Soluble Intercellular Adhesion Molecule, Vascular Cell Adhesion Molecule, and Impaired Microvascular Reactivity Are Early Markers of Vasculopathy in Type 2 Diabetic Individuals Without Microalbuminuria

Objective: Using von Willebrand Factor (vWF) as a marker of endothelial function, previous studies have shown that the development of microalbuminuria is associated with the onset of endothelial dysfunction in individuals with type 2 diabetes. We tested the hypothesis that endothelial dysfunction is already evident in normoalbuminuric individuals with type 2 diabetes.

Research Design And Methods: We used laser Doppler imaging scanning to measure vasodilation in the forearm skin in response to iontophoresis of 1% acetylcholine (endothelium-dependent) and 1% sodium nitroprusside (endothelium-independent). Multiple indicators of endothelial function--soluble intercellular adhesion molecule (sICAM), soluble vascular cell adhesion molecule (sVCAM), vWF, and microvascular reactivity--were measured in 20 healthy control subjects, 45 normoalbuminuric (urinary albumin/creatinine ratio < 30 micrograms/mg) individuals with type 2 diabetes, and 14 microalbuminuric (urinary albumin/creatinine ratio between 30 and 300 micrograms/mg) individuals with type 2 diabetes.

Results: Serum sICAM and sVCAM levels were elevated in the normoalbuminuric (305 +/- 120, 851 +/- 284 ng/ml) and microalbuminuric (300 +/- 89, 845 +/- 252 ng/ml) individuals with diabetes when compared with the healthy control subjects (213 +/- 58, 661 +/- 176 ng/ml) (P < 0.01). Furthermore, the microvascular endothelium-dependent and -independent vasodilation was reduced in the normoalbuminuric (76 +/- 44, 70 +/- 33) (percent increase in perfusion over baseline) and microalbuminuric (74 +/- 41, 73 +/- 28) individuals with diabetes compared with healthy control subjects (126 +/- 67, 120 +/- 47) (P < 0.05). In contrast, plasma vWF was elevated only in the microalbuminuric individuals with diabetes (129 +/- 35%) compared with the normoalbuminuric individuals with diabetes (110 +/- 34) and healthy control subjects (111.3 +/- 39) (P < 0.05). On stepwise multivariate analysis, fasting blood glucose was the most important contributing factor to the variation in microvascular reactivity and sVCAM, whereas insulin resistance (by homeostasis model assessment) was the most important contributing factor to the variation in sICAM. Addition of all clinical and biochemical measures explained only 15-22% of the variation in sICAM, sVCAM, and microvascular reactivity.

Conclusions: Multiple markers of endothelial dysfunction were evident in normoalbuminuric individuals with type 2 diabetes. The pathogenic process of vasculopathy in type 2 diabetes occurs early and may be operative before the development of microalbuminuria.