Objective: To investigate the effect of different periods of hyperglycemia on the reversal of endothelial dysfunction by glucose normalization and antioxidant therapy.

Research Design and Methods: Ten healthy subjects and three subgroups of ten type 1 diabetic subjects were enrolled as follows: 1) patients within one month of diagnosis; 2) patients between 4.5 to 5.2 years from diagnosis and with HbA1c levels 7% since diagnosis; 3) patients between 4.8 to 5.4 years from diagnosis and with HbA1c levels >7% since diagnosis.

Each patient participated in three experiments: a) 24 hour insulin treatment, achieving a near-normalization of glycemia, together with the addition of the antioxidant vitamin C during the last 12 hours; b) 24 hours vitamin C treatment with insulin treatment for the last 12 hours; c) treatment with both vitamin C and insulin for 24 hours.

Results: Endothelial function, as measured by flow-mediated vasodilation (FMD) of the brachial artery and levels of nitrotyrosine, an oxidative stress marker, were normalized by each treatment in subgroups 1 and 2. In the third subgroup, neither glucose normalization or vitamin C treatment alone was able to normalize endothelial dysfunction or oxidative stress. Combining insulin and vitamin C, however, normalized endothelial dysfunction and nitrotyrosine.

Conclusions: This study suggests that long-lasting hyperglycemia in type 1 diabetic patients induces long-term alterations in endothelial cells, which may contribute to endothelial dysfunction and is interrupted only by both glucose and oxidative stress normalization.