The mechanisms by which vascular disease develops include Glycosylation of serum and tissue proteins with formation of advanced glycation end products Superoxide production Activation of protein kinase C, a signaling molecule that increases vascular permeability and causes endothelial dysfunction Accelerated hexosamine biosynthetic and polyol pathways leading to sorbitol accumulation within tissues Hypertension and dyslipidemias that commonly accompany diabetes mellitus Arterial microthromboses Proinflammatory and prothrombotic effects of hyperglycemia and hyperinsulinemia that impair vascular autoregulation Microvascular disease underlies 3 common and devastating manifestations of diabetes mellitus: Retinopathy Nephropathy Neuropathy Microvascular disease may also impair skin healing, so that even minor breaks in skin integrity can develop into deeper ulcers and easily become infected, particularly in the lower extremities.