Tomokazu Oyama

Circulating angiotensin II is associated with body fat accumulation and insulin resistance in obese subjects with type 2 diabetes mellitus

Adipocytes express all components of the renin-angiotensin system, and the renin-angiotensin system is involved in obesity and insulin resistance. Circulating angiotensin II (Ang II) is detectable in blood, but its significance in human obesity remains unknown. The aim of this study was to investigate plasma Ang II in obese patients with type 2 diabetes mellitus (T2D) and the change during weight loss. Fifty Japanese obese subjects with T2D (body weight, 75.0 +/- 14.1 kg; body mass index, 29.1 +/- 3.7 kg/m(2); visceral fat area [VFA], 169.3 +/- 54.3 cm(2); hemoglobin A(1c), 7.6% +/- 1.5%) were enrolled. The subjects were prescribed a diet of daily caloric intake of 20 kcal/kg for 24 weeks. Plasma Ang II was measured by radioimmunoassay. Leptin, adiponectin, and lipoprotein lipase mass in preheparin serum were also measured as adipocyte-derived factors. After 24 weeks of weight reduction diet, the mean body weight, VFA, and hemoglobin A(1c) decreased significantly by 2.3%, 7.0%, and 8.3%, respectively. The mean plasma Ang II decreased by 24% (P < .0001) and correlated with body weight both at baseline (r = 0.425, P = .0018) and at 24 weeks (r = 0.332, P = .0181). The change in Ang II correlated with changes in body weight (r = 0.335, P = .0167) and VFA (r = 0.329, P = .0191). The change in Ang II also correlated positively with change in leptin (r = 0.348, P = .0127) and tended to correlate negatively with change in lipoprotein lipase mass in preheparin serum (r = -0.260, P = .0683), which is a marker of insulin sensitivity. Plasma Ang II is associated with body weight, decreases during weight loss, and is associated with markers of insulin resistance in obese subjects with T2D.

Improvement of cardio‐ankle vascular index by glimepiride in type 2 diabetic patients

Aims:  Glimepiride, a third generation sulfonylurea (SU), is known to have extrapancreatic effects, but its vascular effect is unclear. We investigated the efficacy of glimepiride in improving arterial stiffness assessed by cardio‐ankle vascular index (CAVI) in type 2 diabetic patients, compared with glibenclamide, a conventional SU.

Effects of body weight reduction on cardio-ankle vascular index (CAVI)

OBJECTIVE Obesity is associated with type 2 diabetes, dyslipidemia and hypertension, contributing to atherogenesis. Weight reduction is the fundamental therapy for obesity. Recently, a novel arterial stiffness parameter called cardio-ankle vascular index (CAVI) has been developed. We hypothesized that CAVI may be a candidate marker of increased vascular stiffness in obese patients. The aim of this study is to investigate the effect of weight reduction on CAVI. SUBJECTS AND METHODS Using CAVI as an indicator, we assessed the changes in arterial stiffness in 47 obese Japanese subjects (aged 46 ± 13 years) who underwent a 12-week weight reduction program consisting of a calorie restriction diet (20-25 kcal/day) and exercise therapy. Visceral fat area (VFA) was evaluated by CT. RESULTS At baseline, CAVI correlated positively with age (r = 0.70), blood pressure (r = 0.23), VFA (r = 0.26) and HbA1c (r = 0.39). After 12 weeks of weight reduction, mean BMI decreased from 33.3 ± 7.5 to 30.7 ± 6.4 kg/m(2) (p < 0.0001), and mean CAVI decreased from 8.3 to 7.9 (p < 0.01). The change in VFA correlated positively with change in CAVI in subjects with decrease in CAVI (r = 0.47). Furthermore, change in VFA was a significant independent predictor for change in CAVI. No significant correlation was observed between change in CAVI and clinical variables such as BMI, HbA1c and lipids. CONCLUSION This study demonstrated that CAVI decreased after weight reduction, and was associated with a decrease in VFA. CAVI reduction maybe a marker of improved vascular stiffness after weight reduction in subjects with visceral adiposity.

Improvement of postprandial hyperglycemia and arterial stiffness upon switching from premixed human insulin 30/70 to biphasic insulin aspart 30/70

Postprandial hyperglycemia is known to be associated with increasing cardiovascular mortality in type 2 diabetes mellitus patients. Cardio-ankle vascular index (CAVI) reflects arterial stiffness and is more useful for predicting coronary atherosclerosis than intima-media thickness. Premixed human insulin 30/70 (BHI30) containing rapid-acting insulin has been used conventionally as a biphasic insulin. Recently, a biphasic insulin analogue preparation, biphasic insulin aspart 30/70 (BIAsp30), containing ultrarapid-acting insulin has been approved and expected to improve postprandial hyperglycemia. The aim of this study was to clarify the effects of switching the biphasic insulin from BHI30 to BIAsp30 on arterial stiffness in type 2 diabetes mellitus patients. Twenty-six type 2 diabetes mellitus patients (glycosylated hemoglobin >6.5%) who were already receiving biphasic insulin therapy with BHI30 twice daily were observed for 3 months. Afterward, BHI30 was switched to BIAsp30. At 3 months after switching, relative mobility of the peak of LDL fraction decreased significantly (from 0.3462 ± 0.041 to 0.3356 ± 0.035, P < .01); and CAVI also decreased significantly (from 9.77 ± 1.11 to 9.35 ± 1.17 m/s, P < .005). A significant negative correlation was observed between the change in CAVI and change in 1,5-anhydroglucitol (1,5-AG) (r = -0.3929, P < .05). A stronger correlation between change in CAVI and change in 1,5-AG was observed in the subgroup of patients whose 1,5-AG levels were elevated after switching (r = -0.6261, P < .05) compared with all subjects. These results suggest that switching biphasic insulin from BHI30 to BIAsp30 improves arterial stiffness, and the improvement of arterial stiffness may be associated with improvement of postprandial hyperglycemia.

Determination of serum 7-ketocholesterol concentrations and their relationships with coronary multiple risks in diabetes mellitus

Oxysterols have cytotoxic effects and contribute to the development of atherosclerosis. To examine association between 7-ketocholesterol and diabetes mellitus, and other coronary risk factors, we developed a reliable quantitative method to measure serum 7-ketocholesterol (s-7KCHO) and studied s-7KCHO in patients with type 2 diabetes mellitus (T2DM). The s-7KCHO was detected by gas chromatography-mass spectrometry assay. The s-7KCHO was significantly higher in patients with T2DM (n=137, 33.8 ng/ml) compared to non-diabetic healthy subjects (n=89, 16.1 ng/ml). Patients with T2DM were divided into two groups with two or more than two risk factors (defined as multiple risk factors group) and with zero or one risk factor (non-multiple risk factors group). The s-7KCHO was significantly higher in multiple risk factors group (39.5 ng/ml) compared to non-multiple risk factors (30.1 ng/ml). Among patients with multiple risk factors group, s-7KCHO was significantly higher in patients with high low-density lipoprotein cholesterol (LDL-C) levels (45.1+/-5.9 ng/ml) compared to those with normal LDL-C levels (35.3+/-7.0 ng/ml). Furthermore, s-7KCHO increased according to the number of concurrent coronary risk factors. These results suggest that serum 7-ketocholesterol levels may depend on the multiple risk factors and serum LDL-C levels.

Effect of deposited lipids in atheromatous lesions on migration of vascular smooth muscle cells

In advanced atherosclerotic lesions, a decrease in smooth muscle cells is observed in the cap tissue. This causes the thinning of the cap, and may lead to plaque rupture. We studied the effect of deposited lipids on the migration of vascular smooth muscle cells, and identified the main cause of the effect. The lipids were extracted from atherosclerotic lesions in the human aorta at autopsy, and separated into three fractions with a Sep-Pak ODS cartridge. Then, each fraction was added to the lower part of a chemotaxis chamber, and cultured vascular smooth muscle cells to the upper part. After 4 hours incubation, the cells that had migrated to the opposite side were counted. The oxysterol-rich fraction (10 microg/ml) inhibited the migration, whereas the cholesterol ester and free cholesterol fractions did not. Finally, we tested the pure oxysterols, 7-ketocholesterol and 27-hydroxycholesterol. Both inhibited migration, whereas the free cholesterol and cholesterol ester did not. Oxysterols generated in the lipid pool might inhibit the migration of smooth muscle cells.