An enhanced paracrine/autocrine activity of the insulin-like growth factor (IGF) system within the glomerulus has been implicated together with up-regulation of transforming growth factor-beta (TGFbeta) in the pathogenesis of diabetic glomerular disease. This would imply their ability to modulate extracellular matrix (ECM) and cell turnover at the mesangial level, but the direct effects of IGFs on ECM production have not been demonstrated to date. These experiments in cultured human mesangial cells were aimed at assessing the effects of IGF-I and IGF-II, compared with those of TGFbeta, on 1) ECM medium accumulation and gene expression, and 2) total protein synthesis and cell proliferation. Human mesangial cells were grown to subconfluence, growth arrested for 48 h, and then exposed for 4-24 h to serum-free medium containing IGF-I (10(-7) - 10(-11) M), IGF-II (10(-7) - 10(-11) M), TGFbeta (10(-9) - 10(-11) M), or various combinations of two of these growth factors (10(-9)M). All three growth factors dose dependently increased ECM protein and messenger RNA levels. The combination of either IGF-I or IGF-II with TGFbeta, but not the two IGFs together, produced additive effects on matrix production. Total protein synthesis was also increased by IGF-I, IGF-II, and TGFbeta, although to a lesser extent than ECM production, whereas cell proliferation was enhanced by IGFs but not by TGFbeta. These results demonstrate that IGF-I and IGF-II are effective, although less potent than TGFbeta, in stimulating the production of the ECM components that accumulate in the mesangial region during the course of diabetic glomerular disease.