Pathophysiological correlation of arginase-1 in development of type 2 diabetes from obesity in adolescents

Abstract

BACKGROUND: There is great interest to understand causal pathophysiological correlation between obesity and diabetes mellitus (DM). Vascular endothelial dysfunction is crucially involved in pathogenesis of vascular complications in DM. Recently, increased arginase expression and activity have been described as underlying mechanisms of endothelial dysfunction in DM and vascular inflammation in obesity. By limiting L-arginine bioavailability to endothelial nitric oxide synthase (NOS III), nitric oxide production is potentially impaired. METHODS: We investigated the impact of plasma from diabetic and obese adolescents on arginase and NOS III expression in cultured human endothelial cells (ECs). A total of 148 male adolescents participated in this study including 18 obese, 28 type 1-, 28 type 2-DM patients, and 74 age-matched healthy volunteers. RESULTS: A concurrent increase in arginase-1 (1.97-fold) and decrease in NOS III expression (1.45-fold) was observed in ECs exposed to type 2 diabetic plasma compared to control subjects. ECs incubated with type 1 DM plasma had a diminished NOS III level without impact on arginase-1 expression. Urea-assay featured an increased arginase activity in treated ECs with type 1- or 2-DM plasma. Despite increased pro-inflammatory cytokines and chemokines in obese plasma, arginase-1 expression/activity did not change in treated ECs. However, NOS III expression was significantly reduced. Pearson analysis revealed positive correlation between arginase-1, but not NOS III, expression with FBS in ECs treated with type 2-DM plasma. CONCLUSIONS: Our data demonstrate that increased arginase-1 expression/activity in ECs, as critical pathogenic factor is correlated with development of obesity-related type 2-DM and linked vascular disease.