Endothelial Adhesion Molecules in Diabetes - Adhesion Molecules - page 191

Loscalzo 1999, Kim et al. 2006). Although the underlying mechanisms are not
well understood, several pathways, including increased superoxide production
and oxidative stress, activation of protein kinase C (PKC), and production of
advanced-glycation end products (AGEs), have been proposed to explain the
inl uence of hyperglycemia-mediated endothelial dysfunction on the development
and progression of diabetic angiopathy (Fig. 4) .
Numerous studies have shown increased levels of E-selectin, ICAM-1, and
VCAM-1 in type 2 diabetes patients with microangiopathy or macroangiopathy
compared to non-diabetic controls (Schram and Stehouwer 2005). First, elevated
levels of adhesion molecules have been associated with hyperglycemia and/or
insulin resistance in patients with type 2 diabetes. Several other cardiovascular
risk factors such as cigarette smoking, hypertension, and dyslipidemia have also
been associated with elevated levels of adhesion molecules. Since these factors
tend to coexist to inl uence vascular function among diabetic patients, elevated
levels of endothelial adhesion molecules may rel ect the net involvement of several
pathophysiological changes underlying insulin resistance and/or progressive β-cell
dysfunction, including alterations of innate immune response, oxidative stress,
thrombosis, and other metabolic homeostasis. It is tempting to further explore
the temporal relation of endothelial function as rel ected by adhesion molecules
and diabetic complications; however, a few prospective studies have yielded
inconsistent results. h e Hoorn study reported that elevated VCAM-1 levels
were signii cantly associated with the development of elevated urinary albumin
excretion rate during a follow-up of 6.1 yr (Jager et al. 2002). h is i nding was
coni rmed by another prospective study of 328 type 2 diabetic patients, in which
VCAM-1 and E-selectin were associated with increased urinary albumin excretion
in patients with type 2 diabetes with 9-yr follow-up (Stehouwer et al. 2002). In
these two studies, increased levels of VCAM-1 were signii cantly associated with
increased risk of cardiovascular mortality (Jager et al. 2000) and total mortality
in type 2 diabetes (Stehouwer et al. 2002). h ese associations were independent
of inl ammatory marker levels. Previous studies of endothelial adhesion
molecules and retinopathy in type 2 diabetes have yielded conl icting results.
In the Hoorn study of 625 individual with and without type 2 diabetes, baseline
levels of ICAM-1, von Willebrand factor, and urinary albumin:creatinine ratio
were combined to calculate a summary z score for endothelial dysfunction (van
Hecke et al. 2005). h is score was signii cantly associated with retinopathy among
diabetic individuals but not in non-diabetic individuals (van Hecke et al. 2005). In
the latter study, E-selectin was associated with the progression of retinopathy but
not independently of HbA1c (Spijkerman et al. 2007). Given the complexity of the
interactions involved in the pathophysiological cascade of diabetes with multiple
abnormalities, dif erences in the population samples and basic characteristics may
help account for inconsistencies in the literature. Whether and to what extent
endothelial adhesion molecules have a direct causal impact on the multifactorial
etiology of diabetic angiopathy remains elusive and requires further evaluation.