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Biomedical subjects

Michio Shimabukuro

Publications and source records attributed to Michio Shimabukuro.

17 recordsLinked to original sources
PubMed2006

A novel index of insulin resistance determined from the homeostasis model assessment index and adiponectin levels in Japanese subjects.

Insulin resistance is the principal cause of glucose intolerance and type 2 diabetes and induces progression of severe atherosclerosis in these patients. Adiponectin, the adipose-specific proteins, is known to correlate negatively with insulin resistance in patients with obesity and type 2 diabetes. The purpose of this study was to evaluate the potential of using serum adiponectin levels as a marker of insulin resistance in various states of insulin resistance. Furthermore, we attempted to establish a modified index of the homeostasis model assessment index (HOMA-IR), calculated from the product of serum insulin and plasma glucose levels divided by serum adiponectin levels (HOMA-AD). We recruited 117 Japanese subjects with various degrees of glucose tolerance and determined serum adiponectin levels and insulin sensitivity (M-value) by using the euglycemic hyperinsulinemic clamp technique. M-value, the gold standard index of insulin resistance, correlates significantly and independently with fasting insulin (r=-0.313, P<0.001), glucose (r=-0.319, P<0.001), and adiponectin (r=0.241, P<0.002) levels. M-values were more significantly correlated with HOMA-AD (r=-0.643, P<0.001) than HOMA-IR values (r=-0.591, P<0.001). In subjects with moderate hyperglycemia (fasting glucose levels>8.0mmol/L, n=30), HOMA-AD showed a more significant correlation with the M-value than HOMA-IR (r=-0.535, P=0.005 versus r=-0.461, P=0.010). We would therefore like to propose a novel index, HOMA-AD, as a simple and adequate index for determining insulin resistance even in diabetic patients with overt hyperglycemia.

Adiponectin↗
PubMed2006

Vascular lipotoxicity: endothelial dysfunction via fatty-acid-induced reactive oxygen species overproduction in obese Zucker diabetic fatty rats.

Vascular endothelial dysfunction has been demonstrated in obesity, but the molecular basis for this link has not been clarified. We examined the role of free fatty acids (FFA) on vascular reactivity in the obese fa/fa Zucker diabetic fatty (ZDF) rat. Addition of acetylcholine produced a dose-dependent relaxation in aortic rings of ZDF and lean +/+ rats, but the ED(50) value was higher in ZDF (-6.80 +/- 0.05 vs. -7.11 +/- 0.05 log(10) mol/liter, P = 0.033). A 2-wk treatment with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, pitavastatin (3 mg/kg/d) or a reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin (5 mmol/liter in drinking water), improved the response in ZDF (ED(50), -7.16 +/- 0.03 and -7.14 +/- 0.05 log(10) mol/liter, P = 0.008 and P = 0.015 vs. vehicle, respectively). Vasodilator response to sodium nitroprusside was identical between ZDF and +/+ rats. Vascular reactive oxygen species (ROS) levels and NADPH oxidase activity in aorta were increased in ZDF rats but were decreased by pitavastatin. In in vitro cell culture, intracellular ROS signal and NADPH oxidase subunit mRNA were increased by palmitate, but this palmitate-induced ROS production was inhibited by NADPH oxidase inhibitor or pitavastatin. In conclusion, FFA-induced NADPH oxidase subunit overexpression and ROS production could be involved in the endothelial dysfunction seen in obese ZDF rats, and this could be protected by pitavastatin or NADPH oxidase inhibitors.

Acetophenones↗
PubMed2006

Systemic oxidative stress is associated with visceral fat accumulation and the metabolic syndrome.

BACKGROUND: The metabolic syndrome (MetS) is a major target for prevention of atherosclerotic cardiovascular diseases and visceral fat accumulation is an underlying component of MetS. The aim of this study was to investigate the association of systemic oxidative stress with visceral fat accumulation and MetS. METHODS AND RESULTS: The study group consisted of Japanese men (n=44; 51.2+/-11.4 years) and women (n=61; 55.4 +/-13.4 years). Urinary 8-epi-prostaglandin F2alpha (8-epi-PGF2 alpha) concentration, a biomarker of systemic oxidative stress, was significantly high in the subjects with MetS. As the urinary concentration of 8-epi-PGF2alpha increased, the number of criteria for MetS were significantly met (abdominal obesity, hypertriglyceridemia, low high-density lipoprotein-cholesterol, hypertension, and high fasting glucose). Among parameters associated with MetS, the correlation coefficient of visceral fat area (VFA) with urinary 8-epi-PGF2alpha concentration was the highest (r=0.636, p<0.0001). In non-obese subjects, the correlation coefficient of VFA with urinary 8-epi-PGF2alpha concentration was higher (r=0.728, p<0.0001), although there was no significant correlation between subcutaneous fat area and urinary 8-epi-PGF2 alpha. Stepwise multiple regression analysis identified VFA as the strongest and independent determinant of urinary 8-epi-PGF2 alpha (p<0.0001) followed by adiponectin (p=0.0212) and, high sensitive C-reactive protein (p=0.0365). CONCLUSIONS: Systemic oxidative stress, as measured by urinary 8-epi-PGF2alpha , is strongly associated with visceral fat accumulation and MetS.

Adiponectin↗
PubMed2005

Effects of a single administration of acarbose on postprandial glucose excursion and endothelial dysfunction in type 2 diabetic patients: a randomized crossover study.

CONTEXT: Postprandial hyperglycemia has been reported to elicit endothelial dysfunction and provoke future cardiovascular complications. A reduction of postprandial blood glucose levels by the alpha-glucosidase inhibitor acarbose was associated with a risk reduction of cardiovascular complications, but effects of acarbose on endothelial function have never been elucidated. DESIGN: This study was aimed to assess the efficacy of acarbose on postprandial metabolic parameters and endothelial function in type 2 diabetic patients. Postprandial peakglucose (14.47 +/- 1.27 vs. 8.50 +/- 0.53 mmol/liter), plasma glucose excursion (PPGE), and change in the area under the curve (DeltaAUC)glucose after a single loading of test meal (total 450 kcal; protein 15.3%; fat 33.3%; carbohydrate 51.4%) were significantly higher in diet-treated type 2 diabetic patients (n = 14) than age- and sex-matched controls (n = 12). RESULTS: The peak forearm blood flow response and total reactive hyperemic flow (flow debt repayment) during reactive hyperemia, indices of resistance artery endothelial function on strain-gauge plethysmography, were unchanged before and after meal loading in controls. But those of diabetics were significantly decreased 120 and 240 min after the test meal. A prior administration of acarbose decreased postprandial peakglucose, PPGE, and DeltaAUCglucose. The peak forearm blood flow and flow debt repayment were inversely well correlated with peakglucose, PPGE, and DeltaAUCglucose but not with DeltaAUCinsulin or the other lipid parameters. CONCLUSIONS: Even a single loading of test meal was shown to impair endothelial function in type 2 diabetic patients, and the postprandial endothelial dysfunction was improved by a prior use of acarbose. Acarbose might reduce macrovascular complication by avoiding endothelial injury in postprandial hyperglycemic status.

Acarbose↗
PubMed2005

Inhibition of the renin-angiotensin system prevents free fatty acid-induced acute endothelial dysfunction in humans.

OBJECTIVE: An elevated free fatty acid (FFA) level impairs endothelium-dependent vasodilation in humans, which may be pathophysiologically relevant to the development of endothelial dysfunction in patients with insulin resistance. We investigated the effect of inhibition of the renin-angiotensin system (RAS) on FFA-induced endothelial dysfunction. METHODS AND RESULTS: Changes in forearm blood flow during intra-arterial infusion of acetylcholine were measured by plethysmography before and after systemic infusion of lipid/heparin in 10 healthy subjects given a single dose of placebo, losartan (50 mg), or perindopril (8 mg). Endothelial function after lipid/heparin infusion was also investigated with the coinfusion of vitamin C or NG-monomethyl-L-arginine (L-NMMA). Elevated FFA significantly reduced the response to acetylcholine by 37.7% (P=0.0096) without L-NMMA, but not the response with L-NMMA, whereas FFA did not affect the response to nitroprusside. The single dose of either losartan or perindopril completely prevented FFA-induced endothelial dysfunction. Vitamin C also prevented FFA-induced endothelial dysfunction. CONCLUSIONS: Elevated FFA levels by lipid/heparin infusion, which may partly mimic the abnormal lipid profile in patients with insulin resistance, caused endothelial dysfunction via RAS activation and the presumably resultant oxidative stress in humans. Our results suggest the therapeutic rationale for RAS inhibition in patients with high FFA levels.

Acetylcholine↗
PubMed2005

Electrophysiologic characteristics of atrial myocytes in levo-thyroxine-treated rats.

To investigate whether thyroid hormone modulates electrical properties of atrial myocytes, electrocardiogram (ECG), action potentials (APs), and ionic currents were measured. Male Sprague-Dawley rats were randomly divided into control and levo-thyroxine (T4)-treated groups at 6 weeks of age. Levo-thyroxine (500 microg/kg of body weight) was injected daily into the peritoneal cavity for 14 days (T4-treated rats) and the same volume of saline was injected in control rats daily. ECG signals were recorded using apex-base leads. APs, voltage-dependent Na+ and L-type Ca2+ channel current (I(Na) and I(Ca(L))), inwardly rectifying K+ channel current (I(K1)), transient outward K+ channel current (I(to)), and delayed rectifier K+ channel current (I(K(delay))) were measured using patch-clamp techniques. T4 treatment significantly changed electrical properties in rat atrial myocytes, including (1) the increase in heart rate, (2) the increase in cell size, (3) the shortening of action potential duration (APD), (4) the increase in cell membrane capacitance (C(m)), and (5) the decrease in input resistance (R(in)). Although the current densities of I(Na) and I(K1) in T4-treated atrial myocytes did not differ from those in control cells, I(Ca(L)) was significantly decreased and I(K(delay)) was significantly increased in T4-treated rats. Thus, thyrotoxicosis could induce the shortening of APD by alterations in current density of both I(Ca(L)) and I(K(delay)) in rat atrial myocytes.

Action Potentials↗
PubMed2005

Effect of sodium channel blocker, pilsicainide hydrochloride, on net inward current of atrial myocytes in thyroid hormone toxicosis rats.

To investigate effect of pilsicainide hydrochloride (pilsicainide) on electrocardiogram (ECG) signals and action potentials (APs) of atrial myocytes, levo-thyroxine (T4, 500 microg/kg body weight) was daily injected into peritoneal cavity of Sprague-Dawley rats for 14 days. T4-treatment significantly shortened RR interval, P wave, and QRS complex durations on ECG. Although pilsicainide did not affect the heart rate, P wave and corrected QT interval (QTc) was increased in T4-treated rats. AP recordings revealed that AP durations at 20%, 50%, and 90% repolarization were significantly shortened and maximal rate of rise (Max dV/dt) was significantly increased in T4-treated rat atrial cells. Pilsicainide significantly decreased AP amplitude (APA) and Max dV/dt in both control and T4-treated rat atrial cells. Concentration-inhibition study demonstrated that pilsicainide significantly inhibited net inward current of T4-treated rats at lower concentration (IC50 of 29.2 microg/mL) than that of control rats (133 microg/mL). In conclusion, pilsicainide could decrease the conduction velocity in T4-treated rat atrium by decreasing the Max dV/dt and net inward current, which could be a possible treatment of thyrotoxicosis-induced arrhythmia.

Action Potentials↗
PubMed2005

High prevalence of metabolic syndrome among men in Okinawa.

We determined the prevalence of metabolic syndrome (MS) in Okinawa from cross-sectional results of an annual physical checkup. We also calculated the homeostasis model assessment ratio (HOMA-R) as an index of insulin resistance, and examined the relationship between HOMA-R and MS. We studied 3,839 men (mean age 49.2 years) and 3,146 women (mean age 50.0 years), a total of 6,985 people aged from 30 to 79 years, who underwent an annual physical checkup in our hospital between May 2003 and March 2004. The diagnosis of MS was based on the criteria in the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III: ATP III). Abdominal circumference was assessed in accordance with the diagnostic criteria of the Japan Society for the Study of Obesity. The prevalence of MS was 30.2% in men and 10.3% in women. Mean HOMA-R significantly increased with an increase in the number of ATP III risk factors. Logistic regression analysis with the independent variables of sex, age, and HOMA-R gave an odds ratio of MS of 3.6 for men, 1.4 for a 10-year age increment, and 2.0 for an elevation of HOMA-R above 1.0.

Abdominal Fat↗
PubMed2004

Fluvastatin improves endothelial dysfunction in overweight postmenopausal women through small dense low-density lipoprotein reduction.

Small dense low-density lipoprotein (sdLDL), which are often associated with obesity, are considered as the most atherogenic and have been shown to impair endothelial function. It is not known whether reduction of sdLDL by pharmacological intervention can improve endothelial function. Thirty-four consecutive postmenopausal women with >/=5.70 mmol/L total cholesterol were placed into either an overweight (body mass index [BMI] >/= 25.0, n = 22) or a normal-weight (BMI < 25.0, n = 12) group, and forearm blood flow (FBF) was measured using strain-gauge plethysmography during reactive hyperemia before and after fluvastatin treatment. At baseline, the peak FBF during reactive hyperemia in the overweight group was less than that in the normal-weight group (mean +/- SD, 13.6 +/- 4.4 v 22.2 +/- 4.0 mL/min/100 mL, P <.01). The maximal FBF after nitroglycerin was similar in both groups. In the stepwise multiple regression analysis, only the concentration of sdLDL was the predictor for peak FBF (standard coefficient = -0.517, P =.0115). The nonsignificant parameters for the correlations in the model were age, BMI, systolic blood pressure, the homeostasis model assessment of insulin resistance (HOMA-IR), hemoglobin A(1c) (HbA(1c)), and LDL-cholesterol. Fluvastatin treatment was associated with the recovery of the peak FBF in the overweight group but it did not influence that of the normal-weight group. Changes in sdLDL fractions by fluvastatin correlated well with the peak FBF recovery. These results suggested that an increased sdLDL was linked to endothelial dysfunction in overweight postmenopausal women and fluvastatin treatment improved endothelial dysfunction by decreasing the atherogenic sdLDL fraction in this population.

Aged↗
PubMed2004

Cilostazol, a phosphodiesterase inhibitor, reduces microalbuminuria in the insulin-resistant Otsuka Long-Evans Tokushima Fatty rat.

We evaluated association between hyperinsulinemia/insulin resistance and microalbuminuria in the insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rat. OLETF rats showed glomerular hyperfiltration (an increase in creatinine clearance and a decrease in fractional excretion of Na) and microalbuminuria at the insulin-resistant prediabetic stage, and both were related to expression of transforming growth factor (TGF)-beta(1) and extracellular matrix protein such as fibronectin and collagen (a(1)) IV. Cilostazol, a selective type III cyclic nucleotide phosphodiesterase (PDE) inhibitor, normalized glomerular hyperfiltration and microalbuminuria with a parallel decline of TGF-beta(1) and extracellular matrix protein mRNA expression. Cilostazol may be beneficial to lessen early glomerular nephropathy in a state of hyperinsulinemia/insulin resistance.

Albuminuria↗
PubMed2004

Increased oxidative stress in obesity and its impact on metabolic syndrome.

Obesity is a principal causative factor in the development of metabolic syndrome. Here we report that increased oxidative stress in accumulated fat is an important pathogenic mechanism of obesity-associated metabolic syndrome. Fat accumulation correlated with systemic oxidative stress in humans and mice. Production of ROS increased selectively in adipose tissue of obese mice, accompanied by augmented expression of NADPH oxidase and decreased expression of antioxidative enzymes. In cultured adipocytes, elevated levels of fatty acids increased oxidative stress via NADPH oxidase activation, and oxidative stress caused dysregulated production of adipocytokines (fat-derived hormones), including adiponectin, plasminogen activator inhibitor-1, IL-6, and monocyte chemotactic protein-1. Finally, in obese mice, treatment with NADPH oxidase inhibitor reduced ROS production in adipose tissue, attenuated the dysregulation of adipocytokines, and improved diabetes, hyperlipidemia, and hepatic steatosis. Collectively, our results suggest that increased oxidative stress in accumulated fat is an early instigator of metabolic syndrome and that the redox state in adipose tissue is a potentially useful therapeutic target for obesity-associated metabolic syndrome.

3T3-L1 Cells↗
PubMed2003

PAX4 mutation (R121W) as a prodiabetic variant in Okinawans.

We previously reported that a missense mutation at codon 121 (CGG(Arg) to TGG(Trp), R121W) of PAX4 may be associated with the onset of type 2 diabetes in Japanese. In this study, we determined the frequency of the R121W mutation of PAX4 and characterized the prodiabetic phenotype in a population-based study. Healthy 372 residents participated in annual health check-ups in Nishihara (Okinawa, Japan) and unrelated 193 type 2 diabetic patients from the outpatient clinic of Ryukyu University Hospital were enrolled. Diagnosis of diabetes was based on the 1997 American Diabetes Association criteria. The R121W mutation in PAX4 was genotyped by PCR-RFLP analysis. In healthy residents, R121W mutation was detected in 12 of 372 residents (3.1%). The prevalence of newly diagnosed type 3 diabetes (25% vs. 5%, p=0.004) and HbA(1c) (5.6+/-1.9 vs. 5.1+/-0.7, p=0.026) was higher in the variants than in the wild-types. The odds ratio of diabetes in the R121W variants was 5.98 with 95% confidence interval from 1.50 to 23.9. The R121W mutation was observed in 12 of the 193 type 2 diabetic patients (6.2%). Onset-ages of diabetes were earlier (37+/-10 vs. 47+/-13 years, p=0.010) and the rate of insulin user was two times higher (83% vs. 41%, p=0.005) in the variants. The R121W mutation in PAX4 is a predisposing factor for the development of type 2 diabetes in Okinawans.

Aged↗
PubMed2003

Hypoadiponectinemia is closely linked to endothelial dysfunction in man.

Vascular endothelial dysfunction has been demonstrated in overweight or obese patients, but the molecular basis for this link has not been clarified. We asked what the relationship was between adiponectin, an adipose-specific molecule, and endothelial function. Forearm blood flow (FBF) was measured during reactive hyperemia by using strain-gauge plethysmography in 76 Japanese subjects without a history of cardiovascular or cerebrovascular disease, diabetes mellitus, hepatic, or renal disease. The peak FBF and total reactive hyperemic flow [flow debt repayment (FDR)] during reactive hyperemia were correlated with waist circumference (r = -0.418 and -0.414, respectively) and body mass index (r = -0.597 and -0.626, respectively). After correcting for age, gender, and body mass index, the peak FBF was correlated with systolic blood pressure (r = -0.294; P = 0.010), free fatty acid (FFA) (r = -0.331; P = 0.004), and adiponectin in log 10 (r = 0.492; P < 0.001), and FDR was correlated with adiponectin in log 10 (r = 0.462; P = 0.001). In stepwise multiple regression analyses, predictive variables for peak FBF were adiponectin in log 10 (r = 0.468) and FFA (r = -0.292; r(2) = 0.487; P < 0.0001); and predictive variables for FDR were adiponectin in log 10 (r = 0.474) and FFA (r = -0.275; r(2) = 0.346, P < 0.0001). Endothelial function was impaired in proportion to the severity of obesity, and the level of severity was closely related to plasma adiponectin levels. Adiponectin may play a protective role against the atherosclerotic vascular change, and loss of effects enhances endothelial dysfunction, as in obese people.

Adiponectin↗
PubMed2002

Evidence for a deficient pancreatic beta-cell response in a rat model of hyperthyroidism.

To clarify mechanism behind the abnormal glucose tolerance, observed in hyperthyroidism, we studied genomic and nongenomic effects of thyroid hormone on insulin secretion using a rat model of hyperthyroidism. Male Sprague-Dawley rats were intraperitoneally injected with vehicle, low (100 microg/kg) or high dose (600 microg/kg) of thyroxin (T(4)) for 2 weeks. Rats treated with high dose, but not low dose, of T(4), showed an increase in serum T(3) levels, and a decrease in body weight as compared to control rats. In rats treated with either dose of T(4), fasting blood glucose levels were increased, but serum insulin levels were similar to those of controls. After an oral glucose load, blood glucose levels were increased in rats treated with high dose, but not low dose, of T(4). Serum insulin levels after the oral glucose load were decreased in rats treated with either dose of T(4). After an intravenous glucose load, blood glucose levels were comparable among groups, but serum insulin levels tended to be low in T(4)-treated rats. Steady-state blood glucose levels were comparable among groups. The insulin secretory responses to high glucose (20mM) or arginine (10mM) of the isolated pancreas was decreased in rats treated with high dose, but not low dose, of T(4). Mean insulin secretory response to glucose and arginine were decreased by 40.1% and by 60.4% in high-dose-T(4)-treated rats. Addition of T(3) in the perfusion medium decreased glucose-induced insulin release. Ratios of proinsulin mRNA levels to beta-actin mRNA were decreased in the islets of T(4)-treated rats (0.45 +/- 0.07 vs control 0.61 +/- 0.03, p < 0.05). Levels of TR (thyroid hormone nuclear receptor) alpha1 + cErb Aalpha2 mRNA, but not TRbeta1, were decreased in the pancreatic islets of T(4)-treated rats. Calculated islet area was increased, but the number of beta-cells determined immunohistochemically was not increased in T(4)-treated rats, nor the volume density of insulin positive islets. We concluded that a deficient pancreatic beta-cell response to glucose, rather than insulin resistance, was responsible for abnormal glucose tolerance in this model of hyperthyroidism. Thyroid hormone causes a decrease in glucose-induced insulin secretion. We observed nongenomic and genomic effects of thyroid hormone on glucose-induced insulin secretion.

Animals↗
PubMed2002

Atrophic change of rat salivary gland during adenovirus-induced hyperleptinemia.

Sustained hyperleptinemia in normal rats induced by infusing a recombinant adenovirus containing the rat leptin cDNA (AdCMV-leptin) exhibited a remarkable reduction in food intake (AdCMV-leptin, 9.3 +/- 2.6 vs untreated, 20.6 +/- 1.0 g/day) and ablated body fat without any significant changes in wet weight of liver and left ventricle. In those hyperleptinemic rats, we found a 52% reduction in wet weight of salivary gland compared with that in the pair-fed AdCMV-beta-gal-treated rats, which received a recombinant virus containing the beta-galactosidase gene (AdCMV-beta-gal) and were fed on the same amount of food as had been consumed by the AdCMV-leptin-treated group on the previous day. Microscopic examination with hematoxylin-eosin staining revealed that atrophic change was induced in both serous and mucous gland only in the AdCMV-leptin-treated group, but not in the pair-fed controls. Thus, the atrophic changes in hyperleptinemic rats were due to neither a decrease of food intake nor disuse of the salivary gland related with anorexia. Our data suggested that size of the salivary gland was controlled, at lease in part, by "non-anorexic" effect of leptin.

Adenoviridae↗
PubMedDate not supplied

Comparison of the antioxidant and vascular effects of gliclazide and glibenclamide in Type 2 diabetic patients: a randomized crossover study.

The aim of the present study is to compare the short-term effects of gliclazide and glibenclamide on the oxidative state and vascular endothelium function of Type 2 diabetic patients in an observer-blinded, randomized crossover study. Thirteen Type 2 diabetic patients were enrolled: one group of seven patients took daily 160 mg of gliclazide for the first 4 weeks and then daily 5 mg of glibenclamide for the next 4 weeks; another group of six patients took daily 5 mg of glibenclamide for the first 4 weeks and 160 mg of gliclazide for the next 4 weeks. Forearm blood flow (FBF) measurement for endothelial function and biochemical analyses were conducted before and after each crossover treatment. Four weeks of treatment with either sulfonylurea showed the similar antihyperglycemic effects and enhancement of the peak FBF and total reactive hyperemic flow (flow debt repayment: FDR) during reactive hyperemia. Treatment with gliclazide resulted in the significant reduction to about 60% of baseline in urinary 8-iso-prostaglandin F2alpha (8iPGF2alpha) excretion while no such change was detected in the glibenclamide period. The increases in peak FBF and FDR were in parallel with its anti-hyperglycemic effect, but not with antioxidant state. Results suggest that gliclazide and glibenclamide can protect vascular endothelium from hyperglycemia-induced injury in Type 2 diabetic patients.

Aged↗