Clinical impact of the leptin to soluble leptin receptor ratio on subclinical carotid atherosclerosis in patients with type 2 diabetes.

AIM: The adipocyte-derived hormone leptin plays a key role in the regulation of food intake and energy expenditure. Recent studies have suggested that leptin is also involved in the pathogenesis of obesity-associated atherosclerosis and cardiovascular disease. In this study, we investigated the associations of leptin and the soluble leptin receptor (sOb-R) with atherosclerosis in patients with type 2 diabetes. METHODS: Three hundred seventeen type 2 diabetic subjects were enrolled in this cross-sectional study. Fasting plasma leptin and sOb-R concentrations were measured by enzyme-linked immunosorbent assays. The intima-media thickness (IMT) of the common carotid artery was measured by ultrasound. RESULTS: The IMT was significantly associated with sOb-R concentrations, age, diabetes duration, serum creatinine (sCre) levels, and systolic blood pressure (SBP), but not with leptin concentrations or the leptin/sOb-R ratio. The concentrations of leptin (r=0.478, p<0.001) and the sOb-R (r= -0.404, p<0.001) and the leptin/sOb-R ratio (r=0.501, p<0.001) were strongly correlated with IMT in subjects treated with insulin for glycemic control, but not in those treated with diet alone or oral hypoglycemic agents. Multiple regression analysis, including age, sex, diabetes duration, body mass index, SBP, HbA1c, triglycerides, LDL-cholesterol, sCre, smoking, and insulin therapy, revealed that plasma leptin and the leptin/sOb-R ratio were independently associated with IMT in subjects treated with insulin. CONCLUSIONS: Plasma leptin and the leptin/sOb-R ratio are associated with atherosclerosis in patients with type 2 diabetes on insulin therapy, and these associations were independent of obesity and other cardiovascular risk factors.

Undercarboxylated osteocalcin does not correlate with insulin resistance as assessed by euglycemic hyperinsulinemic clamp technique in patients with type 2 diabetes mellitus.

BACKGROUND: Recent in vitro and in vivo studies have suggested a critical role of osteocalcin (OC), especially the undercarboxylated form (ucOC), in insulin secretion and insulin sensitivity. The objective of this study was to investigate the association between serum ucOC levels and insulin resistance in humans with type 2 diabetes mellitus. FINDINGS: We measured serum ucOC levels in 129 patients with type 2 diabetes. Insulin resistance was assessed using the euglycemic hyperinsulinemic clamp technique. The insulin resistance indices used were the M value, which is the total body glucose disposal rate, and the M/I value, which is the M value adjusted for the steady state plasma insulin level. ucOC levels were not correlated with the M value (ρ = -0.013, p = 0.886) or the M/I value (ρ = 0.001, p = 0.995). CONCLUSIONS: We found no association between ucOC levels and insulin resistance in patients with type 2 diabetes mellitus.

Association of serum TRAIL levels with atherosclerosis in patients with type 2 diabetes mellitus.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was originally isolated as an inducer of apoptosis. Recent cross-sectional and prospective studies suggest an inverse association of serum TRAIL levels with the severity of coronary artery disease (CAD) and with an adverse outcome in patients with CAD or heart failure. However, it is unknown whether TRAIL can inversely reflect the progression of atherosclerosis from its early stage. We therefore examined the association between TRAIL measured by ELISA and intima-media thickness (IMT) in carotid and femoral arteries evaluated by ultrasonography as a surrogate marker of atherosclerosis in 416 type 2 diabetic patients without any symptoms of CAD and heart failure. Concurrently, the existence of calcified plaque (CP) was examined. There was no significant association between TRAIL and carotid IMT (ρ=-0.096, p=0.052) or femoral IMT (ρ=-0.025, p=0.610), although TRAIL was associated with carotid IMT in a subset of patients with macrovascular diseases (ρ=-0.174, p=0.034). No difference in TRAIL levels was found between two groups with or without CP. TRAIL may not be a good candidate as a biomarker to evaluate early-stage atherosclerotic lesions.

Fetuin-A and atherosclerotic calcified plaque in patients with type 2 diabetes mellitus.

Fetuin-A is a multifunctional circulating glycoprotein. Among its roles, inhibition of ectopic calcification is a prominent feature. Low fetuin-A levels in dialysis patients are associated with cardiovascular mortality, possibly via accelerating vascular calcification. However, except for dialyzed conditions, a correlation between fetuin-A levels and vascular calcification remains controversial. Furthermore, any inhibitory effect of fetuin-A on atherosclerotic calcified plaques (CPs) remains unclear compared with its effect on medial artery calcification that is often found in dialyzed patients. Therefore, we examined the association between fetuin-A levels and atherosclerotic CPs. For this study, 416 consecutive patients with type 2 diabetes mellitus and without renal dysfunction were examined. We measured serum fetuin-A levels and investigated for the presence of CP in the common carotid and femoral arteries using ultrasonography. Fetuin-A levels were significantly lower in patients with CP than those without CP (262.6 +/- 56.7 and 281.5 +/- 64.6 microg/mL, respectively; P = .001). Multivariate logistic regression analysis showed that fetuin-A levels were inversely associated with the presence of CP (odds ratio = 0.753; 95% confidence interval, 0.608-0.933; P = .010). These results suggest that fetuin-A may inhibit the calcification of atherosclerotic plaques independently of the dialyzed condition.

Glimepiride increases high-density lipoprotein cholesterol via increasing adiponectin levels in type 2 diabetes mellitus.

The aims of the present study are to investigate the effect of glimepiride 1 mg/d on plasma adiponectin and to assess the contribution of adiponectin in changing high-density lipoprotein cholesterol (HDL-c) levels after glimepiride treatment. Forty patients with type 2 diabetes mellitus were included. Plasma adiponectin, fasting plasma glucose, insulin, hemoglobin A(1c), and cholesterol were measured at study entry and after 3 months of treatment with glimepiride. Both plasma adiponectin level (7.5 +/- 4.5 vs 8.3 +/- 4.5 microg/mL, P = .040) and HDL-c level increased significantly (50 +/- 11 vs 53 +/- 10 mg/dL, P = .041) in the all-subjects group. In the low-adiponectin group (initial plasma adiponectin level <6 microg/mL), both plasma adiponectin level (4.5 +/- 0.9 vs 5.9 +/- 2.0 microg/mL, P = .004) and HDL-c level increased significantly (44 +/- 8 vs 49 +/- 9 mg/dL, P = .011). There was no significant change in the high-adiponectin group (initial plasma adiponectin level >or=6 microg/mL). Change in plasma adiponectin level was an independent factor for change in HDL-c level after adjustment for other factors (beta = .574, P = .009, R(2) = 0.524, P = .036). In conclusion, glimepiride improved plasma adiponectin level, especially in the subjects with type 2 diabetes mellitus with low adiponectin level before treatment, and may directly contribute to improving HDL-c level.

The combination of IMT and stiffness parameter beta is highly associated with concurrent coronary artery disease in type 2 diabetes.

AIMS: The clinical implications of stiffness of the carotid artery (CA) have not been fully clarified in the prediction of coronary artery disease (CAD), although intima-media thickness (IMT) has been established as a surrogate marker. We examined the associations of stiffness parameter beta (ST) and IMT with concurrent CAD. METHODS: IMT and ST were measured by ultrasound in 439 nondiabetic subjects as a control and 1528 type 2 diabetic subjects (T2DM) with or without CAD in a cross-sectional study. RESULTS: Both IMT and ST significantly increased with age and group category, in the order of control, T2DM without CAD, and T2DM with CAD (p<0.001). The area under the curve on ROC analysis of ST for concurrent CAD was comparable to that for IMT. On multivariate logistic regression analysis, High IMT (>or=1.30 mm) and High stiffness (>or=20.0) had significant odds ratios for concurrent CAD (2.205, p<0.001 and 1.548, p<0.05, respectively). The group with High IMT and High Stiffness exhibited a stronger multivariate odds ratio (3.115, p=0.0001). CONCLUSIONS: ST and IMT are associated with CAD and exhibited significant odds ratios for CAD. Our findings suggest that the combination of IMT and ST is a useful marker of atherosclerosis.

Effects of pioglitazone on serum fetuin-A levels in patients with type 2 diabetes mellitus.

Fetuin-A (alpha2-Heremans-Schmid glycoprotein), a circulating glycoprotein, can inhibit insulin signaling both in vivo and in vitro. Recently, we and another independent group have shown that fetuin-A is positively associated with insulin resistance in humans. Furthermore, it has been reported that higher fetuin-A levels are associated with metabolic syndrome and atherogenic lipid profiles. These data suggest that fetuin-A might be a regulator of insulin resistance and/or metabolic syndrome. However, it is not clear how fetuin-A levels are regulated. To address this, we investigated the effects of representative insulin-sensitizing therapies such as pioglitazone, metformin, and aerobic exercise on fetuin-A levels. Twenty-seven patients with type 2 diabetes mellitus were divided into pioglitazone-treated (Pio), metformin-treated (Met), and exercise-treated (Ex) groups. Ten patients in the Pio group and 9 patients in the Met group took 15 or 30 mg/d pioglitazone or 500 or 750 mg/d metformin, respectively, for 6 months. Eight patients in the Ex group underwent a 3-month aerobic exercise program. Serum fetuin-A levels were measured before and after each intervention. Intervention significantly decreased hemoglobin A(1c) in all groups. After treatment, serum fetuin-A levels significantly decreased in the Pio group (291.2 +/- 57.7 to 253.1 +/- 43.9 microg/mL, P = .006), whereas there were no changes in serum fetuin-A after intervention in either the Met or the Ex groups. We hypothesize that pioglitazone could partially ameliorate insulin resistance via modulating fetuin-A levels.

Association of serum fetuin-A with carotid arterial stiffness.

OBJECTIVE: Fetuin-A is a circulating glycoprotein which is well characterized as an inhibitor of ectopic calcification. Vascular calcification commonly found in chronic kidney disease (CKD) patients is a predictor of cardiovascular death. Recently, several groups have demonstrated that low fetuin-A levels are associated with mortality in uraemic patients, possibly through regulation of vascular calcification. However, the physiological significance of fetuin-A in atherosclerosis remains unknown, except in specific conditions, such as vascular calcification in CKD patients. The objective of this study was to investigate the association between serum fetuin-A levels and arterial stiffness, a functional property of atherosclerosis, in healthy subjects. PATIENTS AND MEASUREMENTS: The study subjects comprised 141 healthy subjects. We measured serum fetuin-A levels and stiffness parameter beta for the common carotid artery, which was assessed by ultrasound using a phase-locked echo-tracking system. RESULTS: Simple regression analyses indicated that serum fetuin-A levels were significantly correlated with stiffness parameter beta (r = 0.200, P = 0.018). Multiple regression analyses showed that, besides age, fetuin-A (beta = 0.166, P = 0.033) independently contribute to the stiffness parameter beta (R(2) = 0.310, P < 0.0001). CONCLUSIONS: Serum fetuin-A level is associated with carotid arterial stiffness, independent of known atherogenic factors in healthy subjects.