ABSTRACT Habitual physical activity (PA) impacts the plasma proteome and reduces the risk of developing type 2 diabetes (T2D). Using a large-scale proteome-wide approach in Atherosclerosis Risk in Communities Study participants, we aimed to identify plasma proteins associated with PA and determine which of these may be causally related to lower T2D risk. PA was associated with 92 plasma proteins in discovery (p<1.01x10-5), and 40 remained significant in replication (p<5.43x10-4). Eighteen of these proteins were independently associated with incident T2D (p<1.25x10-3) including neuronal growth regulator 1 (NeGR1) (HR per SD: 0.85; p-value=7.5x10-11). Two-sample Mendelian randomization inverse variance weighted analysis indicated that higher NeGR1 reduces T2D risk (OR per SD: 0.92; p=0.03) and was consistent with MR-Egger, weighted median, and weighted mode sensitivity analyses. A stronger association was observed for the single cis-acting NeGR1 genetic variant (OR per SD: 0.80; p=6.3x10-5). Coupled with previous evidence that low circulating NeGR1 levels promote adiposity, its association with PA and potential causal role in T2D shown here suggest that NeGR1 may link PA exposure with metabolic outcomes. Further research is warranted to confirm our findings and examine the interplay of PA, NeGR1, adiposity, and metabolic health. Article Highlights Physical activity alters tissue and plasma proteomes, which have been shown to have roles in type 2 diabetes development We aimed to identify protein signatures through which physical activity may influence type 2 diabetes pathogenesis Forty proteins associated with physical activity, and 18 of these were further related to incident type 2 diabetes over an approximate 24-year follow-up Two-sample Mendelian randomization analysis indicated that circulating neuronal growth regulator 1 reduces risk of type 2 diabetes · These findings suggest that plasma neuronal growth regulator 1 may link physical activity to reduced risk of type 2 diabetes
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