Glaucoma drainage surgery in diabetic patients is associated with a relatively poor prognosis due to increased scarring at the site of surgery, secondary to increased proliferation of human Tenon's capsule fibroblasts (hTCF). This is in marked contrast to diabetic wound healing at other sites, where it is generally impaired. The aim of this study was to determine why diabetics show an increased ocular scarring response in comparison to that found at other sites. Under normoglycemic conditions, hTCF isolated from diabetics showed a mean reduction in short-term proliferation (95% CI) of 45 +/- 12% compared with normal controls (p < 0.001). Under hyperglycemic conditions, proliferation of diabetic hTCF was reduced by 21 +/- 11% (p < 0.01) compared with nondiabetic controls. When exposed to transforming growth factor-beta2 (1-10,000 pg/ml) and platelet-derived growth factor-BB (0.5-500 ng/ml) under both normo- and hyperglycemic conditions, there was a dose-related increase in proliferation of both diabetic and nondiabetic controls. There was no significant difference in response to cytokine stimulation between the two groups at any of the cytokine concentrations used. Western blot analysis did not show any apparent difference in the expression of platelet-derived growth factor receptor alpha, mitogen-activated protein kinase/ERK2, or transforming growth factor-beta receptor II to account for the reduced proliferation of diabetic hTCF. These results suggest that hTCF behave in a manner similar to fibroblasts from other nonocular sites and that the increased proliferation and scarring response found in vivo may be secondary to the previously noted elevated cytokine concentrations in the aqueous and vitreous of diabetics.