Biomedical subjects

Tomokazu Oyama

Publications and source records attributed to Tomokazu Oyama.

14 recordsLinked to original sources

PubMed2006

Preheparin serum lipoprotein lipase mass might be a biomarker of metabolic syndrome.

Lipoprotein lipase mass in preheparin serum (preheparin LPL mass) is assumed to reflect some of the LPL production in the whole body and insulin sensitivity. While metabolic syndrome is a common underlying condition for cardiovascular diseases, biological marker of this syndrome has not been fully established. To clarify the characteristics of preheparin LPL mass in metabolic syndrome, 362 Japanese subjects were studied to examine the relationship between symptoms of metabolic syndrome and preheparin LPL mass and compare with plasma adiponectin. Furthermore the relation with urinary 8-hydroxydeoxyguanosine (8-OHdG) that reflects oxidative stress to DNA was also studied. Both preheparin LPL mass and plasma adiponectin correlated positively with HDL-cholesterol and negatively with body weight and triglyceride. Only preheparin LPL mass showed a negative correlation with fasting blood glucose and HbA1c. Both mean preheparin LPL mass and plasma adiponectin decreased with an increase in severity of the metabolic syndrome with/without obesity and with/without diabetes. The correlation coefficient between preheparin LPL mass and plasma adiponectin was r=0.562. A negative correlation between preheparin LPL mass and urinary 8-OHdG was observed. These results suggest that low preheparin LPL mass may reflect systemic oxidative stress and also a biomarker of the severity of metabolic syndrome.

Adiponectin↗

PubMed2006

The angiotensin II receptor antagonist valsartan enhances lipoprotein lipase mass in preheparin serum in type 2 diabetes with hypertension.

Recent studies suggest that blockade of angiotensin type 1 (AT1) receptor may have some effect on glucose and lipoprotein metabolism. Serum level of preheparin lipoprotein lipase (LPL) reflects LPL production mainly in adipocytes and is believed to be related to insulin sensitivity. We studied the effect of a selective AT1 antagonist, valsartan, on glucose, lipid metabolism and the preheparin LPL mass in 55 patients with type 2 diabetes and hypertension. Patients were randomized into a group administered valsartan 80 mg/day for 12 weeks or a group not administered valsartan (control). Blood pressure decreased significantly. HbA1c and TG levels decreased and HDL-C level increased, but these changes tended to be significantly different. TC and LDL-C levels were not significant changes. Preheparin LPL mass increased after valsartan administration compared with control (P = 0.0307), and migration ratio of LDL (LDL-Rm), which correlated negatively with LDL particle size, decreased compared with control (P < 0.0001). DeltaLDL-Rm correlated inversely with Delta preheparin LPL mass (r = -0.459). Among subjects treated with valsartan, greater improvement in preheparin LPL mass and blood pressure was observed in the subgroup with preheparin LPL mass <40 ng/ml. The results of this study suggest that valsartan may enhance LPL production in adipocytes, resulting in enlarged LDL particle size.

Aged↗

PubMed2006

The role of polyol pathway in high glucose-induced endothelial cell damages.

To clarify the mechanism by which hyperglycemia in diabetes mellitus causes endothelial cell damages, the effects of high glucose on DNA fragmentation and caspase-3 activity of cultured endothelial cells and on the generation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) were studied. Furthermore, the involvement of the polyol pathway in this process was investigated using aldose reductase inhibitor (SNK-860). Human umbilical vein endothelial cells (HUVECs) were incubated with 5.5mmol/L (low glucose medium) or 28mmol/L (high glucose medium) of glucose. The amounts of fragmented DNA, caspase-3 activity and 8-OHdG in the medium increased in significantly greater extent in high glucose-incubated HUVECs than in low glucose-incubated HUVECs. No significant increase in fragmented DNA or 8-OHdG was observed when HUVECs were incubated with mannitol (500mg/mL). The concentration of intracellular sorbitol was significantly higher in HUVECs incubated in high glucose medium than that in low glucose medium. Addition of the aldose reductase inhibitor SNK-860 dose-dependently decreased the intracellular sorbitol concentration in HUVECs incubated in high glucose medium, and also significantly suppressed the increases in fragmented DNA, caspase-3 activity and 8-OHdG by conditioning with high glucose medium. These results suggest that high glucose-induced endothelial cell damages may be mediated by activation of the polyol pathway accompanied by augmented oxidative stress.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2006

Enhancement of serum lipoprotein lipase mass levels by intensive insulin therapy.

We previously reported that lipoprotein lipase mass level in preheparin serum (preheparin LPL mass) was significantly lower in type 2 diabetes mellitus compared to healthy subjects and increased by conventional insulin therapy using NPH (intermediate-acting) insulin. The aim of this study was to investigate the effects of intensive insulin therapy on preheparin LPL mass. Thirty-two subjects (total group) with type 2 diabetes receiving treatment by NPH insulin injection twice a day in the morning and evening were switched to basal bolus insulin (BBI) therapy (fast-acting insulin after each meal and NPH insulin before bedtime). In 14 subjects, the total daily insulin dose was not change after switching to BBI therapy (iso-dose group). After 3 months of BBI therapy, preheparin LPL mass increased significantly from 47 to 56 ng/ml in total group. Glycosylated hemoglobin and serum triglyceride levels decreased significantly, and high-density lipoprotein-cholesterol increased significantly. Low-density lipoprotein levels did not changed but increase in size was suggested by PAG disc electrophoresis. Similar changes were observed in the iso-dose group. These results suggest that BBI therapy enhances preheparin LPL mass, accompanied by antiatherogenic changes in glucose and lipid metabolism.

Body Mass Index↗

PubMed2006

Effect of combination therapy of benidipine hydrochloride and candesartan cilexetil on serum lipid metabolism and blood pressure in elderly hypertensive patients with type 2 diabetes mellitus.

The effects of combination therapy of angiotensin II receptor blockers (ARBs) and a calcium antagonist, benidipine hydrochloride, on glucose and lipid metabolism and pulse pressure were studied in elderly hypertensive patients with type 2 diabetes mellitus. Twenty-five hypertensive diabetic patients aged 65 years or older, who had been receiving candesartan cilexetil, were administered benidipine hydrochloride (4 mg/day) and followed for 4 months. After 4 months, systolic and diastolic blood pressure decreased significantly from 154/91 mmHg to 139/78 mmHg (p<0.01 versus before benidipine hydrochloride administration). Body mass index (BMI) and glycosylated hemoglobin (HbA1c) were apparently reduced but the changes were not statistically significant. The serum lipid profile showed no significant changes in serum total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). Serum lipoprotein lipase mass levels (preheparin LPL mass) increased significantly from 51 to 59 ng/dl (p<0.01 versus before benidipine hydrochloride administration), and the LDL/HDL motility ratio calculated from PAG disc electrophoresis decreased significantly (p<0.05 versus before benidipine hydrochloride administration). When patients were divided into a systolic hypertension group (systolic blood pressure > or =140 mmHg and diastolic blood pressure <90 mmHg) and non-systolic hypertension group (others), preheparin LPL mass was significantly lower in the systolic hypertension group, and the decrease in pulse pressure and increase in preheparin LPL mass were significantly greater in the systolic hypertension group. Stepwise regression analysis showed that low preheparin LPL mass at baseline was associated with a decrease in pulse pressure. Add-on benidipine hydrochloride therapy in elderly hypertensive patients with type 2 diabetes mellitus significantly decreases the LDL/HDL motility ratio and pulse pressure, and significantly increases preheparin LPL mass, in addition to improving blood pressure control. These findings suggest that combination therapy with benidipine hydrochloride and candesartan cilexetil may contribute to the suppression of arteriosclerosis and may be useful for elderly hypertensive patients with diabetes mellitus.

Aged↗

PubMed2006

Probucol and atorvastatin decrease urinary 8-hydroxy-2'-deoxyguanosine in patients with diabetes and hypercholesterolemia.

To clarify whether probucol and statins suppress oxidative stress in diabetic patients, we studied the effects of probucol and the statin atorvastatin on urinary 8-hydroxy-2'deoxyguanosine (8-OHdG) levels in diabetics with hypercholesterolemia. A randomized, open study was performed on a total of 36 patients with type 2 diabetes and hypercholesterolemia. The patients were randomly assigned to a probucol group (500 mg/day, n = 18) or an atorvastatin group (10 mg/day, n = 18). During three months, total- and LDL-cholesterol decreased significantly in both groups. LDL-cholesterol was significantly lower in the atorvastatin group than probucol group. HDL-C decreased significantly in the probucol group and did not change in the atorvastatin group. 8-OHdG decreased significantly in both groups after 3 months; 12.4 +/- 7.5 to 8.1 +/- 4.2 ng/mg/Cr in the atorvastatin group (p < 0.05) and 12.3 +/- 8.8 to 6.8 +/- 2.6 ng/mg/Cr in the probucol group (p < 0.05), and these changes did not differ significantly between the two groups. But, in patients with high 8-OHdG levels (more than 10 ng/mg/Cr) before administration, urinary 8-OHdG decreased significantly from 19.5 +/- 4.9 to 9.2 +/- 3.4 ng/mg Cr (p < 0.01) in the atorvastatin group, and from 19.7 +/- 8.2 to 6.67 +/- 2.2 ng/mg Cr (p < 0.01) in the probucol group. Urinary 8-OHdG was significantly lower in the probucol group than in the atorvastatin group after the second and third months of administration (p < 0.05). These results suggest that while probucol and atorvastatin both reduce systemic oxidative stress, probucol might be the more useful in patients with strong oxidative stress.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2005

Probucol delays progression of diabetic nephropathy.

Probucol has antioxidant and cholesterol-lowering effects. This study examined the effect of probucol on progression of diabetic nephropathy. We performed a randomized, open trial on 102 type 2 diabetes patients with clinical albuminuria (urinary albumin excretion >300 mg/g Cr). Fifty-one patients were assigned to probucol treatment (500 mg/day) and 51 to no probucol treatment. Among all patients, 40 who had serum creatinine >or=2mg/dl at baseline were defined as advanced cases. All patients were followed for a maximum 3 years. HbA1c levels were not different between two groups. High-density lipoprotein cholesterol decreased significantly in probucol group. Increase in urinary protein (g/day/month) was significantly greater in non-probucol than in probucol group. Hemodialysis was initiated in 23 patients (10 in probucol group and 13 in non-probucol group). The mean interval to initiation of hemodialysis was significantly longer in probucol group (20.7+/-8.2 months) than in non-probucol group (11.3+/-7.4 months). In advanced cases, increases of both serum creatinine and urinary protein were significantly suppressed in probucol group. In advanced cases, the hemodialysis-free rate was significantly higher in probucol group than in non-probucol group. These results suggest that probucol may suppress the progression of diabetic nephropathy.

Aged↗

PubMed2005

Pitavastatin enhanced lipoprotein lipase expression in 3T3-L1 preadipocytes.

It is known that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) enhance the expression- of the low-density lipoprotein (LDL) receptor and lower the level of LDL cholesterol in the blood. But, a triglyceride (TG)-lowering effect is also observed during their administration. To clarify the possibility that statins enhance LPL activity and its mechanism, the effects of statins on the expression of LPL in adipocytes were studied. When statins (pravastatin, simvastatin, atorvastatin and pitavastatin) were added to the culture medium of mouse 3T3-L1 preadipocytes at final concentrations of 1 microM for 3 days, LPL activity increased. Pitavastatin increased the activity the most. Western and Northern blotting showed that LPL protein and m-RNA were strongly expressed on the addition of pitavastatin. With the addition of mevalonate (10 microM, 3 days), LPL activity weakened significantly. Statins, especially pitavastatin, increased the expression of LPL in 3T3-L1 preadipocytes. The TG-lowering effect of pitavastatin might be mediated by enhancement of LPL production in adipocytes.

3T3-L1 Cells↗

PubMed2005

Usefulness of preheparin lipoprotein lipase mass as a parameter for predicting the efficacy of colestimide.

This study was conducted to clarify the characteristics of colestimide responders. Forty-seven non-diabetic patients with high levels of low-density lipoprotein cholesterol (LDL-C) received colestimide at 3,000 mg/day and were followed up for 4 months. After 4 months, body weight was reduced but the change was not statistically significant. Total serum cholesterol (TC) and LDL-C levels significantly decreased from 280 to 232 mg/dl and from 195 to 150 mg/dl, respectively (p<0.01 versus before colestimide was administered). Serum triglyceride (TG) levels increased, but the change was not significant. Preheparin lipoprotein lipase mass (preheparin LPL mass) at baseline was significantly higher in colestimide responders (greater than a 20% decrease of LDL-C: n=28) than non-responders (76.2 ng/ml versus 50.3 ng/ml, p<0.05: n=19). Next, the subjects were divided into those with a high (n=33) and low (n=14) preheparin LPL mass at baseline. LDL-C levels were significantly decreased in patients with a high preheparin LPL mass while TG levels were significantly increased in patients with a low preheparin LPL mass. These results suggest that baseline preheparin LPL mass may be a marker of the response to colestimide.

Anion Exchange Resins↗

PubMed2005

Apoptosis induced by 7-ketocholesterol is enhanced in smooth muscle cells derived from OLETF rats.

To clarify whether an increased proliferative potential of vascular smooth muscle cells (SMC) under diabetic conditions augments the susceptibility of the cells to 7-ketocholesterol-induced apoptosis, we investigated the difference in sensitivity to 7-ketocholesterol between SMC obtained from diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats and the control Long-Evans Tokushima Otsuka (LETO) rats. The outgrowth rate from aortic wall explants and cell proliferation were higher in SMC derived from OLETF rats (OLETF-derived SMC) compared to those from LETO rats (LETO-derived SMC). When 7-ketocholesterol was added to SMC, the amount of fragmented DNA increased significantly in OLETF-derived compared to LETO-derived SMC. The amount of fragmented DNA induced by 7-ketocholesterol decreased significantly in both OLETF- and LETO-derived SMC when they were incubated without fetal bovine serum. By adding PDGF-BB to LETO-derived SMC, the amount of fragmented DNA induced by 7-ketocholesterol increased significantly. These results suggest that apoptosis of SMC induced by 7-ketocholesterol may be accelerated when SMC acquire a high proliferative potential by prolonged exposure to diabetic condition.

Animals↗

PubMed2004

Beneficial effect of low carbohydrate in low calorie diets on visceral fat reduction in type 2 diabetic patients with obesity.

The adequate composition of carbohydrate and fat in low calorie diets for type 2 diabetes mellitus patients with obesity is not fully established. The aim of this study was to investigate the effects of low carbohydrate diet on glucose and lipid metabolism, especially on visceral fat accumulation, and comparing that of a high carbohydrate diet. Obese subjects with type 2 diabetes mellitus were randomly assigned to take a low calorie and low carbohydrate diet (n = 11, 1000 kcal per day, protein:carbohydrate:fat = 25:40:35) or a low calorie and high carbohydrate diet (n = 11, 1000 kcal per day, protein:carbohydrate:fat = 25:65:10) for 4 weeks. Similar decreases in body weight and serum glucose levels were observed in both groups. Fasting serum insulin levels were reduced in the low carbohydrate diet group compared to the high carbohydrate diet group (-30% versus -10%, P < 0.05). Total serum cholesterol and triglyceride levels decreased in both groups, but were not significantly different from each other. High-density lipoprotein-cholesterol (HDL-C) increased in the low carbohydrate diet group but not in the high carbohydrate diet group (+15% versus 0%, P < 0.01). There was a larger decrease in visceral fat area measured by computed tomography in the low carbohydrate diet group compared to the high carbohydrate diet group (-40 cm(2) versus -10 cm(2), P < 0.05). The ratio of visceral fat area to subcutaneous fat area did not change in the high carbohydrate diet group (from 0.70 to 0.68), but it decreased significantly in the low carbohydrate diet group (from 0.69 to 0.47, P < 0.005). These results suggest that, when restrict diet was made isocaloric, a low calorie/low carbohydrate diet might be more effective treatment for a reduction of visceral fat, improved insulin sensitivity and increased in HDL-C levels than low calorie/high carbohydrate diet in obese subjects with type 2 diabetes mellitus.

Adipose Tissue↗

PubMed2004

Atorvastatin and pravastatin elevated pre-heparin lipoprotein lipase mass of type 2 diabetes with hypercholesterolemia.

To clarify whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statin) increases lipoprotein lipase mass in preheparin plasma (preheparin LPL mass), we observed the change in preheparin LPL mass during administration of atorvastatin and pravastatin to type 2 diabetes mellitus patients with hypercholesterolemia. The subjects were randomly divided into two groups. One group was 24 patients given atorvastatin (10 mg/day), and the other was 23 patients given pravastatin (20 mg/day) for 4 months. After 4 months of administration, no significant change of HbA1c was observed. TC significantly decreased in the atorvastatin group compared to the pravastatin group. TG significantly decreased in the atorvastatin group. Low density lipoprotein cholesterol level significantly decreased in both groups (- 36.3%, p < 0.01 in atorvastatin, - 24.3%, p < 0.01 in pravastatin). Preheparin LPL mass slightly increased in both groups after 4 months of administration. Especially in patients who showed low preheparin LPL mass (less than 50 ng/ml) before statin administration, preheparin LPL mass significantly increased in both groups (+ 25.8% in the atorvastatin group, + 24.39% in the pravastatin group). These results suggested that administration of atorvastatin and pravastatin to type 2 diabetic patients with hypercholesterolemia increased serum preheparin LPL mass concentration. Especially, its effect was remarkable in patients who showed low preheparin LPL mass.

Anticholesteremic Agents↗

PubMed2002

Effect of deposited lipids in atheromatous lesions on the 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.

Arteriosclerosis↗

PubMed2002

Oxysterol-induced apoptosis of vascular smooth muscle cells is reduced by HMG-CoA reductase inhibitor, pravastatin.

We investigated the mechanism by which 7-ketocholesterol damages vascular smooth muscle cells and the protective effect of the hydroxymethyl glutary CoA reductase inhibitor, pravastatin on it. When 7-ketocholesterol (50 micromol/L) was added to cultured human vascular smooth muscle cells, the extent of cell detachment increased and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling was positive. DNA extracted from the smooth muscle cells exposed to 7-ketocholesterol showed a ladder pattern on agarose electrophoresis. The fragmented DNA also increased in smooth muscle cells incubated with 7-ketocholesterol dose-dependently. In the presence of pravastatin, the cell detachment induced by 7-ketocholesterol was inhibited and the amount of fragmented DNA decreased significantly. These effects of pravastatin were inhibited by mevalonate. The results suggest that 7-ketocholesterol-induced apoptosis of vascular smooth muscle cells is inhibited by pravastatin, and mevalonate acts as a trigger of the apoptosis.

Anticholesteremic Agents↗