Accelerated modification of proteins by glucose terminating in the formation of advanced glycation endproducts (AGEs) is one of the main pathogenetic mechanisms of diabetes-associated complications. One pathway by which AGEs may exert their effects is by interaction with specific receptors initially identified on macrophages, monocytes and endothelial cells. As AGE-induced autocrine upregulation of AGE receptors has been observed in vitro, we hypothesized that AGE-binding might be enhanced in diabetic patients to compensate for the elevated levels of circulating AGEs. We therefore examined the expression of AGE-binding sites on peripheral monocytes, serum levels of AGEs and AGE-induced cytokine production in patients with insulin-dependent diabetes mellitus (IDDM) compared to age-matched, healthy control subjects. In patients, AGE-binding capacity was significantly increased and there was only one class of binding sites, as revealed by Scatchard analysis (1.8 x 10(5) vs 1.4 x 10(5) binding sites per cell). Affinity of binding was, however, similar (Ka 1.5 x 10(6) vs 1.4 x 10(6) mol(-1)). Saturation of binding was reached at 2.0-3.0 micromol/l with AGE-bovine serum albumin (BSA) as ligand. In contrast, cytometry using fluorescein isothiocyanate-labelled AGE-proteins showed no saturability and reversibility of AGE-binding up to 80 micromol/l, indicating non-specific binding in this concentration range. Again, this non-specific binding was significantly higher in IDDM patients. In addition, we found much higher levels of circulating AGEs in patients as compared to controls and studied possible functional consequences of increased AGE binding in vitro, monocyte stimulation by AGEs triggering cytokine release to a similar extent in patients and controls, i.e. independently of the AGE-binding capacity. Our finding of an enhanced overall AGE-binding capacity of peripheral monocytes in IDDM could be instrumental in limiting the plasma concentration of AGEs, the non-specific binding coming into play after saturation of specific binding sites by higher plasma AGE-levels. Both binding strategies may act in concert as "damage limitation mechanisms" in the development of AGE-dependent diabetic complications.