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Biomedical subjects

Y Saito

Publications and source records attributed to Y Saito.

At least 37 records · Page 2Linked to original sources
PubMed2006

Insulin resistance and increased pancreatic beta-cell proliferation in mice expressing a mutant insulin receptor (P1195L).

Several mutations of the tyrosine kinase domain of insulin receptor (IR) have been clinically reported to lead insulin resistance and insulin hypersecretion in humans. However, it has not been completely clarified how insulin resistance and pancreatic beta-cell function affect each other under the expression of mutant IR. We investigated the response of pancreatic beta-cells in mice carrying a mutation (P1195L) in the tyrosine kinase domain of IR beta-subunit. Homozygous (Ir(P1195L/P1195L)) mice showed severe ketoacidosis and died within 2 days after birth, and heterozygous (Ir(P1195L/wt)) mice showed normal levels of plasma glucose, but high levels of plasma insulin in the fasted state and after glucose loading, and a reduced response of plasma glucose lowering effect to exogenously administered insulin compared with wild type (Ir(wt/wt)) mice. There were no differences in the insulin receptor substrate (IRS)-2 expression and its phosphorylation levels in the liver between Ir(P1195L/wt) and Ir(wt/wt) mice, both before and after insulin injection. This result may indicate that IRS-2 signaling is not changed in Ir(P1195L/wt) mice. The beta-cell mass increased due to the increased numbers of beta-cells in Ir(P1195L/wt) mice. More proliferative beta-cells were observed in Ir(P1195L/wt) mice, but the number of apoptotic beta-cells was almost the same as that in Ir(wt/wt) mice, even after streptozotocin treatment. These data suggest that, in Ir(P1195L/wt) mice, normal levels of plasma glucose were maintained due to high levels of plasma insulin resulting from increased numbers of beta-cells, which in turn was due to increased beta-cell proliferation rather than decreased beta-cell apoptosis.

Animals↗
PubMed2005

Effects of barbiturates on ATP-sensitive K channels in rat substantia nigra.

ATP-sensitive K channels are widely expressed in cytoplasmic membranes of neurons, and they couple cell metabolism to excitability. They are thought to be involved in neuroprotection against cell damage during hypoxia, ischemia and excitotoxicity by hyperpolarizing neurons and reducing excitability. Although barbiturates are often used in patients with brain ischemia, the effects of these agents on neuronal ATP-sensitive K channels have not been clarified. We studied the effects of thiopental and pentobarbital on surface ATP-sensitive K channels in principal neurons of rat substantia nigra pars compacta. Whole cell voltage- and current-clamp recordings were made using rat midbrain slices. ATP-sensitive K channels were activated by intracellular dialysis with an ATP-free pipette solution during perfusion with a glucose-free solution. When the pipette solution contained 4mM ATP and the perfusing solution contained 25 mM glucose, the membrane current at -60 mV remained stable. When intracellular ATP was depleted, hyperpolarization and an outward current developed slowly. Although thiopental did not affect the membrane current in the presence of ATP and glucose, it reversibly inhibited the hyperpolarization and outward current induced by intracellular ATP depletion at 100 and 300 microM. Thiopental reduced the ATP depletion-induced outward current by 4.7%, 36.7% and 87% at 30, 100 and 300 microM, respectively. The high dose of pentobarbital also exhibited similar effects on ATP-sensitive K channels. These results suggest that barbiturates at high concentrations but not at clinically relevant concentrations inhibit ATP-sensitive K channels activated by intracellular ATP depletion in rat substantia nigra.

Adenosine Triphosphate↗
PubMed2005

Differential effects of RAS inhibitors associated with ACE gene polymorphisms in type 2 diabetic nephropathy.

Blood pressure and genetic factors are important factors for diabetic nephropathy. We investigated the relationship between the efficacy of renin angiotensin system (RAS) inhibitors and angiotensin-converting enzyme (ACE) genotypes. Patients with type 2 diabetes without proteinuria, were treated with RAS inhibitors, the first being an ACE inhibitor (ACEI) and the second, an angiotensin II (ATII) receptor blocker (ARB) for 8 weeks each. There was no significant difference (except serum ACE activity) between the two treatments. However, by analysis segregated with ACE gene polymorphism, ARB significantly decreased transforming growth factor-beta1 (TGF-beta) compared to ACEI in patients with the I/I genotype but not in patients with the D/I+D/D genotype. DeltaATII and DeltaTGF-beta have a negative correlation with the I/I genotype and a positive correlation with the D/I+D/D genotypes. These correlation coefficients are significantly different. We suggest that in I/I patients, TGF-beta was reduced by ARB via effects on (ATII) type 2 receptors (AT2). In our experiments, the effect of ARB on TGF-beta reduction was only detected by segregation of ACE genotypes. This indicates that the selection of medicine in light of a patient's genotype is important in treating diabetic nephropathy.

Aged↗
PubMed2005

Implantation of primary cultured adipocytes that secrete insulin modifies blood glucose levels in diabetic mice.

AIM/HYPOTHESIS: In type 1 diabetic patients, basal insulin supplementation plays a central role in tight glycaemic control. Therefore, safe and steady supplementation of basal insulin is strongly desirable, despite the need for multiple injections. The aim of this study was to investigate a procedure for supplementation using genetically engineered, primary-cultured adipocytes in diabetic mice. METHODS: Furin-cleavable human proinsulin cDNA was transferred into murine primary-cultured adipocytes using a retroviral vector. The cells were implanted subcutaneously into streptozotocin-induced diabetic mice. RESULTS: The transfected cells secreted substantial amounts of mature insulin, as well as C-peptide, into conditioned medium. Syngeneic implantation of the cells significantly improved hyperglycaemia and blood HbA(1)c concentrations in a manner that was dependent on cell number, without causing hypoglycaemia. The plasma insulin concentration was dependent on the implanted cell number, and the systemic effect of the circulating insulin was confirmed by marked improvement of body weight reduction and liver glycogen content. Additionally, surgical resection of the implants, in which the insulin secretion was immunologically confirmed after transplantation, diminished the glucose-lowering effect, suggesting that in vivo expression could be eliminated if necessary. CONCLUSIONS/INTERPRETATION: These results indicate that the autotransplantation of functionalised adipocytes may lead to a clinical application in the treatment of diabetes.

Adipocytes↗
PubMed2005

Independent accumulations of tau and amyloid beta-protein in the human entorhinal cortex.

BACKGROUND: Previous studies have repeatedly described that neurofibrillary tangles arise earlier than senile plaques (SPs) in the entorhinal cortex, but one study suggested that SPs, if present, enhance the former lesions. All of these studies were performed at the histologic or immunocytochemical level, which may not accurately reflect the actual levels of amyloid beta-protein (Abeta) and tau. OBJECTIVE: To determine whether there is significant interaction between Abeta and tau in the human entorhinal cortex with regard to the Braak stage. METHODS: Biochemical studies were conducted on 50 brains from elderly people, who were mainly at Braak stages I to III. All the cases were examined neuropathologically and staged according to Braak and Braak. A small piece of brain tissue for each case was dissected from the anterior portion of the right entorhinal cortex. The amounts of tau and Abeta in the insoluble fraction of the tissue were quantified using western blotting. RESULTS: The levels of tau and possibly Abeta42 in the entorhinal cortex appeared to rise steeply at approximately age 75. The levels of insoluble tau increased as the Braak stage increased from I to II; however, it had a tendency to remain between stages II and III. The levels of Abeta42 showed a small increase, whereas those of Abeta40 increased continuously as the Braak stage advanced. In contrast, the extent of Abeta42 accumulation increased with increasing Braak stage for SPs. There was no significant correlation between the levels of insoluble tau and Abeta42 in the entorhinal cortex. Even if Abeta did not accumulate to significant extents, substantial accumulation of insoluble tau occurred. CONCLUSION: Accumulations of tau and amyloid beta-protein occur independently in the human entorhinal cortex.

Aged↗
PubMed2005

Genotoxicity studies on dietary diacylglycerol (DAG) oil.

Dietary diacylglycerol (DAG) oil is an edible oil enriched in DAG (more than 80%). A recent investigation indicated that DAG oil or its components may have beneficial effects on the prevention and management of obesity. We evaluated the genotoxic potential of DAG oil using standard genotoxicity tests. Bacterial reverse mutation assay (Ames test), the chromosomal aberration assay in cultured Chinese hamster lung cells (CHL/IU), and a bone marrow micronucleus assay in ICR CD mice were employed in the present study. In addition we have tested the possibility that genotoxic substances may be formed during cooking, heated DAG oil (HDG) was prepared by batch frying potato slices in the oil at 180 degrees C for 8 h/day for three consecutive days. Therefore, genotoxicity tests were also performed on HDG. Results obtained did not show any genotoxic effect on either unheated DAG oil (UDG) or HDG. We conclude that there are no safety concerns on the genotoxicity of DAG oil under the conditions for normal use.

Animals↗
PubMed2005

Genetic polymorphisms and haplotypes of the human cardiac sodium channel alpha subunit gene (SCN5A) in Japanese and their association with arrhythmia.

Genetic variations in cardiac ion channels have been implicated not only as the causes of inherited arrhythmic syndromes, but also as genetic risk factors for some acquired arrhythmias. To elucidate the potential roles of genetic polymorphisms of the alpha subunit of the voltage-gated sodium channel type V (SCN5A) in cardiac rhythm disturbance, the entire SCN5A coding exons and their flanking introns were sequenced in 166 Japanese arrhythmic patients and 232 healthy controls. We detected 69 genetic variations, including 54 novel ones. Out of the 12 novel nonsynonymous single nucleotide polymorphisms (SNPs), p.Leu1988Arg was found at a frequency of 0.015. The other 11 SNPs were rare (0.001), with 6 found in arrhythmic patients and 5 in healthy controls. The frequency of a novel intronic SNP, c.703+130G>A, was significantly higher in the patients than in the controls, suggesting this SNP is associated with an unknown risk factor for arrhythmia. Following linkage disequilibrium analysis, the haplotype structure of SCN5A was inferred using high-frequency SNPs. The frequency of the haplotype harbouring both p.Leu1988Arg and the common SNP p.His558Arg (haplotype GG) was significantly lower in the patients than in the controls. This finding suggests that this haplotype (GG) might have been positively selected in the controls because of its protective effect against arrhythmias. This study provides fundamental information necessary to elucidate the effect of genetic variations in SCN5A on channel function and cardiac rhythm in Japanese, and probably in the Asian population.

Arrhythmias, Cardiac↗
PubMed2005

New "pre-diabetes" category and the metabolic syndrome in Japanese.

BACKGROUND: Recently, impaired fasting glucose (IFG) was redefined as fasting plasma glucose of 100-125 mg/dl, and individuals with IFG and/or impaired glucose tolerance (IGT) were referred to as having "pre-diabetes". However, there is a lack of data using the new definition of IFG and "pre-diabetes". OBJECTIVE: The aim of this study was to examine associations of the metabolic syndrome components with the new "pre-diabetes" category in relatively lean Japanese. METHODS: Six hundred and sixty-one Japanese study participants underwent a 75 g oral glucose tolerance test. They were classified into three groups-normal (n=225), pre-diabetes (n=308), and diabetes (n=128). The metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III, as modified for waist circumference criteria by the Regional Office for the Western Pacific Region of WHO. RESULTS: Prevalence of the metabolic syndrome in each group was 10.7%, 27.9%, and 53.9%, respectively. Of the metabolic syndrome components, the OR for prevalent pre-diabetes was 2.00 (95% CI, 1.73-2.31, p<0.001) for fasting glucose, 1.93 (95% CI, 1.54-2.42, p<0.001) for waist circumference, and 1.36 (95% CI, 1.10-1.68, p=0.005) for triglycerides. Similar associations were found in prevalent diabetes. Insulin resistance assessed using Stumvoll's index was significantly associated with both pre-diabetes and diabetes. CONCLUSION: Pre-diabetes and the metabolic syndrome frequently coexist in relatively lean Japanese. This association seems to link with abdominal adiposity and insulin resistance.

Adult↗
PubMed2005

Haemodynamic effects of thoracic epidural anaesthesia during induction of anaesthesia: an investigation into the effects of tracheal intubation during target-controlled infusion of propofol.

We compared haemodynamic changes following induction of anaesthesia with propofol during tracheal intubation with and without epidural anaesthesia. Nineteen patients were divided into two groups to receive epidurally administered saline (Group C) or lidocaine 1.5% (Group E). The propofol infusion was started to produce blood concentrations of 3 microg.ml(-1), and following fentanyl and vecuronium administration, tracheal intubation was performed. Mean arterial blood pressure (MBP), heart rate (HR), Bispectral index and effect-site propofol concentration were recorded. Time to loss of consciousness was significantly shorter in Group E than in Group C. The effect-site propofol concentration at loss of consciousness was significantly lower in Group E than in Group C. MBP and HR were significantly lower following propofol induction in both groups, and were significantly increased following intubation in Group C but not in Group E. In conclusion, epidural anaesthesia did not produce profound hypotension following induction of anaesthesia and produced a reduction in the haemodynamic response to tracheal intubation during a target controlled infusion of propofol.

Adult↗
PubMed2005

Beta-cell function and insulin sensitivity contribute to the shape of plasma glucose curve during an oral glucose tolerance test in non-diabetic individuals.

To clarify whether beta-cell function and/or insulin resistance contributes to the shape of plasma glucose curve during an oral glucose tolerance test (OGTT), we investigated 583 Japanese subjects with normal glucose tolerance (NGT, n = 306) or impaired glucose tolerance (IGT, n = 277). Each subject was subdivided into three shapes of plasma glucose curve as follows: monophasic pattern (M type), biphasic pattern (B type) and two peaks (T type). Homeostasis model assessment of insulin resistance, quantitative insulin sensitivity check index and insulinogenic index were assessed by plasma glucose and insulin concentrations obtained at fasting or during an OGTT. There was a greater proportion of M type in the IGT group (M = 80.9%, B = 15.5% and T = 3.6%), whereas the prevalence of B and T types was much higher in the NGT group (M = 66.6%, B = 26.5% and T = 6.9%). There were significant differences in the proportions of shape types between the NGT and IGT groups (p = 0.0006). Among the NGT category, insulin sensitivity was significantly higher in the B type than in the M type, and beta-cell function adjusted for insulin resistance was significantly higher in the B and T types than in the M type. Among the IGT category, no significant differences were seen among the three shape types with respect to insulin sensitivity, but the beta-cell function adjusted for insulin resistance was significantly lower in the M type than in the B and T types. In conclusion, both impaired insulin secretion and insulin resistance may contribute to the underlying mechanisms of the shape of plasma glucose curve in Japanese subjects.

Area Under Curve↗
PubMed2005

Tubulointerstitial macrophage infiltration in a patient with hypokalemic nephropathy and primary Sjögren's syndrome.

We report a case of hypokalemic nephropathy associated with primary Sjögren's syndrome (SS). The patient presented with profound and persistent hypokalemia secondary to distal renal tubular acidosis (RTA). A renal biopsy exhibited tubular degeneration, marked interstitial fibrosis and intense macrophage infiltration. Hypokalemia has been reported to induce macrophage infiltration in experimental animal models but not in humans. This is the first report of intense tubulointerstitial macrophage infiltration in a patient with hypokalemic nephropathy associated with SS.

Adult↗
PubMed2005

[Lung cancer combined with idiopathic interstitial pneumonias].

It is known that patients with idiopathic interstitial pneumonias (IIPs) have an increased incidence of lung cancer. The purpose of this study was to evaluate the outcome of surgical treatment and to establish the surgical strategy for lung cancer with IIPs. Twenty-five patients with lung cancer and IIPs who were admitted in our hospital from 1996 to 2004 were examined. Eight patients underwent lobectomy with mediastinal lymph node dissection, while 17 patients underwent limited resection. The actuarial 3-year survival rate was 43%. There were no postoperative acute exacerbation of IIPs. We considered most patients were in a stable state of IIPs preoperatively, and we made effort to treat IIPs with limited resection. The prognosis of IIPs was poor. It is difficult to decide whether to carry out limited resection.

Adenocarcinoma↗
PubMed2004

Effect of pitavastatin on apolipoprotein A-I production in HepG2 cell.

There are few reports describing the mechanism of HDL-elevating action of HMG-CoA reductase inhibitors (statins). As it is considered that the key step of HDL production is the secretion of apolipoprotein A-I (apoA-I), we investigated the effect of statins on apoA-I synthesis and secretion by HepG2 cell to elucidate the mechanism of the action. Each statin induced apoA-I expression (mRNA and protein) dose-dependently: the rank order of the apoA-I induction pitavastatin (3 microM)>simvastatin (10 microM)>atorvastatin (30 microM). The induction of apoA-I by statins disappeared with addition of mevalonate, which indicates that the effect is HMG-CoA reductase inhibition-dependent. Based on HMG-CoA reductase inhibition, pitavastatin-induced apoA-I more efficiently than simvastatin and atorvastatin. Further study revealed that pitavastatin increased ABCA1 mRNA in HMG-CoA reductase-dependent manner and that Rho and Rho kinase inhibitor (C3T and Y27632) increased apoA-I production in the HepG2 cells. These results suggest that pitavastatin efficiently increases apoA-I in the culture medium of HepG2 cells by promoting apoA-I production through inhibition of HMG-CoA reductase and suppression of Rho activity and by protecting apoA-I from catabolism through ABCA1 induction and lipidation of apoA-I.

Apolipoprotein A-I↗
PubMed2004

Impaired glucose tolerance is accompanied by decreased insulin sensitivity in tissues of mice implanted with cells that overexpress resistin.

AIM/HYPOTHESIS: Resistin, the expression of which is suppressed by thiazolidinedione treatment in adipocytes, is one of the key molecules for the tight link between adiposity and insulin resistance. Here, we show the in vivo effects of resistin on insulin sensitivity in mature mice using a cell implantation method. METHODS: Resistin cDNA was transfected into 3T3-L1 pre-adipocytes, which were then implanted into subcutaneous areas of nude mice. Metabolic analyses were performed 4 or 6 weeks after implantation. RESULTS: The mice implanted with 3T3-L1 cells overexpressing resistin (R-mice) showed significantly (p<0.05) increased plasma resistin levels. After a glucose load plasma insulin levels were significantly greater in R-mice than in mice implanted with mock-transfected cells (M-mice). The AUC of insulin after glucose loading was positively correlated with circulating resistin levels. Significantly decreased glucose responses after insulin injection were observed in R-mice, compared to M-mice. The insulin-induced phosphorylation level of IRS-1 was significantly lower in muscles of R-mice than M-mice. The expression of TNF-alpha mRNA in intra-peritoneal fat tissues was significantly greater in R-mice than in M-mice, but there was no difference between the two groups with regard to subcutaneous fat tissues. The concentration of TNF-alpha in plasma was positively correlated with resistin levels in R-mice. CONCLUSIONS/INTERPRETATION: Resistin, when actually secreted from cells in mature mice, causes disturbed glucose metabolism, possibly based on decreased insulin sensitivity in muscle. The in vivo effects of resistin on insulin sensitivity might be in part mediated by increased TNF-alpha expression in visceral fat tissues.

3T3 Cells↗
PubMed2004

Preoperative airway evaluation using multi-slice three-dimensional computed tomography for a patient with severe tracheal stenosis.

A 71-yr-old female with a malignant thyroid tumour was to undergo thyroidectomy under general anaesthesia. Preoperative chest x-ray and plain computed tomography (CT) showed severe tracheal stenosis. Three-dimensional figures of the trachea and a virtual bronchoscopic movie were obtained from multi-slice CT to evaluate the stenotic region and to simulate fibroscopic tracheal intubation, respectively. After induction of general anaesthesia with propofol, a tracheal tube was successfully passed through the stenotic region under the guide of a fibroscope as simulated in the virtual movie. We conclude that multi-slice CT is useful for preoperative airway evaluation for patients with stenosis and distortion of the trachea.

Aged↗
PubMed2004

Void fraction and velocity measurement of simulated bubble in a rotating disc using high frame rate neutron radiography.

To evaluate measurement error of local void fraction and velocity field in a gas-molten metal two-phase flow by high-frame-rate neutron radiography, experiments using a rotating stainless-steel disc, which has several holes of various diameters and depths simulating gas bubbles, were performed. Measured instantaneous void fraction and velocity field of the simulated bubbles were compared with the calculated values based on the rotating speed, the diameter and the depth of the holes as parameters and the measurement error was evaluated. The rotating speed was varied from 0 to 350 rpm (tangential velocity of the simulated bubbles from 0 to 1.5 m/s). The effect of shutter speed of the imaging system on the measurement error was also investigated. It was revealed from the Lagrangian time-averaged void fraction profile that the measurement error of the instantaneous void fraction depends mainly on the light-decay characteristics of the fluorescent converter. The measurement error of the instantaneous local void fraction of simulated bubbles is estimated to be 20%. In the present imaging system, the light-decay characteristics of the fluorescent converter affect the measurement remarkably, and so should be taken into account in estimating the measurement error of the local void fraction profile.

Journal Article↗