© 2017 American College of Cardiology Foundation Objectives This study sought to investigate how cumulative exposure to glycemic abnormalities and trajectories of insulin resistance (IR) relate to left ventricular (LV) remodeling and function during young to middle adulthood. Background Cumulative exposure to glycemic abnormalities and trajectories of IR may adversely influence LV remodeling and function over a 25-year period in subjects who were young adults, predisposing individuals to heart failure later in life. Methods In the CARDIA (Coronary Artery Risk Development in Young Adults) Year 25 examination, 3,179 participants were identified with information on glucose metabolism; these participants were stratified into 4 subgroups: group 1 normal glucose tolerance (NGT), group 2 impaired glucose tolerance (IGT) or impaired fasting glucose, group 3 late diabetes mellitus (DM) (DM diagnosed at year 15 or later), and group 4 early DM (DM diagnosed at year 0 to year 15). Among the subgroup without DM, 3 trajectory groups of change in the homeostasis model assessment of IR were identified: low IR, moderate IR, and high IR. LV mass, relative wall thickness, LV ejection fraction (LVEF), longitudinal systolic strain (Ell), and early diastolic strain rate (Ell_SRe) at year 25 were assessed by echocardiography. Clinically relevant systolic and diastolic dysfunction were defined as LVEF <50% for systolic dysfunction, and E/e′ ≥13 for diastolic dysfunction. Results The early DM group had less favorable LV mass (coefficient = 11.04; p < 0.001), LVEF (coefficient = −2.72; p < 0.05), Ell (coefficient = 1.53; p < 0.001), and Ell_SRe (coefficient = −0.09; p < 0.05) than did the NGT group. Being in the early DM group and having high hemoglobin A1c were independently associated with greater odds of having systolic dysfunction (odds ratio = 5.44; p < 0.005) compared with the NGT group. High IR was associated with worse relative wall thickness (coefficient = 0.019; p < 0.0001) and worse Ell, E′, and Ell_SRe, depending on obesity level. Conclusions Cumulative exposure to DM or higher IR beginning in early adulthood adversely impacts LV remodeling and function at middle age.