OBJECTIVE -The binding of advanced glycation end products (AGEs) to their receptor (RAGE) plays an important role in the development of diabetic vascular complications. In the present study, we examined circulating endogenous secretory RAGE (esRAGE) levels in subjects with type 1 diabetes and explored the possible association between esRAGE levels and the severity of diabetic vascular complications.RESEARCH DESIGN AND METHODS -Circulating esRAGE levels in serum were examined in 67 Japanese type 1 diabetic patients (22 men and 45 women, age 24.0 Ϯ 4.4 years [means Ϯ SD]) and 23 age-matched healthy nondiabetic subjects (10 men and 13 women aged 24.9 Ϯ 1.4 years). Daily urinary albumin excretion, the presence of retinopathy, and intimamedia thickness (IMT) of the carotid artery were also evaluated. We further explored the association between esRAGE levels and severity of diabetic vascular complications.RESULTS -Circulating esRAGE levels were significantly lower in subjects with type 1 diabetes than in nondiabetic subjects (0.266 Ϯ 0.089 vs. 0.436 Ϯ 0.121 ng/ml, respectively, P Ͻ 0.0001) and was inversely correlated with HbA 1c (A1C) levels (r ϭ Ϫ0.614, P Ͻ 0.0001). In addition, multivariate regression analysis demonstrated that A1C was an independent risk factor for a low esRAGE value. Furthermore, circulating esRAGE levels were inversely correlated with carotid IMT (r ϭ Ϫ0.325, P ϭ 0.0017) and was one of the independent risk factors for IMT thickening. Furthermore, there was a significant difference (P ϭ 0.0124) in esRAGE levels between patients without retinopathy (0.286 Ϯ 0.092 ng/ml) and those with retinopathy (0.230 Ϯ 0.074 ng/ml).CONCLUSIONS -Circulating esRAGE levels were significantly lower in type 1 diabetic patients than in nondiabetic subjects and were inversely associated with the severity of some diabetic vascular complications. Diabetes Care 28:2716 -2721, 2005M icrovascular complications and atherosclerosis, which are accelerated in patients with prolonged duration of type 1 diabetes, lead to the impairment of quality of life and are major causes of mortality. Reducing sugars such as glucose can react nonenzymatically with the amino groups of proteins. After further complex reactions, irreversibly cross-linked, heterogeneous derivatives termed advanced glycation end products (AGEs) are formed. AGEs accumulate in circulating blood and various tissues and are implicated in the development of diabetic vascular complications (1,2). Recent studies have shown that the system of AGEs and their receptor (RAGE) plays an important role in the development of diabetic vascular complications (3-6). The binding of AGE to RAGE is known to cause phenotypic changes in various cells such as endothelial cells, smooth muscle cells, pericytes, and renal mesangial cells, leading to the pathogenesis of diabetic retinopathy, nephropathy, and macroangiopathies (7-14).RAGE belongs to the immunoglobulin superfamily of cell surface molecules and is composed of an extracellular region containing one V-type and two C-type immunog...

OBJECTIVE -To evaluate whether low-grade inflammation contributes to early-stage advanced carotid atherosclerosis in young subjects with type 1 diabetes.RESEARCH DESIGN AND METHODS -The mean and maximum (max) intimamedia thicknesses (IMT) of the carotid artery were assessed using ultrasound B-mode imaging in 55 patients with type 1 diabetes (22 men and 33 women, aged 22.1 Ϯ 3.6 years (Ϯ SD), duration of diabetes 14.2 Ϯ 5.7 years) and 75 age-matched healthy nondiabetic subjects (28 men and 47 women). High-sensitive C-reactive protein (hs-CRP) levels were measured with a latex-enhanced immunonephelometer.RESULTS -The patients with type 1 diabetes had significantly higher hs-CRP levels (median 0.35, range 0.05-1.47 mg/l vs. median 0.14, range 0.05-1.44 mg/l; P ϭ 0.001) as well as significantly higher mean IMT and max IMT than the nondiabetic subjects (mean IMT 0.76 Ϯ 0.09 vs. 0.72 Ϯ 0.04 mm, P ϭ 0.003; max IMT 0.84 Ϯ 0.11 vs. 0.77 Ϯ 0.06 mm, P Ͻ 0.0001). Hs-CRP levels were significantly correlated with the mean and max IMT of patients with type 1 diabetes and with the max IMT of nondiabetic patients. Multivariate regression analyses for both diabetic and nondiabetic subjects as a single group showed that hs-CRP levels are independently correlated with the mean IMT and max IMT levels (P ϭ 0.002 and P ϭ 0.023, respectively) as well as with diastolic blood pressure, sex, and duration of diabetes.CONCLUSIONS -Our data indicate that hs-CRP levels are elevated in young patients with type 1 diabetes, possibly corresponding with early-stage advanced carotid atherosclerosis.

Aim/hypothesis. Metformin is a well-known oral hypoglycaemic agent and has been commonly used, in combination with sulphonylurea, to treat type 2 diabetes. However, the advantageous effect of metformin plus sulphonylurea on diabetic macroangiopathy has yet to be clarified. To evaluate whether sulphonylurea or sulphonylurea plus metformin prevent diabetic macroangiopathy, we examined the progression of carotid artery intima-media thickness (IMT) as a surrogate end point. Methods. Subjects with type 2 diabetes were divided into three groups, receiving the following treatments: (i) glibenclamide (n=59); (ii) gliclazide (n=30); and (iii) glibenclamide + metformin (n=29). Maximum IMT and average IMT (the greatest value among 6 average values of each 3 points including greatest thickness) were measured at the beginning and end of the observation period. Results. For the follow-up period of 3 years, the annual change in average IMT of the glibenclamide plus metformin group (0.003±0.048 mm) was smaller than that of the glibenclamide group (0.064±0.045 mm) and gliclazide group (0.032±0.036 mm) (p<0.0001 and p=0.043 respectively). In the gliclazide group, average IMT increased during the follow-up period, but annual change in average IMT was significantly smaller than that of the glibenclamide group (p=0.005). Glibenclamide + metformin or gliclazide also attenuated the progression of maximum IMT, compared with that of glibenclamide (0.041±0.105, 0.044±0.106, 0.114±0.131 mm/year respectively, p=0.029 and p=0.035 respectively). Multivariable regression analysis implied that administration of metformin or gliclazide significantly and independently (p<0.05) reduces the progression of average IMT, compared with glibenclamide monotherapy. Conclusions/interpretation. These data indicate that metformin or gliclazide, rather than glibenclamide, have a potent anti-atherogenic effect in type 2 diabetes.

OBJECTIVE -To evaluate the association between the C242T polymorphism of the p22 phox gene, an essential component of NAD(P)H oxidase in the vasculature, with intima-media thickness (IMT) of the carotid artery and risk factors for atherosclerosis in type 2 diabetic subjects.RESEARCH DESIGN AND METHODS -C242T polymorphism of the p22 phox gene was detected by polymerase chain reaction-restriction fragment-length polymorphism in 200 Japanese type 2 diabetic subjects and 215 nondiabetic subjects. We examined the association with this mutation and carotid atherosclerosis as well as the patients' clinical characteristics and the level of 8-hydroxy-2Јdeoxyguanosine (8-OHdG) as an index of oxidative DNA damage.RESULTS -The diabetic subjects with the TCϩTT genotypes displayed a significantly lower average IMT (1.13 Ϯ 0.31 vs. 1.31 Ϯ 0.34 mm; P ϭ 0.0099) and a not significantly lower serum 8-OHdG level than those with the CC genotype, despite no difference in the risk factors.Stepwise multiple regression analysis showed that the risk factors for increased IMT in the diabetic subjects were systolic blood pressure (P ϭ 0.0042) and p22 phox CC genotype (P ϭ 0.0151). In nondiabetic subjects, the average IMT of the TCϩTT group was not different from that of the CC group (0.85 Ϯ 0.14 vs. 0.94 Ϯ 0.30 mm, P ϭ 0.417). Fasting plasma insulin concentration (41.4 Ϯ 15.6 vs. 64.2 Ϯ 59.4 pmol/l, P ϭ 0.0098) and insulin resistance index of homeostasis model assessment (HOMA-R) (1.58 Ϯ 0.66 vs. 2.60 Ϯ 2.56, P ϭ 0.0066) were significantly lower in the TCϩTT group than in the CC group.CONCLUSIONS -These results show that the C242T mutation in the p22 phox gene is associated with progression of asymptomatic atherosclerosis in the subjects with type 2 diabetes and is also associated with insulin resistance in nondiabetic subjects. Diabetes Care 26:458 -463, 2003T he production of vascular reactive oxygen species (ROS) is increased in pathophysiological conditions such as atherosclerosis, hypertension, and diabetes (1-3).NAD(P)H oxidase is a membraneassociated enzyme that catalyzes the 1-electron reduction of oxygen using NAD(P)H as the electron donor. Several studies indicate that NAD(P)H oxidase is the most important source of ROS in intact arteries, rather than arachidonic acid-metabolizing enzymes, xanthine oxidase, or mitochondrial sources (4 -8). It has recently been shown that high glucose stimulates ROS production through the protein kinase C-dependent activation of NAD(P)H oxidase in both vascular smooth muscle cells and endothelial cells (9) and in diabetic vessels (10,11).The p22 phox, cytochrome b 558 of vascular NAD(P)H oxidase, plays an important role in the process of O 2 Ϫ production. Expression of p22 phox was markedly increased in the aorta from OLETF rats compared with that of LETO rats (12). Recently, Guzik et al. (11) showed that the p22 phox was significantly increased in human diabetic veins and arteries. This activation of p22 phox may contribute to the acceleration of atherosclerosis in patients with diabetes.The C2...

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