Takahiro Araki

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.

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.

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.

Non‐oxidative glucose disposal is reduced in type 2 diabetes, but can be restored by aerobic exercise

Whole‐body glucose utilization consists of mitochondrial glucose oxidation and non‐oxidative glycogen synthesis. We examined whether reduction of both non‐oxidative glucose disposal and glucose oxidation contributes to insulin resistance in type 2 diabetes. We also examined the effects of exercise on these two components. Whole‐body glucose disposal rate (GDR, mg/kg/min) was evaluated in 37 type 2 diabetic (T2DM) and 17 non‐diabetic (non‐DM) subjects as the mean of glucose infusion rate during steady state in the euglycaemic–hyperinsulinaemic clamp study. Glucose oxidation rates were assessed by indirect calorimetry, and non‐oxidative GDR was calculated by subtracting glucose oxidation rate from GDR. Intramyocellular lipid (IMCL) content of the soleus muscle was measured using 1H‐magnetic resonance spectroscopy. In 10 T2DM subjects, the changes in oxidative and non‐oxidative glucose disposal during clamp were examined after 3‐month exercise intervention. GDR (2.93 ± 1.55 vs. 4.55 ± 1.83, p = 0.001) and non‐oxidative GDR (1.45 ± 1.52 vs. 3.01 ± 1.87, p = 0.002) were significantly lower in T2DM than in non‐DM subjects. Glucose oxidation rate was comparable in the two groups, and inversely correlated with IMCL (n = 15, r =−0.565, p = 0.028). GDR (2.28 ± 1.67 to 4.63 ± 2.42, p = 0.021) and non‐oxidative GDR (0.72 ± 1.27 to 2.26 ± 1.91, p = 0.047) were increased after exercise intervention, although the change in glucose oxidation rate was not significant. In summary, reduction of non‐oxidative glucose disposal may contribute to decreased whole‐body glucose utilization. In addition, exercise improves insulin resistance mainly by increasing non‐oxidative glucose disposal in type 2 diabetes.