known about its early disease stages, its effects on biological processes or the transition to clinical T2D
Prediabetes and T2D are often associated with insulin resistance, where individuals produce insulin but are hyperglycaemic because their cells do not respond to insulin
We still do not have a systematic understanding of how healthy individuals and those with prediabetes differ at baseline or change over time or in response to stresses such as viral infections, and whether such responses depend on insulinresistance status
Summary
For seven years; early findings for this individual have been published previously[8]. We assessed the influence of time on healthy baseline variation within individuals, with a specific emphasis on markers that increased or decreased monotonically over time We identified both host molecules and gut microorganisms that significantly correlated, positively or negatively, with time (examples in Extended Data Fig. 3a, b, Supplementary Table 7). Among immunization-induced changes, the family Erysipelotrichaceae, which is associated with obesity[33] and high fat intake[34], was decreased, underscoring our observation that immunization inversely correlates with T1D and T2D signalling, which have overlapping biology with those metabolic disorders These data reveal extensive differences in molecular pathway changes upon RVI and immunization, and identify dysregulated pathways that include immune responses, metabolic and neurological pathways, as well as gut and nasal microorganisms.
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