Intensive treatment of risk factors in patients with type-2 diabetes mellitus is associated with improvement of endothelial function coupled with a reduction in the levels of plasma asymmetric dimethylarginine and endogenous inhibitor of nitric oxide synthase

Aims Vascular endothelium is a major organ involved in hyperglycaemia and is affected by plasma asymmetric dimethylarginine (ADMA). ADMA is an endogenous, competitive inhibitor of nitric oxide synthase and is induced by inflammatory cytokines of tumour necrosis factor (TNF)-alpha in vitro. We hypothesized that a tight glycaemic control may restore endothelial function in patients with type-2 diabetes mellitus (DM), in association with modulation of TNF-alpha and/or reduction of ADMA level. Methods and results In 24 patients with type-2 DM, the flow-mediated, endothelium-dependent dilation (FMD: %) of brachial arteries during reactive hyperaemia was determined by a high-resolution ultrasound method. Blood samples for glucose, cholesterol, TNF-alpha, and ADMA analyses were also collected from these patients after fasting. No significant glycaemic or FMD changes were observed in 10 patients receiving the conventional therapy. In 14 patients who were hospitalized and intensively treated, there was a significant decrease in glucose level after the treatment [from 190 +/- 55 to 117 +/- 21 (mean +/- SD) mg/dL, P < 0.01]. After the intensive control of glucose level, FMD increased significantly (from 2.5 +/- 0.9 to 7.2 +/- 3.0%), accompanied by a significant (P < 0.01) decrease in TNF-alpha (from 29 +/- 16 to 11 +/- 9 pg/dL) and ADMA (from 4.8 +/- 1.5 to 3.5 +/- 1.1 mu M/L) levels. The changes in FMD after treatment correlated inversely with those in TNF-alpha (R=-0.711, P < 0.01) and ADMA (R=-0.717, P < 0.01) levels. Conclusion The intensive correction of hyperglycaemia is associated with the improvement of endothelial function, which is coupled with the decrease in the levels of reduction of plasma TNF-alpha and ADMA in patients with type-2 DM. A strict glycaemic control may exert anti-cytokine and anti-atherogenic effects and may therefore be pathophysiologically important.