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Long-Term Glycemic Control Influences the Long-Lasting Effect of Hyperglycemia on Endothelial Function in Type 1 Diabetes

Centre of Excellence in Diabetes and Endocrinology (A.C.), University Hospital of Coventry and Warwickshire, Warwick Medical School, University of Warwick, Coventry CV 2DX, United Kingdom; Division of Metabolic Diseases (K.E., D.G.), Center of Excellence for Cardiovascular Diseases, 2nd University of Naples SUN, 80138 Naples, Italy; and Department of Cell Biology (M.I., J.T.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104

Address all correspondence and requests for reprints to: Professor Antonio Ceriello, Warwick Medical School, Clinical Science Research Institute, Clinical Science Building, University Hospital, Walsgrave Campus, Clifford Bridge Road, Coventry CV2 2DX, United Kingdom. E-mail: antonio.ceriello{at}warwick.ac.uk.

Objective: The objective of the study was 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 10 type 1 diabetic subjects were enrolled as follows: 1) patients within 1 month of diagnosis; 2) patients between 4.5 and 5.2 yr from diagnosis and with glycosylated hemoglobin levels 7% or greater since diagnosis; 3) patients between 4.8 and 5.4 yr from diagnosis and with glycosylated hemoglobin levels greater than 7% since diagnosis. Each patient participated in three experiments: 1) 24-h insulin treatment, achieving a near normalization of glycemia, together with the addition of the antioxidant vitamin C during the last 12 h; 2) 24-h vitamin C treatment with insulin treatment for the last 12 h; and 3) treatment with both vitamin C and insulin for 24 h.

Results: Endothelial function, as measured by flow-mediated vasodilation 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 nor 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.