Abstract
Introduction: Circulating plasminogen activator inhibitor-1 (PAI-1) levels are elevated in obesity and diabetes mellitus (DM) in cross-sectional studies. Preclinical studies support a role for PAI-1 in obesity development and insulin signaling. To date, no studies have investigated the prospective association of PAI-1 in young adults with incident obesity and DM. Hypothesis: Higher PAI-1 concentrations and greater increases in PAI-1 during young adulthood are associated with higher incidence of obesity and diabetes. Methods: We performed an ancillary study in CARDIA measuring PAI-1 in plasma at exam year (Y) 7 and Y20 in a subset of 1200 participants (ppts) free of obesity and DM at Y7. Multivariable logistic regression was used to examine the association between PAI-1 at Y7 and change from Y7 to Y20 with incident obesity and diabetes by Y30. Covariates for adjustment included demographics (age, race, sex, center, education), lifestyle risk factors (physical activity, energy intake, smoking), metabolic traits (BMI, fasting glucose [for DM]), and Y7 PAI-1 level. Results: At Y7, ppts (32±4 years, 54% female, 37% black) had mean BMI 24.5±3 kg/m 2 , fasting glucose 89±8 mg/dL, and median PAI-1 14 (IQR: 8-24) ng/mL. Median change in PAI-1 from Y7 to Y20 was +10.0 ng/mL (IQR: +1.0-28.0 ng/dL). Each 1 standard deviation higher ln(PAI-1) at Y7 was associated with an adjusted hazards ratio for incident DM of 1.35 (95% CI: 1.09-1.67). Each 1 standard deviation greater increase in PAI-1 from Y7 to Y20 was associated with an adjusted odds ratio (OR) for incident obesity and DM of 1.21 (1.02-1.43) and 1.36 (1.10-1.68), respectively. When examined by quartiles, the highest (vs. lowest) quartile of Y7 to Y20 PAI-1 change was associated with an adjusted OR of 2.37 (1.33-4.21) for incident obesity and 3.11 (1.45-6.68) for incident DM by Y30, independent of Y7 BMI and PAI-1 (FIGURE) . Conclusions: Higher plasma PAI-1 levels and greater increases in PAI-1 during young adulthood are positively associated with incident obesity and DM by middle age.
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