The Association Between Soluble P-selectin and Insulin Sensitivity in Healthy Humans

INTRODUCTION

Inflammation is a common precursor of both diabetes and atherosclerotic vascular disease, suggesting common inflammatory mediators. Inflammation leading to atherosclerosis promotes endothelial dysfunction, lipid oxidation, and recruitment of inflammatory cells within the vascular wall [].

Selectins are a family of cell adhesion molecules consisting of a lectin-like domain, an epidermal growth factor-like domain, and a variable number of domains that encode proteins homologous to complement-binding proteins. In general, they mediate the binding of leukocytes to the vascular endothelium, which may contribute to inflammatory processes related to the pathogenesis of type 2 diabetes. P-selectin is a member of the selectin family expressed by activated platelets and endothelial cells []. The soluble version (sP-selectin) has been implicated as a biomarker of cardiovascular disease (CVD) [], is upregulated on vulnerable plaques prone to rupture leading to acute coronary events [], and has also been related to CVD risk factors including hypertension and diabetes []. Apart from its role in coagulation, P-selectin plays a key role in leukocyte rolling and primes leukocytes for integrin-mediated leukocyte adhesion []. Importantly, P-selectin-deficient mice manifest impaired leukocyte adhesion, which can be rescued by sP-selectin [].

Many studies have identified that soluble markers of inflammation, including adhesion molecules, selectins, and acute phase response proteins are increased in obesity and to be predictive of future type 2 diabetes development. A recent large-scale epidemiological trial has reported that sP-selectin levels were higher in subjects with impaired glucose tolerance and highest in subjects with diabetes []. Furthermore, there was an association between sP-selectin levels and HOMA-IR (an indirect measure of insulin resistance) in non-diabetic subjects []. No study to date has examined the relationship between sP-selectin and insulin resistance measured directly by glucose clamp in non-diabetic individuals. Therefore, the relationship between soluble adhesion molecules and the etiology of insulin resistance and type 2 diabetes remains unclear.

Low levels of adiponectin, an adipocyte-derived protein with insulin-sensitizing and anti-inflammatory properties [], predicts insulin resistance, type 2 diabetes [], and is associated with CVD, acute coronary syndrome, and promotion of an unstable plaque phenotype [–]. Interestingly, adiponectin deficiency was shown to increase leukocyte–endothelium interactions via upregulation of endothelial cell adhesion molecules . Furthermore, adiponectin inhibits the production of P-selectin, a mechanism that may act to regulate the recruitment of inflammatory cells to the vessel wall []. This would suggest that interaction between adhesion molecules and adiponectin might be necessary for successful adhesion and migration of leukocytes through the endothelium []. Nuclear factor kappa B (NFκB) and its kinases have been identified as key molecules responsible for inflammation-induced insulin resistance [] and there has been a suggestion that P-selectin might be under transcriptional control via the NFκB pathway [].

There is some evidence that inflammation and endothelial markers, including selectins, change after an acute bout of aerobic exercise and relate to habitual physical activity and fitness [, ]. However, it remains to be fully elucidated whether acute aerobic exercise and/or habitual physical activity reduce circulating adhesion molecule levels and other markers of inflammation independently of adiposity.

In the present study, we hypothesized that selectins and other adhesion molecules directly or via changes in adiponectin contribute to the development of insulin resistance. Therefore, elevated plasma sP-selectin, VCAM-1, and ICAM-1 levels should be associated with insulin resistance in non-diabetic subjects. Furthermore, as exercise is protective against both obesity and insulin resistance, we hypothesized that soluble adhesion molecules would be inversely related to indices of physical activity and fitness. To this end, we measured plasma sP-selectin, sVCAM-1, sICAM-1, adiponectin levels, insulin sensitivity by hyperinsulinemic euglycemic glucose clamp, physical activity, and fitness and assessed adhesion molecules before and after exercise.

Keywords

adhesion molecules, sP-selectin, ICAM-1, VCAM-1, inflammation, insulin resistance, obesity, adiponectin,