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Y Oka

Publications and source records attributed to Y Oka.

At least 253 records · Page 14Linked to original sources
PubMed1996

Glucose-regulated translational control of proinsulin biosynthesis with that of the proinsulin endopeptidases PC2 and PC3 in the insulin-producing MIN6 cell line.

In the short term (< 2 h), proinsulin biosynthesis is predominately glucose regulated at the translational level; however, the details at the molecular level behind this mechanism are not well defined. One of the major hindrances for gaining a better understanding of the proinsulin biosynthetic mechanism has been a lack of an abundant source of beta-cells that express a phenotype of regulated proinsulin biosynthesis in the appropriate 2.8-16.7 mmol/l glucose range as defined in normal pancreatic islets. In this study, we demonstrate that in the MIN6 cell line, specific glucose-regulated translational control of proinsulin biosynthesis is present in the appropriate glucose concentration range. In addition to that of proinsulin, the biosynthesis of the two proinsulin conversion endopeptidases, PC2 and PC3, was coordinately glucose regulated in MIN6 cells, whereas that of the exopeptidase, carboxypeptidase H, was unaffected by glucose. Proinsulin, PC2 and PC3 biosynthesis was specifically stimulated over that of total MIN6 cell protein synthesis above a threshold of 4 mmol/l glucose that reached a maximum rate between 8 and 10 mmol/l glucose. Glucose-induced proinsulin, PC2, and PC3 biosynthesis was rapid (occurring after a 20-min lag period but reaching a maximum by 60 min), unaffected by the presence of actinomycin D; and in parallel experiments, stimulatory glucose concentrations did not alter MIN6 cell total preproinsulin, PC2, or PC3 mRNA levels. Thus, short-term (< 2 h) glucose stimulation of proinsulin, PC2 and PC3 biosynthesis in MIN6 cells, like that in isolated islets, was mediated at the translational level. Intracellular signals for mediating glucose-stimulated proinsulin PC2 and PC3 biosynthesis translation in MIN6 cells also appeared to be similar to those in pancreatic islets, requiring glucose metabolism and a supporting role for protein kinase A. However, protein kinase C or a Ca(2+)-dependent protein kinase did not appear to be required for glucose-regulated proinsulin biosynthesis in MIN6 cells, as in islets. MIN6 cells are the first beta-cell line that indicate glucose-regulated proinsulin biosynthesis translation essentially identical to that in differentiated islet beta-cells and will be an important experimental model to better define the mechanism of proinsulin biosynthesis in detail.

Animals↗
PubMed1996

Effect of mitochondrial and/or cytosolic glycerol 3-phosphate dehydrogenase overexpression on glucose-stimulated insulin secretion from MIN6 and HIT cells.

The glycerol phosphate shuttle consists of FAD-linked mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH) and its cytosolic NAD-linked isoform (cGPDH). Impaired mGPDH activity has recently been suggested to be one of the primary causes of insulin secretory defects in beta-cells. We found that mGPDH and cGPDH activities in MIN6 cells are comparable to those of isolated islets and higher than those in HIT cells by eightfold and threefold, respectively. Therefore, we selected the MIN6 cell line as a beta-cell model with normally regulated insulin secretion and normal shuttle enzyme activities and the HIT cell line as a beta-cell model with impaired insulin secretion and lower activities of these enzymes. The role of these dehydrogenases in glucose-stimulated insulin secretion was addressed by examining the effects of overexpression of mGPDH and/or cGPDH via recombinant adenoviruses in these cells. Infection with recombinant adenovirus with a cDNA encoding the Escherichia coli beta-galactosidase gene resulted in expression of its gene in 90% of MIN6 and HIT cells. Infection with a recombinant adenovirus with mGPDH cDNA (Adex1CAmGPDH) caused 2.1-fold and 5.7-fold increases in dehydrogenase activity as compared with those of control MIN6 and HIT cells, respectively. Infection with a recombinant adenovirus with cGPDH cDNA (Adex1CAcGPDH) caused a more than 50-fold increase in activity in both cell lines. Glycerol phosphate shuttle flux, as estimated by [2-3H]glycerol conversion to [3H]H2O, was increased to 120-130% by infection with Adex1CAmGPDH, but not with Adex1CAcGPDH infection, in both MIN6 and HIT cells. No further increase in flux through the glycerol phosphate shuttle was detected when the cells were infected with Adex1CAmGPDH together with Adex1CAcGPDH. Furthermore, neither [U-14C]glucose oxidation nor the insulin secretory response to glucose was affected in either cell line. Thus, mGPDH abundance in MIN6 and HIT cells is not directly related to their insulin secretory capacity in response to glucose, and reduced expression of mGPDH is not the primary cause of abnormal insulin secretory responses in HIT cells. The present data indicate that the emerging hypothesis pointing to mGPDH deficiency as a possible cause of NIDDM needs to be carefully evaluated.

Adenoviridae↗
PubMed1996

Dose-dependent effect of niceritrol on plasma lipoprotein-a.

Lipoprotein-a, Lp(a), is a variant form of low density lipoprotein (LDL) that contains apolipoprotein-a, whose structure has 75-85% homology with plasminogen. Elevated plasma levels of Lp(a) are considered to be one of the independent risk factors for cardiovascular disease. We studied the effects of niceritrol, a nicotinic acid derivative, on plasma Lp(a) levels in 72 patients with hypercholesterolaemia. The dose of niceritrol was increased every 4 weeks, from 750 to 1500 and then to 2250 mg day-1. The final dose was adjusted to obtain a plasma cholesterol level less than 5.69 mmol l-1. Niceritrol led to significant decreases in plasma levels of median Lp(a), from 16.1 mg dl-1 (interquartile intervals, 8.7 to 32.8) to 11.1 mg dl-1 (interquartile intervals, 6.6 to 21), the mean reduction rate being 17.6%. In the group with pretreatment Lp(a) levels of over 20 mg dl-1, Lp(a) decreased by 10.0, 22.0 and 31.8% at the doses of 750, 1500, and 2250 mg day-1, respectively. In the group with levels less than 20 mg dl-1, only the dose of 2250 mg day-1 was effective in the reduction of Lp(a). The results suggest that the reduction of Lp(a) was dependent on the dose of niceritrol and on the pretreatment level of Lp(a). In conclusion, niceritrol is effective, in a dose-dependent manner, for reducing Lp(a) levels.

Aged↗
PubMed1996

[A case of dural AVM detected after STA-MCA anastomosis].

A case of dural arteriovenous malformation (AVM) in the posterior cranial fossa detected after STA-MCA anastomosis surgery. A 52-year-old male consulted a neighbourhood hospital for sudden headache and vomiting. He was diagnosed as having intraventricular hemorrhage on CT scan. Though the obstruction of the right internal carotid artery was revealed angiographically, his symptoms improved after conservative therapy. Two weeks after onset, his consciousness deteriorated and he developed left hemiparesis. Thereafter, he was transferred to our hospital. After thorough examination, right STA-MCA anastomosis surgery was performed. Approximately 2 months after surgery, right tinnitus developed and gradually exacerbated. Since it was thought to be due to increased blood flow in the right superficial temporal artery, it was kept under observation. On angiogram, 8 months after surgery, good blood flow supplied from the right superficial temporal artery to the territory of the right middle cerebral artery was shown, and a dural AVM fed by the right occipital artery was found. Fourteen months after the surgery, an enlarged dural AVM with backflow to the superficial cerebral veins fed by the enlarged right occipital artery and right ascending pharyngeal artery was revealed. Embolization therapy to the right occipital and ascending pharyngeal artery was performed using coils and ivalon, and irradiation of 30 Gy was added. After this treatment, right tinnitus improved. On angiography 2 years later, transverse sinus was slightly visible via the right occipital artery and ascending pharyngeal artery, but the dural AVM was significantly reduced. The origin of dural AVMs remains controversial. In our case, dural AVM was not found before the STA-MCA anastomosis surgery, and sinus thrombosis was not found throughout the course of observation. It is thought that the occult dural AVM was disclosed and enlarged by the increased blood flow through the external carotid artery via the STA-MCA anastomosis. Therefore, the dural AVM seemed to be congenital in origin.

Arteriovenous Malformations↗
PubMed1996

Donor leukocyte transfusions and discontinuation of immunosuppressants to achieve an initial remission after allogeneic bone marrow transplantation in a patient with primary refractory acute leukemia.

We present a female patient who received an allogeneic bone marrow transplantation for primary refractory Philadelphia-positive acute biphenotypic leukemia. Since leukemic blasts were persistently present in peripheral blood and bone marrow, in spite of the evidence for engraftment of male donor hematopoiesis, we performed donor leukocyte transfusions and discontinued immunosuppression. An initial complete remission was obtained 15 weeks after allogeneic bone marrow transplantation, and lasted for 24 weeks. We concluded that the prominent mechanism for the eradication of the refractory leukemic clone in the patient was the graft-versus-leukemia effect.

Adult↗
PubMed1996

Disposition of oligonucleotides in isolated perfused rat kidney: involvement of scavenger receptors in their renal uptake.

The objective of this study was to clarify the renal disposition characteristics of a 20-mer model phosphodiester oligonucleotide and its partially (PS3) and fully (PS) phosphorothioated derivatives, in isolated rat perfused kidney. Venous outflow and urinary excretion pattern, as well as tissue accumulation of radioactivity after bolus injection of 32P-labeled oligonucleotides, were evaluated under both filtering and nonfiltering conditions. The binding affinity of oligonucleotides to bovine serum albumin in the perfusate increased as the number of sulfur atoms present in the oligonucleotide molecules increased, resulting in 21, 60 and 86% binding to bovine serum albumin for phosphodiester oligonucleotide, PS3 and PS, respectively. The apparent steady-state distribution volumes of the oligonucleotides, as calculated from the venous outflow patterns, were larger than that of inulin, which corresponds to the extracellular volume of the kidney, suggesting their interaction with tissue from the vascular space. PS showed the largest distribution volume. Urinary excretion of oligonucleotides was greatly restricted, compared with that of inulin, which was used as a marker of glomerular filtration rate. The accumulation of these oligonucleotides was ascribed to both tubular reabsorption and uptake from the capillary side. The uptake of oligonucleotides from the capillary side increased as the number of sulfur atoms present in the molecules increased, suggesting sulfur atom-dependent interactions between oligonucleotides and renal tissue. In addition, the uptake of PS3 was a saturable process. Furthermore, coadministration of dextran sulfate and polyinosinic acid inhibited the renal uptake of PS3, whereas polycytidic acid and 4-acetamido-4'-isothiocyanato-stilbene-2,2'-disulfonic acid did not, suggesting that oligonucleotides were taken up via the scavenger receptor-mediated process for polyanions. These findings provide valuable information for the development of delivery systems for antisense oligonucleotides.

Animals↗
PubMed1996

Beta-cell loss and glucose induced signalling defects in diabetes mellitus caused by mitochondrial tRNALeu(UUR) gene mutation.

Japanese diabetic patients with diabetic mothers were screened, using peripheral leukocytes, for an A to G transition at nucleotide pair 3243, a tRNALeu(UUR) mutation of the mitochondrial gene. This mutation was identified in four pedigrees from among 300 unrelated patients. Diabetes mellitus cosegregated with the mutation, except in one young subject, and was maternally inherited. Long-term follow-up revealed that the underlying disorder, in affected individuals, is a progressive impairment of insulin secretion. In accordance with this finding, the mutation was found to be highly prevalent in a diabetes mellitus subset termed slowly progressive IDDM; the mutation was identified in 3 out of 27 subjects enrolled in the prospective study of islet cell antibody (ICA)-positive, initially non-insulin-dependent diabetic Japanese patients, who are at high risk of progressing to insulin dependence over several years. The histologic characteristics of slowly progressive insulin-dependent diabetes mellitus include substantial loss, though incomplete, of pancreatic beta-cells. Mitochondrial gene defects in beta-cells could therefore cause glucose-induced signalling defects as well as beta-cell loss. This would explain the wide range of diabetic phenotypes, from NIDDM to IDDM, in patients with this mitochondrial gene mutation.

Adult↗
PubMed1996

[Glucose transporter].

All mammalian cells contain trans-membrane transport systems for the stereo specific uptake of glucose. These systems are divided into two groups, a facilitated diffusion system driven by the concentration differences across the membrane and an energy-dependent, active transport system. Both are mediated by specific membrane proteins, termed glucose transporter. The facilitated glucose transporters comprise a structurally related family of proteins having 12 membrane-spanning domains, with the amino terminus, a relatively large middle loop and the carboxy-terminus all oriented towards the cytoplasm. The active glucose transport system is also designated Na+/glucose cotransporter, SGLT, the predicted secondary structure of which is still controversial.

Animals↗
PubMed1996

Changes in cortical CBF and vascular response after vascular reconstruction in patients with adult onset moyamoya disease.

Using 133Xe single photon emission tomography, we evaluated the cortical region cerebral blood flow (rCBF) and vascular response to acetazolamide loading before and after vascular reconstructive surgery in 9 hemispheres in 6 patients with adult-onset moyamoya disease. Before the operation, the resting rCBF was not markedly impaired except that several low rCBF regions were present in the frontal and temporal lobes, and after the operation, the number of regions showing normal rCBF was significantly increased. Regional vascular response was more diffusely impaired in the regions with both normal and low rCBF before the operation, the excessively high response observed in the parietal and occipital lobes was well normalized after the operation, while the low response to acetazolamide challenge in the frontal and temporal lobes was not adequately improved.

Acetazolamide↗
PubMed1996

[Effects of the time interval between the first and second balloon inflations on ischemic preconditioning during percutaneous transluminal coronary angioplasty].

Ischemic preconditioning is an attenuation of myocardial ischemia by repeated brief coronary occlusions observed during percutaneous transluminal coronary angioplasty (PTCA). The effects of the time delay between balloon inflations during PTCA on ischemic preconditioning were investigated in 48 patients with chronic stable angina but no rich collateral vessels. After successful predilatation, two 2-min balloon inflations were performed and the ST segment elevation in the electrocardiogram and chest pain were measured during each balloon inflation and compared. Patients were divided into three groups according to the interval between balloon inflations; 1 min (I1), 2 min (I2) and 5 min (I5). There were no significant differences in ST elevation (3.4, 3.2 and 3.7 mm) and chest pain during the first balloon inflation between these three groups. ST elevation and chest pain were decreased in groups I2 and I5 (2.6 and 2.8 mm) during the second balloon inflation compared with those during the first balloon inflation. However, there was no significant difference in ST elevation and chest pain during the first and second (3.7 mm) balloon inflations in group I1. ST elevation and chest pain were reduced more in group I5 than in I2. These results suggest that an interval of more than 2 min between balloon inflations is necessary to obtain the effect of ischemic preconditioning during PTCA.

Aged↗
PubMed1995

Nuclear location of the regulatory protein of glucokinase in rat liver and translocation of the regulator to the cytoplasm in response to high glucose.

Rat liver is known to contain a regulatory protein (RP) that inhibits glucokinase competitively with respect to glucose. By an immunohistochemical technique and by cell fractionation in glycerol, we investigated the distribution of RP in rat liver and its changes in response to high glucose. RP was detected almost exclusively in the nuclei of the parenchymal cells of both fed and fasted rats. In situ perfusion of the liver with 20 mM glucose for 10 min caused a marked decrease in nuclear RP and an increase in cytoplasmic RP. These results indicate that RP is present predominantly in the nuclei of hepatocytes and is translocated from the nucleus to the cytoplasm in response to high glucose.

Animals↗
PubMed1995

Expression and localization of glucose transporter 1 (GLUT1) in the rat oviduct: a possible supplier of glucose to embryo during early embryonic development.

The oviduct fluid mainly derived from the oviduct epithelium is reported to provide the environment necessary for embryonic development. To elucidate the origin of glucose in the oviduct fluid, we examined the expression and localization of glucose transporter 1 (GLUT1) in the rat oviduct by Northern blot analysis, immunoblot analysis and immunohistochemistry using both light and electron microscopy. Northern blot and immunoblot analyses both showed the presence of the GLUT1 mRNA and protein. Specific staining for GLUT1 was observed in the ampulla and the isthmus, but only slightly in the fimbria and the utero-tubal junction. Staining was confined to the luminal surface of the epithelial mucosa. Immunoelectron microscopic analysis revealed that GLUT1 was observed only on the surface of the microvilli in non ciliated secretory cells, but not in ciliated cells. These findings suggest that GLUT1 plays an important role in the glucose transfer from the oviduct epithelium into the lumen and in maintaining the adequate glucose concentration of the oviduct fluid for embryonic development in rat oviduct.

Animals↗
PubMed1995

Inhibition of pancreatic beta-cell glucokinase by antisense RNA expression in transgenic mice: mouse strain-dependent alteration of glucose tolerance.

We have generated transgenic mice, in either C57BL/6 or C3H background, expressing antisense glucokinase mRNA in beta-cells. The glucose phosphorylating activity at 60 mM glucose in transgenic islets was significantly lower than that in controls, and the insulin secretory response to glucose was lower in transgenic islets than in those of controls in both strains. Following i.p. glucose challenge, higher blood glucose levels were observed in transgenic mice than in controls in the C57BL/6 but not the C3H background. These data suggest that a beta-cell secretory defect, in combination with other undefined genetic factors, causes impaired glucose homeostasis in mice.

Animals↗
PubMed1995

Structural and functional analysis of the canine histamine H2 receptor by site-directed mutagenesis: N-glycosylation is not vital for its action.

G-protein-coupled receptors generally share a similar structure containing seven membrane-spanning domains and extracellular site(s) for N-glycosylation. The histamine H2 receptor is a member of the family of G-protein-coupled receptors, and has three extracellular potential sites for N-glycosylation (Asn-4, Asn-162 and Asn-168). To date, however, no information has been presented regarding N-glycosylation of the H2 receptor. To investigate the presence, location and functional roles of N-glycosylation of the H2 receptor, site-directed mutagenesis was performed to eliminate the potential site(s) for N-glycosylation singly and collectively. The wild-type and mutated H2 receptors were expressed stably in Chinese hamster ovary (CHO) cells or transiently in COS7 cells. Immunoblotting of the wild-type and mutated H2 receptors with an antiserum directed against the C-terminus of the H2 receptor showed that mutation at Asn-162, but not at Asn-168, resulted in a substantial decrease in the molecular mass. A mutation at Asn-4 led to a further decrease in the molecular mass. Tunicamycin treatment of the transfected cells yielded a sharp band with a molecular mass identical to that of the mutant devoid of all three potential sites for N-glycosylation. These findings indicate that the H2 receptor is N-glycosylated, and that N-glycosylation takes place mainly at two sites, Asn-4 and Asn-162. Neither the affinity for tiotidine nor that for histamine was affected by the mutagenesis. Immunocytochemistry and tiotidine binding showed that the mutated receptors were exclusively distributed on the cell surface in a fashion similar to that of the wild-type. In addition, the glycosylation-defective receptor was capable of activating adenylate cyclase and elevating the intracellular Ca2+ concentration in response to histamine in stable CHO cell lines. Thus N-glycosylation of the H2 receptor is not required for cell surface localization, ligand binding or functional coupling to G-protein(s).

1-Methyl-3-isobutylxanthine↗
PubMed1995

Increased susceptibility of angiographically smooth left anterior descending coronary artery to an impairment of vasoresponse to acetylcholine, and the relation between impaired vasoresponse and low-density lipoprotein cholesterol level.

In the present study, we demonstrated that the angiographically smooth LAD is more susceptible than the LC to an impairment of vasoresponse to acetylcholine, suggesting the more severe endothelial dysfunction in the LAD. We also showed that levels of LDL play a partial but important role on endothelial dysfunction.

Acetylcholine↗