The Influences of Obesity and Glycemic Control on Endothelial Activation in Patients with Type 2 Diabetes

Abstract

The aims of this study were to elucidate the factors that contribute to endothelial activation and fibrinolytic abnormalities in patients with poorly controlled type 2 diabetes and to determine whether improved glycemic control reduces endothelial activation. Adhesion molecules [E-selectin, intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1], von Willebrand factor, total nitric oxide (NO), endothelin-1, tissue plasminogen activator, and plasminogen activator inhibitor-1 were measured in 43 type 2 diabetic subjects with hemoglobin A1c of 9.0% or more at baseline (compared with 21 healthy controls) who after 20 wk had been randomized to either improved (IC) or usual (UC) glycemic control. At baseline, type 2 diabetic patients had significant endothelial activation and abnormal fibrinolysis compared with control subjects. Body mass index in the diabetic patients was the only independent predictor of E-selectin (P = 0.007), ICAM-1 (P = 0.01), and NO (P = 0.008) concentrations, but not vascular cell adhesion molecule-1, plasminogen activator inhibitor-1, or tissue plasminogen activator (all P > 0.05). Type 2 diabetic patients with a body mass index of 28 kg/m2 or less had concentrations of E-selectin, ICAM-1, endothelin-1, and NO similar to those in healthy controls. After 20 wk, hemoglobin A1c was significantly lower in IC vs. UC (IC, 8.02 +/- 0.25%; UC, 10.23 +/- 0.23%; P < 0.0001), but there were no significant changes in markers of endothelial activation or indexes of fibrinolysis. Obesity appears to be the most important predictor of endothelial activation in patients with type 2 diabetes. Short-term improvement in glycemic control does not appear to reduce endothelial activation.

The effect of multi‐factorial intervention on plasma von Willebrand factor, soluble E‐selectin and tissue factor in diabetes mellitus: implications for atherosclerotic vascular disease

“…As expected from previous studies [5][6][7][8][9][10][11], plasma vWf, sE-sel and TF were higher in patients compared with controls ( Table 2). There were no significant differences in plasma vWf and sE-sel between those with CVD and without overt CVD.…”

“…Indeed, increased levels of circulating sE-sel and vWf are also associated with increased cardiovascular morbidity and mortality, albeit predominantly in the non-diabetic population [2][3][4][5][6]. However, raised levels of sE-sel and vWf have also been consistently shown in patients with diabetes mellitus [5,[7][8][9][10].…”

“…Management of patients with diabetes has long been dominated by the drive for glycaemic control. However, glucose reduction has inconsistent effects on indices of endothelial abnormalities and hypercoagulability [7,9], implying a persistent adverse vascular milieu. This may account for the limited effects of glycaemic control on vWf and sEsel [10], and on cardiovascular outcomes [14].…”

Cocoa, Glucose Tolerance, and Insulin Signaling: Cardiometabolic Protection

“…26,27 Thus, an imbalance between the endothelial and insulin-dependent pathways (MAPK-dependent and PI3K-dependent signals) might be involved in the endothelial derangements successively participating in the metabolic disturbances with insulin resistance. 5,12 These specific pathophysiological links suggest the strict relationship between metabolic and cardiovascular diseases.…”

Protein O-N-Acetylglucosaminylation Modulates Promoter Activities of Cyclic AMP Response Element and Activator Protein 1 and Enhances E-Selectin Expression on HuH-7 Human Hepatoma Cells

“…8) Serum concentrations of soluble adhesion molecules such as soluble endothelial leukocyte adhesion molecule (ELAM-1, E-selectin), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) are related to the degree of insulin resistance and hyperglycemia in patients with type 2 diabetes. 9,10) Incubation of human umbilical vein endothelial cells (HUVEC) in culture media containing high glucose enhances the expression of cell surface adhesion molecules through a process that involves nuclear factor-kB (NF-kB), 11) protein kinase C, [12][13][14] and poly ADP ribose polymerase, 15) although the precise mechanism remains to be elucidated. In a previous report, 16) we demonstrated that glycated human serum albumin enhanced E-selectin expression on HUVEC by NF-kB and activator protein-1 (AP-1) via NADPH oxidase activation.…”