Insulin-resistant states, including type 2 diabetes mellitus, are associated with increased concentrations of plasminogen activator inhibitor type 1 (PAI-1) in blood and in extracted coronary atheroma, as well as with an increased incidence of acute coronary syndromes, known to be precipitated by the rupture of vulnerable atherosclerotic plaques. However, plaque rupture is potentiated by proteolysis. Accordingly, the parallel relationship between augmentation of concentrations of an inhibitor of proteolysis and plaque vulnerability appears to be paradoxical. The following resolution is proposed. Reduced cellularity of plaques may result when high concentrations of PAI-1 in early atheroma inhibit the migration of vascular smooth muscle cells into the neointima. Such migrating cells subsequently proliferate. If their total number is reduced, the composition of plaques may be altered throughout development with the reduction of vascular smooth muscle cell content and consequent additional changes. In aggregate, such changes may render mature, complex plaques vulnerable to rupture mediated by proteolysis responsible for the degradation of thin fibrous caps on relatively acellular, lipid-laden plaques.