Objectives-Advanced glycation endproducts, AGEs, and its specific receptor, RAGE, are involved in diabetic vascular complications. Endogenous secretory RAGE, esRAGE, has been identified as an alternatively spliced form of RAGE, and shown to act as a decoy receptor for AGE. Here, we measured plasma esRAGE level with a recently developed enzyme-linked immunosorbent assay (ELISA) and examined its association with atherosclerosis in age-and gender-matched 203 type 2 diabetic and 134 nondiabetic subjects. Methods and Results-Plasma esRAGE was inversely associated with carotid or femoral atherosclerosis, as quantitatively measured as intimal-medial thickness (IMT) by arterial ultrasound. Stepwise regression analyses revealed that plasma esRAGE was the third strongest and independent factor associated with carotid IMT, following age and systolic blood pressure. Plasma esRAGE was significantly lower in diabetic patients (0.176Ϯ0.092 ng/mL) than nondiabetic controls (0.253Ϯ0.111). Of note, in all, diabetic or nondiabetic group, plasma esRAGE was significantly and inversely correlated with components of the metabolic syndrome including body mass index, blood pressure, triglyceride, HbA1c, or an insulin resistance index. Stepwise regression analyses showed that body mass index or insulin resistance index was the major factor determining plasma esRAGE in all, nondiabetic or diabetic population. Conclusions-esRAGE is a novel and potential protective factor for the metabolic syndrome and atherosclerosis. Key Words: pathophysiology Ⅲ risk factors Ⅲ type 2 diabetes U nder hyperglycemic conditions, endogenous nonenzymatic glycoxidation of proteins and lipids leads to the formation of heterogeneous products, collectively termed advanced glycation end products (AGEs). 1 AGE engagement of cell surface the receptor for AGE (RAGE) results in cellular signaling including activation of nuclear factor-B, increased expression of cytokines and adhesion molecules, and induction of oxidative stress. 2,3 Transgenic mice overexpressing human RAGE in vascular cells developed advanced nephropathy when they were made diabetic. 4 Thus, the AGE-RAGE system has been thought to play a pivotal role in the development of diabetic microvascular complications.Accumulating evidence suggests that RAGE is also involved in macrovascular complications in diabetes. 5,6 RAGE expression is shown to be upregulated in atherosclerotic plaques of diabetic animals. 7 Some of the human studies also implicate the involvement of RAGE in diabetic vasculopathy. 8,9 Moreover, the group of Stern and Schmidt has shown that augmentation of atherosclerosis in diabetic mice is inhibited by the competition of RAGE with its soluble truncated form termed soluble RAGE (sRAGE), lacking the transmembrane and cytoplasmic domains, produced by recombinant gene engineering. 7,10 Recently, an endogenous secretory RAGE (esRAGE) has been identified as a novel splice variant that directs the synthesis of RAGE proteins carrying all of the extracellular domains but devoid of the transmembrane...
The HOMA IR strongly correlated with the clamp IR in type 2 diabetic patients treated with SUs as well as in those treated with diet alone.
These results indicate that use of oral alfacalcidol was associated with reduced risk for cardiovascular death in this cohort of ESRD patients. The result of this observational study warrants further randomized controlled trials with 1alpha-hydroxy vitamin D3 to confirm the possibility that such medication improves survival of ESRD patients.
Abstract. Insulin resistance is closely associated with atherosclerosis and cardiovascular mortality in the general population. Patients with end-stage renal disease (ESRD) are known to have insulin resistance, advanced atherosclerosis, and a high cardiovascular mortality rate. We evaluated whether insulin resistance is a predictor of cardiovascular death in a cohort of ESRD. A prospective observational cohort study was performed in 183 nondiabetic patients with ESRD treated with maintenance hemodialysis. Insulin resistance was evaluated by the homeostasis model assessment method (HOMA-IR) using fasting glucose and insulin levels at baseline, and the cohort was followed for a mean period of 67 mo. Forty-nine deaths were recorded, including 22 cardiovascular deaths. Cumulative incidence of cardiovascular death by Kaplan-Meier estimation was significantly different between subjects in the top tertile of HOMA-IR (1.40 to 4.59) and those in the lower tertiles of HOMA-IR (0.28 to 1.39), and the hazard ratio (HR) was 2.60 (95% confidence interval [CI], 1.12 to 6.01; P ϭ 0.026) in the univariate Cox proportional hazards model. In multivariate Cox models, the positive association between HOMA-IR and cardiovascular mortality remained significant (HR, 4.60; 95% CI, 1.83 to 11.55; P ϭ 0.001) and independent of age, C-reactive protein, and presence of preexisting vascular complications. Further analyses showed that the effect of HOMA-IR on cardiovascular mortality was independent of body mass index, hypertension, and dyslipidemia. In contrast, HOMA-IR did not show such a significant association with noncardiovascular mortality. These results indicate that insulin resistance is an independent predictor of cardiovascular mortality in ESRD.
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