BACKGROUND: Whether insulin resistance in type 2 (non-insulin-dependent) diabetes is due to compromised endothelial insulin migration or to impaired intracellular hormone action or both is unclear. Coexistent microalbuminuria reflects possible endothelial pathogenesis in insulin resistance. METHODS: Insulin sensitivity (S(I)) was calculated from an intravenous glucose tolerance test in 23 type 2 albuminuric (AER+), 11 type 2 normoalbuminuric (AER-), and 17 control subjects. Cultured fibroblasts from skin biopsies from these subjects were used to study intracellular insulin action on glycogen synthesis. Endothelial damage in type 2 diabetes was evaluated by plasma concentrations of von Willebrand factor (vWf). Results: S(I) and glycogen synthesis in fibroblasts were lower in AER+ and AER- than in controls. Glycogen synthesis in vitro was related to S(I) in vivo (r=0.55, P<0.001). vWf was 169+/-12% in AER+ and 140+/-5% in AER-, P<0.051. No correlation was observed between vWf and S(I) or plasma insulin clearance. CONCLUSIONS: This study demonstrates that reduced insulin-mediated glucose removal in type 2 diabetes is strictly associated with a decreased glycogen synthesis of cultured skin fibroblasts in vitro, but not with markers of endothelial damage in vivo.