The usefulness of a cholesterol absorption inhibitor in Japanese type 2 diabetes patients with dyslipidemia.

AIM: Cholesterol absorption has been suggested to be an independent risk factor for cerebral and cardiovascular events. We studied the clinical efficacy of ezetimibe in Japanese patients with type 2 diabetes mellitus complicated by dyslipidemia, in whom increased cholesterol absorption had been reported. SUBJECTS AND METHODS: Ninety-six patients with type 2 diabetes complicated by dyslipidemia received ezetimibe at 10 mg/day for 12 weeks. The lipid profile, a cholesterol synthesis marker (lathosterol), and cholesterol absorption markers (cholestanol, sitosterol, and campesterol) were measured before and after the therapy to evaluate the clinical efficacy of ezetimibe. RESULTS: Serum low-density lipoprotein-cholesterol (LDL-C) levels were positively associated with cholesterol absorption markers but not associated with a cholesterol synthesis marker, suggesting that serum LDL-C levels are more strongly related to cholesterol absorption than synthesis. During the 12-week ezetimibe treatment period, cholesterol absorption markers significantly decreased, and serum lipid profiles, including LDL-C levels, significantly improved. The LDL-C-lowering rate was greater in those patients who had been receiving statin therapy and were newly started on ezetimibe additionally than in the ezetimibe monotherapy group (-31.4% vs. -18.4%; P<0.001). CONCLUSIONS: It is suggested that ezetimibe improves the lipid profile in Japanese type 2 diabetes patients with dyslipidemia through the substantial reduction of cholesterol absorption.

Vitamin D deficiency is significantly associated with retinopathy in young Japanese type 1 diabetic patients.

The aim of this study was to examine the possible association of vitamin D deficiency with diabetic retinopathy in 75 young Japanese type 1 diabetic patients. A multivariate regression analysis, duration of diabetes and vitamin D deficiency were independent determinants of diabetic retinopathy.

The risk factors associated with ultrasonic tissue characterization of carotid plaque in type 2 diabetic patients.

AIMS: Little is known about the related factors of plaque echogenicity in diabetic subjects. METHODS: This was a single-center, retrospective, study investigating a subgroup of patients of a previously published trial. We enrolled 179 middle-aged and older Japanese type 2 diabetic patients with carotid plaque, and examined the parameters related with echogenicity of carotid plaque evaluated by gray-scale median (GSM). RESULTS: Proportion of males and body mass index (BMI) were significantly higher and HDL-cholesterol was significantly lower in the patients with low GSM (< 48) plaques (n = 89) as compared to those without it (n = 90). A multiple logistic regression analysis with gender, BMI, and HDL-cholesterol as independent variables and the presence of low GSM plaques as an objective variable showed that male (odds ratio (OR) 2.36, 95%CI 1.05-5.31, p = 0.037) and BMI (OR 1.12 [1.01-1.24], p = 0.029) were independently associated with low GSM plaques. Another multiple logistic regression analysis with gender, BMI, and low-HDL-cholesterolemia (HDL-C < 40 mg/dl) as independent variables showed that low-HDL-cholesterolemia (OR 2.30 [1.03-5.13], p = 0.042) and BMI (OR 1.11 [1.00-1.22], p = 0.046) were independently associated with low GSM plaques. CONCLUSIONS: Our study suggests that gender, BMI and low-HDL-cholesterol are important determinants of the content of the vascular wall in diabetic subjects.

The utility of ultrasonic tissue characterization of carotid plaque in the prediction of cardiovascular events in diabetic patients.

OBJECTIVE: The aim of this study was to evaluate whether non-invasive ultrasonic tissue characterization of carotid plaque using gray-scale median (GSM) can be a predictor of future cardiovascular disease (CVD) events in type 2 diabetic patients. METHODS: A total of 287 type 2 diabetic patients with carotid plaque but without CVD were enrolled (male 72%, mean age 65 ± 7 years). We prospectively evaluated the association between GSM, a quantitative parameter of the plaque echogenicity, and CVD. RESULTS: The median follow-up period was 55 months, and there were 34 new CVD events. The risk of CVD event was significantly higher in the patients with echolucent (GSM ≤ 37) plaque (n = 67) as compared to those without (n = 220) (HR = 6.99, 95% CI 3.46-14.14, p < 0.001). Cox proportional hazards regression analysis showed that the presence of echolucent plaque (HR = 4.55, 95% CI 2.10-19.84, p < 0.001) as well as plaque thickness (HR = 1.44, 95% CI 1.01-2.06, p = 0.005) were independent predictors of CVD, even after adjustment for other risk factors. Time-dependent receiver-operating-characteristic curve analysis revealed that the addition of plaque thickness to Framingham risk score (FRS) resulted in significant increase in area under the curve (AUC) [from 0.60 (95% CI; 0.49-0.70) to 0.73 (95% CI; 0.63-0.82), p < 0.05]. Notably, the addition of plaque echogenicity (presence/absence of echolucent plaque) to the FRS and plaque thickness resulted in further and significant increase in AUC [from 0.73 (95% CI; 0.63-0.82) to 0.82 (95% CI; 0.75-0.88), p < 0.05]. CONCLUSION: Ultrasonic tissue characterization of carotid plaque using the GSM can improve the risk prediction of cardiovascular event in asymptomatic type 2 diabetic patients with carotid plaque.

The utility of carotid ultrasonography in identifying severe coronary artery disease in asymptomatic type 2 diabetic patients without history of coronary artery disease.

OBJECTIVE: Although many studies have shown that carotid intima-media thickness (IMT) is associated with coronary artery disease (CAD), it remains inconclusive whether assessment of carotid IMT is useful as a screening test for asymptomatic but severe CAD in diabetic patients. RESEARCH DESIGN AND METHODS: A total of 333 asymptomatic type 2 diabetic patients without history of CAD underwent exercise electrocardiogram or myocardial perfusion scintigraphy for detection of silent myocardial ischemia, and those whose test results were positive were subjected to coronary computed tomography angiography or coronary angiography. The ability of carotid IMT to identify severe CAD corresponding to treatment with revascularization was examined by receiver-operating characteristic (ROC) curve analyses. RESULTS: Among the 333 subjects, 17 were treated with revascularization. A multiple logistic regression analysis showed that maximum IMT was an independent predictor of severe CAD even after adjustment for conventional risk factors. ROC curve analyses revealed that the addition of maximum IMT to conventional risk factors significantly improved the prediction ability for severe CAD (from area under the curve, 0.67 to 0.79; P = 0.039). The greatest sensitivity and specificity were obtained when the cut-off value of maximum IMT was set at 2.45 mm (pretest probability, 5%; posttest probability, 11%; sensitivity, 71%). When we applied age-specific cut-off values, the sensitivity of screening further increased in both the nonelderly (pretest probability, 6%; posttest probability, 10%; sensitivity, 100%) and the elderly subjects (pretest probability, 5%; posttest probability, 15%; sensitivity, 100%). CONCLUSIONS: Our study suggests that carotid maximum IMT is useful for screening asymptomatic type 2 diabetic patients with severe CAD equivalent to revascularization.

Plasma pentraxin 3 levels are associated with carotid IMT in type 1 diabetic patients.

AIMS: Pentraxin3 (PTX3), a recently discovered inflammatory mediator, is produced abundantly in various cells in atherosclerotic lesions, and therefore, its plasma level could reflect local inflammation at the site of atherosclerotic lesion. The present study evaluated whether plasma PTX3 levels are associated with subclinical atherosclerosis in young subjects with type 1 diabetes. METHODS: Plasma PTX3 levels, urinary albumin excretion, diabetic retinopathy, and carotid intima-media thickness (IMT) were examined in 78 Japanese type 1 diabetic patients (30 men and 48 women, aged 28.5 ± 5.3 years (±SD), duration of diabetes 19.7 ± 6.5 years). RESULTS: There was statistically significant association between plasma PTX3 levels and Max-IMT (r=0.363, p=0.001). A stepwise multivariate regression analysis including conventional coronary risk factors as independent variables revealed that plasma PTX3 levels (ß=0.389, p<0.001), duration of diabetes (ß=0.256, p=0.035), and serum triglyceride levels (ß=0.371, p<0.001) were independent determinants of Max-IMT. In addition, plasma PTX3 levels was an independent determinant of urinary albumin excretion, an indicator of diabetic nephropathy (ß=0.258, p=0.018). However, there was no significant association between plasma PTX3 levels and diabetic retinopathy. CONCLUSIONS: Increased levels of plasma PTX3 are associated with accelerated atherosclerotic change and increased albuminuria in young patients with type 1 diabetes.

Ultrasonic tissue characterization of carotid plaque improves the prediction of cardiovascular events in diabetic patients: a pilot study.

OBJECTIVE: The aim of this study is to evaluate whether noninvasive ultrasonic tissue characterization of carotid plaque using integrated backscatter (IBS) analysis can be a predictor of future cardiovascular events (CVE) in asymptomatic type 2 diabetic patients. RESEARCH DESIGN AND METHODS: We prospectively evaluated the association between Calibrated-IBS value, an ultrasonic marker for tissue characteristics of carotid plaque, and CVE in 85 asymptomatic type 2 diabetic patients with carotid plaque. RESULTS: The median follow-up period was 7.9 years, and there were 20 new CVE. The risk of CVE was significantly higher in the subjects with low Calibrated-IBS values (<-17.1 dB; n = 42) as compared with those with high values (≥-17.1 dB; n = 43) (P = 0.004, log-rank test). Cox proportional hazards regression analysis revealed that both Calibrated-IBS value (hazard ratio [HR] 0.802 [95% CI 0.710-0.906]; P < 0.0001) and plaque thickness (1.938 [1.170-3.213]; P = 0.010) were independently associated with CVE, even after adjustment for the 10-year risk for a general cardiovascular disease estimated by Framingham risk scoring (FRS). Time-dependent receiver operating characteristic curve analysis for CVE at 10 years after the baseline examinations revealed that area under the curve for Calibrated-IBS was 0.76 (0.60-0.90) and substantially higher than those for plaque thickness (0.60 [0.45-0.79]) and FRS (0.60 [0.40-0.78]). These analyses also revealed that the addition of both plaque thickness and Calibrated-IBS value to conventional risk factors significantly improved the event prediction. CONCLUSIONS: Calibrated-IBS value could improve the risk prediction of CVE in asymptomatic type 2 diabetic patients with carotid plaque.

Maximum carotid intima-media thickness improves the prediction ability of coronary artery stenosis in type 2 diabetic patients without history of coronary artery disease.

OBJECTIVE: Carotid intima-media thickness (CIMT), a marker of early atherosclerosis and vascular remodelling, is one of the independent predictors of coronary artery disease (CAD). However, it is unknown whether ultrasonic assessment of carotid atherosclerosis, including CIMT, improves the prediction ability for CAD over and above conventional coronary risk factors in the diabetic patients. METHODS: Ultrasonic scanning of the common carotid artery (CCA), the carotid bulb (Bul), and the internal carotid artery (ICA) was performed. The site with the greatest IMT, including plaque lesions, was sought along the arterial walls and max-IMT (the greatest IMT in the observation-possible areas of the CCA, Bul and ICA) was measured. The association of max-IMT with coronary artery stenosis assessed by coronary computed tomography angiography and the incremental effect of adding max-IMT to the conventional risk factors for predicting coronary artery stenosis were evaluated in 241 asymptomatic type 2 diabetic patients. RESULTS: Multiple logistic regression analyses showed that max-IMT was significantly associated with coronary artery stenosis even after adjustment for conventional risk factors. ROC curve analysis revealed that the AUC significantly increased after addition of max-IMT to conventional coronary risk factors [from 0.64 (95% CI; 0.57-0.71) to 0.74 (95% CI; 0.67-0.80), p = 0.020]. The addition of max-IMT to conventional coronary risk factors increased the AUC in obese patients (from 0.58 to 0.76, p = 0.012) but not in non-obese patients (from 0.68 to 0.72, NS). CONCLUSIONS: In type 2 diabetic patients without apparent cardiovascular disease, the addition of max-IMT to conventional risk factors substantially improves the risk stratification for CAD.

Serum endogenous secretory RAGE level is an independent risk factor for the progression of carotid atherosclerosis in type 1 diabetes.

OBJECTIVE: Advanced glycation end-products (AGEs) and the receptor for AGEs (RAGE) system plays an important role in the development of atherosclerosis. It has been recently reported that endogenous secretory RAGE (esRAGE) and total soluble RAGE (sRAGE) levels are associated with diabetic complications. The aim of the present study is to longitudinally evaluate the association between esRAGE and sRAGE levels and the progression of carotid intima-media thickness (IMT), a surrogate marker of atherosclerosis. METHODS AND RESULTS: Japanese type 1 diabetic patients (n=47, aged 24.0+/-3.1 years) were enrolled into a 4-year follow-up study and annual measurements of serum esRAGE and sRAGE levels and IMTs were performed. At baseline, mean-IMT was inversely correlated with circulating esRAGE levels (r=-0.317, p=0.0292), whereas there was not statistical significance between mean-IMT and sRAGE levels. Mean-IMT significantly increased during the follow-up period (from 0.63+/-0.10 to 0.67+/-0.10mm, p=0.0022). Annual increase in mean-IMT (=(mean-IMT after 4 years-mean-IMT at baseline)/4) was positively correlated with the arithmetic average of systolic blood pressure (r=0.310, p=0.0332) and triglyceride (r=0.337, p=0.0201), and inversely correlated with circulating esRAGE levels (r=-0.360, p=0.0124) and sRAGE levels (r=-0.406, p=0.0042) during the follow-up period. Furthermore, stepwise multivariate regression analyses revealed that continuous low levels of circulating esRAGE and sRAGE were determinants of the progression of mean-IMT independently of conventional risk factors. CONCLUSIONS: Circulating esRAGE level as well as sRAGE level was an independent risk factor for the progression of carotid IMT in type 1 diabetic subjects.

Endogenous secretory RAGE but not soluble RAGE is associated with carotid atherosclerosis in type 1 diabetes patients.

Advanced glycation end-products (AGEs) and the receptor for AGEs (RAGE) system play an important role in the development of diabetic complications. The soluble form of RAGE (sRAGE) that potentially counteracts AGEs consists of several forms, including endogenous secretory RAGE (esRAGE; a splice variant of RAGE) and cleaved-type soluble RAGE derived from cell-surface RAGE. The aim of this study was to compare sRAGE and esRAGE directly in patients with type 1 diabetes. The associations of both total sRAGE and esRAGE with markers of glycaemic control and with carotid intima-media thickness (IMT) as a marker of atherosclerosis were examined in 130 type 1 diabetes patients (aged 23.6+/-4.9 years) and 22 age-matched non-diabetic subjects. IMT was inversely correlated with esRAGE (r=-0.254, p=0.0015) but neither with sRAGE nor subtracted soluble RAGE values (that is, circulating total sRAGE values - circulating esRAGE values). Furthermore, a stepwise multivariate regression analysis revealed that esRAGE (F=7.3), but not sRAGE, was a variable that interacted independently of IMT. It is likely that circulating sRAGE and esRAGE are distinct markers and that circulating esRAGE levels, but not sRAGE levels, are associated with the status of early-stage atherosclerosis.

The impact of new-onset diabetes on arterial stiffness after renal transplantation.

New-onset diabetes after renal transplantation (NODAT) is known to be a potent risk factor for cardiovascular events. We therefore investigated the incidence and risk factors for NODAT, and evaluated surrogate endpoints of atherosclerosis in Japanese patients with stable renal function after renal transplantation. Seventy-nine patients were enrolled in the study, and a 75 g oral glucose tolerance test (OGTT) was performed in subjects excluding patients with known NODAT. We evaluated the risk factors for NODAT and the degree of atherosclerosis, determined by brachial-ankle pulse wave velocity (baPWV), ankle-brachial blood pressure index (ABPI) and intima-media thickness (IMT) of the carotid artery. Eleven patients diagnosed as NODAT had significantly higher fasting plasma glucose before transplantation, blood pressure, and incidence of hepatitis C virus (HCV) infection than patients without NODAT. Multivariate regression analysis revealed that the independent determinant of NODAT was fasting plasma glucose pre-transplantation, HCV infection and systolic blood pressure. The baPWV in patients with NODAT was significantly higher compared to that in patients without NODAT. In addition, the independent determinant of baPWV evaluated by multivariate regression analysis was an increase in systolic blood pressure and age, and a decrease of adiponectin levels. In conclusion, we found that high fasting plasma glucose prior to transplantation, HCV infection and high blood pressure are risk factors for NODAT in Japanese patients after renal transplantation. Since NODAT patients have advanced arterial stiffness probably due to high blood pressure, strict control of blood pressure will be important for preventing the development of cardiovascular disease in NODAT.

Oxidative stress and the JNK pathway are involved in the development of type 1 and type 2 diabetes.

Failure of pancreatic beta-cells is the common characteristic of type 1 and type 2 diabetes. Type 1 diabetes mellitus is induced by destruction of pancreatic beta-cells which is mediated by an autoimmune mechanism and consequent inflammatory process. Various inflammatory cytokines and oxidative stress are produced during this process, which has been proposed to play an important role in mediating beta-cell destruction. The JNK pathway is also activated by such cytokines and oxidative stress, and is involved in beta-cell destruction. Type 2 diabetes is the most prevalent and serious metabolic disease, and beta-cell dysfunction and insulin resistance are the hallmark of type 2 diabetes. Under diabetic conditions, chronic hyperglycemia gradually deteriorates beta-cell function and aggravates insulin resistance. This process is called "glucose toxicity". Under such conditions, oxidative stress is provoked and the JNK pathway is activated, which is likely involved in pancreatic beta-cells dysfunction and insulin resistance. In addition, oxidative stress and activation of the JNK pathway are also involved in the progression of atherosclerosis which is often observed under diabetic conditions. Taken together, it is likely that oxidative stress and subsequent activation of the JNK pathway are involved in the pathogenesis of type 1 and type 2 diabetes.

Involvement of oxidative stress in the pathogenesis of diabetes.

Pancreatic beta-cell failure is the common characteristic of type 1 and type 2 diabetes. Type 1 diabetes is induced by pancreatic beta-cell destruction, which is mediated by an autoimmune mechanism and consequent inflammatory process. Various inflammatory cytokines and oxidative stress produced by islet-infiltrating immune cells have been proposed to play an important role in mediating the destruction of beta cells. The JNK pathway is also activated by such cytokines and oxidative stress and is involved in beta-cell destruction. Type 2 diabetes is the most prevalent and serious metabolic disease affecting people all over the world. Pancreatic beta-cell dysfunction and insulin resistance are the hallmark of type 2 diabetes. Once hyperglycemia becomes apparent, beta-cell function gradually deteriorates, and insulin resistance is aggravated. This process is called "glucose toxicity." Under such conditions, oxidative stress is provoked, and the JNK pathway is activated, which is likely involved in pancreatic beta-cell dysfunction and insulin resistance. In addition, oxidative stress and activation of the JNK pathway are involved in the progression of atherosclerosis, which is often observed under diabetic conditions. Taken together, it is likely that oxidative stress and subsequent activation of the JNK pathway are involved in the pathogenesis of type 1 and type 2 diabetes.

Combination of multiple genetic risk factors is synergistically associated with carotid atherosclerosis in Japanese subjects with type 2 diabetes.

OBJECTIVE: Several genetic risk factors, such as single nucleotide polymorphisms (SNPs), in candidate genes have been reported to be responsible for intima-media thickness (IMT), which is one of the surrogate end points of cardiovascular events. However, the synergistic effects of SNPs have not been evaluated in detail. RESEARCH DESIGN AND METHODS: We measured the average IMT of the common and internal carotid artery in Japanese type 2 diabetic patients (n = 690) (>50 years old) using ultrasonography. We also determined their genotypes regarding 106 SNPs in candidate genes responsible for cardiovascular diseases. Among the 106 SNPs, we selected 40 common (frequency of minor allele >/=10%) SNPs. We compared the average IMT of subjects with and without any pairs of four genotypes selected from the 40 common SNPs. RESULTS: The combination of methylen-tetrahydrofolate reductase 677 TT genotype and lymphotoxin-alpha (LTA) 252 GG genotype and that of ACE DD genotype and LTA 252 GG genotype were evaluated as responsible for a statistically significant (P = 2.7 x 10(-9) and 3.5 x 10(-6), respectively) increase in average IMT (mean [+/-SD] 1.54 +/- 0.60 and 1.43 +/- 0.58 mm, respectively) compared with those of the subjects without these combinations (1.04 +/- 0.34 and 1.04 +/- 0.34 mm, respectively). No single genotype was shown to be responsible for the statistically significant difference in average IMT after Bonferroni's multiple comparison procedure. CONCLUSIONS: The present analysis demonstrates an approach to evaluate combinations of multiple genetic risk factors that are synergistically associated with carotid atherosclerosis.

Decreased endogenous secretory advanced glycation end product receptor in type 1 diabetic patients: its possible association with diabetic vascular complications.

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 +/- 4.4 years [means +/- SD]) and 23 age-matched healthy nondiabetic subjects (10 men and 13 women aged 24.9 +/- 1.4 years). Daily urinary albumin excretion, the presence of retinopathy, and intima-media 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 +/- 0.089 vs. 0.436 +/- 0.121 ng/ml, respectively, P < 0.0001) and was inversely correlated with HbA(1c) (A1C) levels (r = -0.614, P < 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 = -0.325, P = 0.0017) and was one of the independent risk factors for IMT thickening. Furthermore, there was a significant difference (P = 0.0124) in esRAGE levels between patients without retinopathy (0.286 +/- 0.092 ng/ml) and those with retinopathy (0.230 +/- 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.