Increased intracellular calcium concentrations ([Ca(2+)](i)) and enhanced sodium-lithium countertransport (Na/Li CT) activities may play a role in the development of diabetic complications such as diabetic nephropathy. The present study was designed to test the hypothesis that albuminuria in patients with type 2 diabetes is associated with increased [Ca(2+)](i) in response to stimulation with platelet-activating factor (PAF) or with enhanced Na/Li CT activities. The study population comprised 203 type 2 diabetic patients. Albuminuria was defined as an albumin excretion rate exceeding 30 mg/d (117 cases). PAF-evoked rises in [Ca(2+)](i) and Na/Li CT activities were determined in Epstein-Barr-virus-immortalized lymphoblasts. Albuminuria was related to high stimulated [Ca(2+)](i) but not to high basal [Ca(2+)](i). The association was independent of age, sex and several non-diabetes related confounders, but depended on diabetes-related factors, such as the duration of diabetes. The risk of albuminuria was highest in subjects with high [Ca(2+)](i) who reported a diabetes duration of < or =10 years. There was no association between Na/Li CT activities and albuminuria. The present results support the hypothesis that albuminuria in type 2 diabetic patients is associated with a primary defect in intracellular calcium homeostasis. The association between stimulated [Ca(2+)](i) and albuminuria is most prominent in early diabetes.