Effect of adiponectin on carotid arterial stiffness in type 2 diabetic patients treated with pioglitazone and metformin.

Adiponectin, an adipocyte-specific plasma protein, has been reported to exhibit protective effects against atherosclerosis as well as an insulin-sensitizing effect. This study was designed to investigate the effect of adiponectin on carotid arterial stiffness in type 2 diabetic patients treated with pioglitazone and metformin. Twenty type 2 diabetic patients were enrolled and divided into 2 groups, a pioglitazone-treated group (n = 10) and a metformin-treated group (n = 10). Before and after intervention, plasma adiponectin levels were measured by enzyme-linked immunosorbent assay and carotid arterial stiffness was evaluated by the stiffness parameter beta, measured by ultrasound equipped with a phase-locked echo-tracking system. In the pioglitazone group, plasma adiponectin level significantly increased and stiffness parameter beta significantly decreased, whereas in the metformin group neither of these parameters changed significantly. The changes in stiffness parameter beta were significantly and inversely correlated with change in plasma adiponectin level after treatment with pioglitazone or metformin in the group of all subjects (r = -0.472, P = .036). In conclusion, the present study is the first to demonstrate that increase in adiponectin level after treatment with the insulin sensitizers pioglitazone and metformin may improve arterial stiffness in patients with type 2 diabetes mellitus.

The association of plasma adiponectin level with carotid arterial stiffness.

Adiponectin plays important roles in protecting against both insulin resistance and the development of atherosclerosis. The aim of the present study was to investigate the clinical impact of plasma adiponectin on arterial stiffness, a functional property of atherosclerosis, in type 2 diabetic and nondiabetic subjects. We evaluated plasma adiponectin levels and stiffness index beta for the common carotid artery assessed by ultrasound using a phase-locked echo-tracking system for 98 type 2 diabetic subjects and 116 nondiabetic subjects as controls. Plasma adiponectin levels were significantly lower in the diabetic than in the nondiabetic group. The stiffness index beta was significantly higher in the diabetic than in the nondiabetic group. Plasma adiponectin level was significantly correlated with stiffness index beta in the group of all subjects (r=-0.189, P=.006) and the nondiabetic group (r=-0.187, P=.045), but not in the diabetic group (r=0.045, P=.665). On multiple regression analysis, plasma adiponectin level was found to be a significant independent contributor to stiffness index beta in the group of all subjects (beta=-0.232, P=.020) and the nondiabetic group (beta=-0.337, P=.016), but not in the diabetic group. In conclusion, adiponectin is significantly but weakly associated with carotid arterial stiffness independently of known atherogenic factors in the nondiabetic group and that of all subjects, although no significant association between these variables was found in the group of diabetic subjects.

Regional arterial stiffness associated with ischemic heart disease in type 2 diabetes mellitus.

Arterial stiffness is increased in type 2 diabetes mellitus, and diabetes preferentially affects arterial stiffness of the central (elastic, capacitive) over peripheral (muscular, conduit) arteries. We hypothesized that arterial stiffness of the central artery may be more closely associated with ischemic heart disease (IHD) than stiffness of peripheral arteries in type 2 diabetes mellitus. The subjects were 595 type 2 diabetes patients including 70 with IHD. Arterial stiffness was measured as pulse wave velocity (PWV) in the heart-carotid, heart-femoral, heart-brachial, and femoral-ankle regions. The PWV values of the four segments correlated with each other in patients without IHD. However, the correlations were less impressive in those with IHD, suggesting unequal stiffening of regional arteries in IHD. As compared with patients without IHD, the IHD group showed significantly higher PWV values of the four arterial segments, particularly of the heart-femoral region. The presence of IHD was significantly associated with higher heart-femoral PWV, and this association remained significant and independent of other factors in a multiple logistic regression analysis. Pulse pressure was more strongly correlated with PWV of the heart-femoral than other arterial regions. Thus, diabetic patients with IHD have increased stiffness of arteries, particularly of the aorta, supporting the concept that central arterial stiffness plays an important role in the development of IHD.

Altered relationship between body fat and plasma adiponectin in end-stage renal disease.

Patients with end-stage renal disease (ESRD) show an inverse association between body mass index and risk of death from cardiovascular disease. Paradoxical epidemiology may suggest some beneficial effects of body fat in ESRD. Because an antiatherogenic adipocytokine adiponectin is increased in uremic plasma, we tested a hypothesis that, in ESRD, plasma adipocytokine profile may be less atherogenic or that the relationship between body fat and adipocytokines may be altered. The subjects were 103 patients with ESRD undergoing hemodialysis and 166 healthy subjects comparable in age and sex. We measured body fat mass by dual-energy x-ray absorptiometry and plasma levels of adiponectin and leptin by enzyme-linked immunosorbent assay. The ESRD group showed a significant increase in plasma adiponectin, leptin, and adiponectin/leptin ratio than the healthy subjects. Although sex and fat mass were significant factors correlating with plasma adiponectin level in the healthy group, none of these were significantly associated with plasma adiponectin in the patients with ESRD. In contrast, leptin showed significant relationships with sex and fat mass regardless of the presence of ESRD. Plasma adiponectin correlated negatively with plasma triglycerides and positively with high-density lipoprotein cholesterol in both healthy and ESRD groups, suggesting that uremic adiponectin retains its actions in favor of its antiatherogenicity. Thus, plasma adipocytokine profile was altered in ESRD, and the effects of body fat and sex on adiponectin were less significant in the patients with ESRD.

The K469E polymorphism of the intercellular adhesion molecule-1 gene is associated with plasma fibrinogen level in type 2 diabetes.

Intercellular adhesion molecule-1 (ICAM-1) is involved in inflammation and development of atherosclerotic change of vascular endothelium. The aim of the present study is to investigate whether K469E polymorphism of the ICAM-1 gene is associated with various clinical factors including plasma fibrinogen in patients with type 2 diabetes. ICAM-1 gene polymorphism was examined using polymerase chain reaction and restriction enzyme analysis in 360 type 2 diabetic patients. Plasma fibrinogen levels and other clinical variables were measured as well as circulating soluble ICAM-1 (sICAM-1) levels by enzyme-linked immunosorbent assay. The distribution of ICAM-1 genotypes, EE, EK, and KK, was not significantly different between type 2 diabetes and 152 healthy control subjects. Among 3 groups according to ICAM-1 genotypes in type 2 diabetes, no difference was found in adiposity, glycemic control, lipid profile, insulin sensitivity evaluated by homeostasis model assessment, or sICAM-1. Regarding fibrinogen, the patients with E allele showed significantly lower plasma fibrinogen levels in a dose-dependent manner (P = .033). Spearman rank correlation analyses revealed that ICAM-1 genotype showed significant correlation with plasma fibrinogen level (P < .001). In multiple regression analysis, ICAM-1 genotype was independent contribution factor of plasma fibrinogen level as well as high-density lipoprotein-cholesterol and urinary albumin excretion (R2 = 0.148, P < .001). In conclusion, K469E polymorphism of the ICAM-1 gene had impact on plasma fibrinogen level independently of other clinical factors in 360 type 2 diabetic patients, suggesting that fibrinogen is a candidate which links the ICAM-1 gene polymorphism to atherosclerosis.

Effect of atorvastatin on regional arterial stiffness in patients with type 2 diabetes mellitus.

OBJECTIVE: A statin, a potent lipid-lowering drug, improves pain-free walking distance in patients with peripheral arterial disease (PAD) without increasing the ankle-brachial pressure index (ABI). Arterial stiffness affects the blood flow of peripheral arteries. The purpose of this study was to evaluate the effect of cholesterol-lowering with atorvastatin on regional arterial stiffness in patients with type 2 diabetes mellitus. METHODS: The subjects were 22 type 2 diabetic patients with hypercholesterolemia, who received atorvastatin at a daily dose of 10 mg for 6 months. Before and after the treatment with atorvastatin, we measured pulse wave velocity (PWV) in the heart-brachial, heart-carotid, heart-femoral and femoral-ankle segments. RESULTS: Following treatment with atorvastatin, femoral-ankle PWV showed a significant reduction. The PWV of other arterial segments tended to decrease, although the changes were not statistically significant. We found no significant changes in blood pressure, heart rate, ABI, or plasma concentrations of glucose, L-arginine and asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial function. CONCLUSIONS: Atorvastatin treatment was associated with an improvement in the stiffness of leg arteries in type 2 diabetes mellitus. This may partly explain the statin-mediated improvement of walking performance in those with PAD.

Does cerebral small vessel disease predict future decline of cognitive function in elderly people with type 2 diabetes?

AIMS: We conducted a 3-year longitudinal study concerning an association between cognitive function and cerebral small vessel disease (SVD) seen on magnetic resonance imaging (MRI) in elderly type 2 diabetic patients. METHODS: Four cognitive function tests--MMSE, word recall, Digit Symbol Substitution (DSS), and Stroop Color Word (Stroop)--were performed in 67 diabetic patients twice in 2006 and 2009. SVD was diagnosed as silent brain infarct (SBI) and white matter lesions (WMLs) according to MRI. RESULTS: Number of SBI was significantly correlated with a decline in DSS and Stroop tests, while WMLs grade was only associated with it in DSS tests after adjustment for age, gender, education years, the presence of hypertension and dyslipidemia, and smoking. Severity of SVD at baseline was stronger associated with cognitive function after the 3-year follow-up than at baseline. WMLs progression was associated with more rapid decline of DSS tests compared to a group without progression. CONCLUSIONS: SVD seen on MRI is a good marker for predicting future cognitive decline, and monitoring of treatment through the use of such markers is expected to maintain a good quality of life for elderly diabetic patients.

Central versus peripheral arterial stiffness in association with coronary, cerebral and peripheral arterial disease.

BACKGROUND: Although stiffness of central arteries is more preferentially associated with coronary artery disease (CAD) than that of peripheral arteries, less is known for cerebrovascular disease (CVD) and peripheral artery disease (PAD). We measured pulse wave velocity (PWV) in four arterial segments, and examined the relative changes in the four regional PWVs in patients with CAD, CVD or PAD. METHODS: The 2798 subjects were selected from 3300 consecutive participants of our non-invasive vascular lab. 342 subjects had one or more pre-existing atherosclerotic diseases including 128 CAD (N=128), CVD (N=195) and PAD (N=83). PWVs were simultaneously measured using an automated pulse wave analyzer (model BP-203RPE, Colin) in the heart-femoral (hf, aorta), heart-carotid (hc), heart-brachial (hb), and femoral-ankle (fa) segments. RESULTS: As compared to the subjects without atheroscletoric disease, those with CAD, CVD, or PAD showed higher levels of PWV in the four arterial segments, particularly in hfPWV. The relative increase in hfPWV remained significant after adjustment for age, sex, hypertension, pulse rate, smoking, diabetes mellistus, dyslipidemia, and chronic kidney disease. CONCLUSION: This study indicates that the preferential increase in central arterial stiffness is found not only in CAD but CVD and PAD as well.

Brachial-ankle pulse wave velocity as an index of central arterial stiffness.

AIM: Stiffness of the central arteries plays an important role in the pathophysiology of cardiovascular disease, and pulse wave velocity (PWV) of the aorta has been used as the standard measure of central arterial stiffness. An automated device for brachial-ankle (ba) PWV is available, although information is limited whether baPWV reflects the stiffness of central or peripheral arteries. We therefore addressed this question in the present study. METHODS: The subjects were 2,806 consecutive participants in our non-invasive vascular laboratory, excluding those with an ankle-brachial index (ABI) lower than 0.95. PWV measurements were simultaneously performed using an automated device for the ba, heart-femoral (hf, aorta), heart-carotid (hc), heart-brachial (hb), and femoral-ankle (fa) segments. Correlational analyses were performed (1) among these PWV values, (2) between PWV and individual risk factors, and (3) between PWV and the Framingham risk score (FRS), a surrogate index for integrated cardiovascular risk. RESULTS: The correlation of baPWV was the highest with hfPWV (r=0.796) and the lowest with hcPWV (r=0.541). Among the known factors preferentially affecting central arterial stiffness, higher age, diabetes mellitus, and chronic kidney disease (CKD) were also closely associated with increased baPWV. Finally, FRS was more closely correlated with hfPWV (r=0.613) and baPWV (r=0.609) than with hbPWV (r=0.523), hcPWV (r=0.509), and faPWV (r=0.393). CONCLUSION: These results indicate that baPWV is an index of arterial stiffness showing similar characteristics to those of aortic PWV.

Small dense low-density lipoprotein cholesterol concentration and carotid atherosclerosis.

Low-density lipoprotein cholesterol (LDL-C) and the small dense LDL (SdLDL) phenotype are both predictors for ischemic heart disease. We examined whether cholesterol of SdLDL (SdLDL-C) is more closely associated with carotid artery intima-media thickness (CA-IMT), a surrogate measure of atherosclerosis, than LDL-C and other lipid parameters. The subjects were 326 consecutive participants including those with dyslipidemia, diabetes mellitus, hypertension, chronic kidney disease, and smokers. SdLDL-C was quantified by a newly developed precipitation method, and CA-IMT by high-resolution B-mode ultrasound. In univariate analysis, CA-IMT was most strongly correlated with SdLDL-C (Spearman's r=0.441, P<0.001), followed by apolipoprotein (apo) B, LDL-C, non-high-density lipoprotein cholesterol (Non-HDL-C), and plasma triglycerides (TG). HDL-C and apo A-I correlated inversely with CA-IMT. Non-lipid variables that were associated with CA-IMT were age, sex, presence of diabetes mellitus, presence of hypertension, estimate glomerular filtration rate (eGFR), and C-reactive protein (CRP). Even after adjustment for age, sex, diabetes mellitus, hypertension, smoking, eGFR and CRP, the positive association of CA-IMT with SdLDL-C remained significant, and again stronger than the associations with others lipid parameters. Further analyses revealed that the level of SdLDL-C was elevated in subgroups of the subjects including men, older subjects, smokers, those with higher CRP levels, those with diabetes mellitus, and hypertensive patients. These results indicate that SdLDL-C was the best marker of carotid atherosclerosis among the lipid parameters tested, and suggest that quantitative measurement of SdLDL-C gives useful information in the risk assessment for atherosclerotic disease.

Plasma angiopoietin-like protein 3 (ANGPTL3) concentration is associated with uremic dyslipidemia.

OBJECTIVE: Angiopoietin-like protein 3, a liver-derived plasma protein, increases plasma triglycerides (TG) in mice by suppressing the activity of lipoprotein lipase, a key enzyme in plasma TG clearance. Uremic dyslipidemia is characterized by increased TG-rich lipoproteins such as very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL), lowered high-density lipoprotein (HDL), and TG-enrichment of low-density lipoprotein (LDL) and HDL. Since the role of angiopoietin-like protein 3 (ANGPTL3) in uremic dyslipidemia is unknown, we examined its possible association with the lipoprotein abnormalities in patients with chronic renal failure (CRF). METHODS: The subjects were 202 hemodialysis patients, 44 predialysis patients with CRF and 148 healthy control subjects comparable in age and sex. Fasting plasma ANGPTL3 was measured by enzyme-linked immunoassay, and lipoproteins were fractioned by ultracentrifugation. RESULTS: Median (25th-75th percentile range) ANGPTL3 levels were 523 (409-645) and 393 (308-511)ng/mL in hemodialysis and predialysis patients, respectively, which were significantly lower than the control level of 700 (570-875)ng/mL. In the total subjects, ANGPTL3 was inversely correlated with VLDL- and IDL-cholesterol levels, and positively with HDL-cholesterol. ANGPTL3 correlated inversely with TG/cholesterol ratios of both LDL and HDL. In multiple regression models, these associations, excluding TG/cholesterol ratio of LDL, remained significant and independent of possible confounders including age, sex, body mass index, insulin resistance index (HOMA-IR), and adiponectin, whereas the associations of ANGPTL3 with the lipoprotein parameters were less significant when apoC-II/C-III ratio was included in the models. CONCLUSION: The reduced ANGPTL3 level in hemodialysis patients was consistently associated with the major components of uremic dyslipidemia. ANGPTL3 may be a novel factor contributing to uremic dyslipidemia.

Association between plasma angiopoietin-like protein 3 and arterial wall thickness in healthy subjects.

BACKGROUND: Angiopoietin-like protein 3 (ANGPTL3) is a liver-derived plasma protein that modulates plasma triglyceride clearance, angiogenesis and atherosclerosis in experimental models. So far, no study has examined its role in atherosclerosis in human subjects. We evaluated the possible association between plasma ANGPTL3 level and carotid artery intima-media thickness (CA-IMT) and femoral artery intima-media thickness (FA-IMT) in healthy human subjects. METHODS: The subjects were 381 healthy volunteers. Plasma ANGPTL3 was determined by a specific ELISA. CA-IMT and FA-IMT were measured by high-resolution B-mode ultrasonography. RESULTS: The plasma ANGPTL3 level was 764 +/- 291 ng/ml (mean +/- SD). CA-IMT showed a significant positive correlation with plasma ANGPTL3 and other classical risk factors such as age, blood pressure, and plasma glucose and lipid levels. The positive association between ANGPTL3 and CA-IMT remained significant after adjustment for age, sex, smoking, body mass index, systolic blood pressure, plasma glucose, insulin resistance index, triglyceride, and high-density and low-density lipoprotein cholesterol levels. ANGPTL3 also showed a positive association with FA-IMT independent of these factors. CONCLUSIONS: These results demonstrate for the first time that ANGPTL3 is closely associated with arterial wall thickness in human subjects.

Regional arterial stiffness in patients with type 2 diabetes and chronic kidney disease.

Increased arterial stiffness is an independent predictor of death from cardiovascular disease, and aortic stiffness is more predictive than stiffness of other arterial regions. Because little is known about the effect of chronic kidney disease (CKD) on regional arterial stiffness, pulse wave velocity (PWV) of four different arterial segments was measured in patients who had type 2 diabetes with and without various stages of CKD. A total of 434 patients had type 2 diabetes, and there were 192 healthy control subjects who were comparable in age and gender. GFR was estimated by the abbreviated Modification of Diet in Renal Disease equation. The patients with diabetes were classified into CKD stages by the definition of the Kidney Disease Outcomes Quality Initiative guidelines. PWV was measured in the heart-femoral, heart-carotid, heart-brachial, and femoral-ankle segments simultaneously using an automatic pulse wave analyzer. PWV of each arterial region was increased in patients who had diabetes without kidney damage and was increased further in a stepwise manner with the advanced stages of CKD. The increase in PWV was greater in the heart-femoral and heart-carotid regions than in the heart-brachial and femoral-ankle segments. However, after adjustment for age, BP, and other confounding factors using a multiple regression model, decreased GFR was independently associated with increased PWV of the heart-femoral region but not with PWV of other arterial segments. In type 2 diabetes, CKD was associated with increased stiffness of arteries, particularly of the aorta. The cross-sectional result may explain the increased risk for cardiovascular disease in CKD, although longitudinal studies are needed to confirm it.