Cytokine and Cytokine-like Inflammation Markers, Endothelial Dysfunction, and Imbalanced Coagulation in Development of Diabetes and Its Complications

Context: Recent developments indicate that pathophysiological mechanisms leading to beta-cell damage, insulin resistance, and the vascular complications of diabetes include an activation of the inflammation cascade, endothelial dysfunction, and procoagulant imbalance. Their circulating biomarkers may therefore provide opportunities for early diagnosis and targets for novel treatments.

Evidence: Circulating biomarkers of these pathways such as TNFalpha, IL-6, C-reactive protein (CRP) (inflammation), vascular cellular adhesion molecule-1, interstitial cellular adhesion molecule-1, E-selectin, von Willebrand factor (endothelial dysfunction), plasminogen activator inhibitor-1, fibrinogen, P-selectin (procoagulant state), and adiponectin (antiinflammation) may be associated with development of both type 1 and type 2 diabetes and some studies, particularly in type 2 diabetes, have demonstrated that certain biomarkers may have independent predictive value. Similarly studies have shown that these biomarkers may be associated with development of diabetic nephropathy and retinopathy, and again, particularly in type 2 diabetes, with cardiovascular events as well. Finally, the comorbidities of diabetes, namely obesity, insulin resistance, hyperglycemia, hypertension and dyslipidemia collectively aggravate these processes while antihyperglycemic interventions tend to ameliorate them.

Conclusions: Increased CRP, IL-6, and TNFalpha, and especially interstitial cellular adhesion molecule-1, vascular cellular adhesion molecule-1, and E-selectin are associated with nephropathy, retinopathy, and cardiovascular disease in both type 1 and type 2 diabetes. Whereas further work is needed, it seems clear that these biomarkers are predictors of increasing morbidity in prediabetic and diabetic subjects and should be the focus of work testing their clinical utility to identify high-risk individuals as well as perhaps to target interventions.