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SIGNIFICANCE These findings provide clear evidence for PAI-1 to participate in inflammation and obesity mediated hyperglycemia, and open up a new prospect for the treatment of T2DM by PAI-1 inhibition. INTRODUCTION Low maximal oxygen uptake (VO2max) is a strong and independent risk factor for all-cause and cardiovascular disease (CVD) mortality. For other CVD risk factors, numerous genetic association studies have been performed, revealing promising risk markers and new therapeutic targets. However, large genomic association studies on V