Biomedical subjects

K Shima

Publications and source records attributed to K Shima.

At least 91 records · Page 5Linked to original sources

PubMed1999

Pathoetiology and prevention of NIDDM lessons from the OLETF rat.

The OLETF rat, a genetic model of spontaneous development of NIDDM, exhibits hyperglycemic obesity with hyperinsulinemia and insulin resistance similar to that in humans. It is still unclear whether a defect in the beta-cell proliferation per se is the primary pathogenetic event in this model rat. To clarify this matter, we used partially pancreatectomized rats as a model. Male rats of 6 weeks of age were allocated at random to two groups: 70% pancreatectomy (Px) and sham-pancreatectomy (sham). Each group was divided into 4 subgroups by the date of sacrifice after surgery. Sustained hyperglycemia was evident in the Px OLETF rats after surgery. This was associated with insufficient proliferation of beta-cells, characterized by a decrease in beta-cell labeling with 5-bromo-2' deoxyuridine in proportion to a decrease in beta-cell mass and reduction in insulin content in the remnant pancreas. Administration of nicotinamide, however, ameliorated the sustained hyperglycemia by increasing beta-cell proliferation. These findings suggest that OLETF rats have a poor capacity for proliferation of pancreatic beta-cells, and that this change may be the critical pathogenetic event prior to the onset of overt diabetes. OLETF rats following long-term caloric restriction and spontaneous exercise training show normal glucose tolerance accompanied by an increase in GIR as shown by a euglycemic clamp. Both exercise training and caloric restriction normalize the abnormalities in the pancreas such as marked hypertrophy of islets and hyperplasia of connective tissues in islets. It is particularly noteworthy that exercise training significantly elevated the beta-cell mass/body weight ratio. This evidence obtained from OLETF rats may be of value when the mechanism of diet and exercise effects on diabetic patients are considered.

Animals↗

PubMed1998

A missense mutation of mouse OCTN2, a sodium-dependent carnitine cotransporter, in the juvenile visceral steatosis mouse.

Carnitine is an essential cofactor for the mitochondrial beta-oxidation of long-chain fatty acids. The juvenile visceral steatosis (JVS) mouse, an animal model of systemic carnitine deficiency, is inherited in an autosomal recessive manner. Recently, a human OCTN2 gene encoding a sodium-dependent carnitine cotransporter was isolated and mapped to human chromosome 5q31. Since the mouse jvs locus was assigned to the region of chromosome 11 where it is syntenic to human chromosome 5q31, we isolated the mouse octn2 gene and screened for its mutation in the jvs mouse. DNA sequencing analysis disclosed a missense mutation from CTG (Leu) to CGG (Arg) at codon 352 located within the sixth transmembrane domain of octn2. This amino acid replacement possibly causes the conformational change of the protein that leads to dysfunction of the gene product. Hence, we conclude that octn2 is a candidate gene responsible for the JVS mouse.

Amino Acid Sequence↗

PubMed1998

Mouse placental cells secrete soluble leptin receptor (sOB-R): cAMP inhibits sOB-R production.

The aims of this study were to identify whether mouse placenta secretes soluble OB-R (sOB-R) and to find the regulating factor of OB-R expression. Total RNAs were extracted from placenta and decidua, and OB-R expression was assessed by Northern blot analysis. Decidua did not express OB-R mRNA. However, OB-R mRNA expression was detectable in the placenta on day 13 of pregnancy, and then it increased and reached a peak on day 17 of pregnancy. Mouse placental cells from day 12 of pregnancy were cultured and OB-R gene expression was assessed by Northern blot analysis. OB-R mRNA expression was detectable from the second day of culture and reached a peak on the third day of culture. To determine whether placental cells release sOB-R, supernatant of cultured placental cells was subjected to Western blot analysis. sOB-R was detected in the medium by the second day of culture and sOB-R release increased up to the fourth day of culture. Addition of leptin to the medium did not affect expression of OB-R mRNA. However, 8-bromo cAMP inhibited both steady-state levels of OB-R mRNA and the amount of sOB-R protein in the medium in a dose- and time-dependent manner. These results suggest that trophoblast cells differentiate, express, and release sOB-R both in vivo and in vitro and that cAMP is one of several potent regulators of sOB-R secretion by the mouse placenta.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1998

Role for cingulate motor area cells in voluntary movement selection based on reward.

Most natural actions are chosen voluntarily from many possible choices. An action is often chosen based on the reward that it is expected to produce. What kind of cellular activity in which area of the cerebral cortex is involved in selecting an action according to the expected reward value? Results of an analysis in monkeys of cellular activity during the performance of reward-based motor selection and the effects of chemical inactivation are presented. We suggest that cells in the rostral cingulate motor area, one of the higher order motor areas in the cortex, play a part in processing the reward information for motor selection.

Animals↗

PubMed1998

Circulating leptin did not associate with the development of the hyperglycemia accompanied by insulin insensitivity in spontaneous noninsulin dependent diabetes mellitus model Otsuka-Long-Evans-Tokushima-Fatty rats.

Leptin, the product of the ob gene, has been reported to regulate feeding behavior and energy metabolism. Plasma leptin concentration was strongly correlated with body fat content in humans. It is well known that increased body fat content is accompanied by insulin insensitivity. In order to study the relationship between serum leptin level and metabolic variables, we performed caloric restriction on Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats, a model of noninsulin dependent diabetes mellitus. The male OLETF rats were allocated at random to three groups: 100% group, and 85% and 70% groups (which consumed 85% and 70% of the amount of food consumed by the 100% group, respectively). A significant correlation between serum leptin level and the body fat content, body weight, triglyceride, and fasting plasma glucose was observed. Using a partial correlation analysis to control for body fat content, however, the correlation between serum leptin and these variables disappeared. No significant changes in serum leptin levels were observed before and after a 1 h hyperinsulinemic euglycemic clamp test. In conclusion, serum leptin was significantly correlated with body fat content rather than fasting plasma glucose, serum insulin and insulin sensitivity. This suggests that circulating leptin per se may not result in hyperinsulinemia and insulin insensitivity in the OLETF rat.

Animals↗

PubMed1998

Leptin receptor signal transduction: OBRa and OBRb of fa type.

We report herein the characterization of activities of signal transduction for three types of leptin receptors (OBRs) from rats, the OBRa, OBRb, and OBRb with fa mutation (OBRb-fa), by measurement of the levels of tyrosine phosphorylation of STAT3 (signal transducers and activators of transcription 3) and MAPK (mitogen-activated protein kinase), which are induced by leptin stimulation of CHO cells stably expressing the OBR (CHO-OBRb, CHO-OBRa, or CHO-OBRb-fa cells). As the result of leptin stimulation, enhanced levels of tyrosine phosphorylation of STAT3 and MAPK were detected in CHO-OBRb cells. In CHO-OBRb-fa cells, enhancement levels for both were lower than those in CHO-OBRb cells. In CHO-OBRa cells, only the phosphorylation of MAPK was detected. These data suggest that these reduced signaling activities cause obesity in fa/fa rats and that OBRa, which has been generally thought to be inactive at signaling, actually transmits signals through the MAPK pathway.

Animals↗

PubMed1998

Autocrine inhibition of leptin production by tumor necrosis factor-alpha (TNF-alpha) through TNF-alpha type-I receptor in vitro.

The aim of this study was to find factors which regulate m-leptin secretion during pregnancy. Mouse parametrial adipocytes from day 13 of pregnancy were cultured with or without mouse placental lactogen (mPL)-I, mPL-II, or mouse tumor necrosis factor-alpha (mTNF-alpha) and mouse-leptin (m-leptin) concentration in the medium was assessed by RIA. Up to four days of mPL-I or mPL-II treatment did not affect m-leptin secretion. However, mTNF-alpha, which is produced by adipocytes, significantly inhibited m-leptin secretion in a dose- and time-dependent manner. Antibody to mTNF-alpha completely blocked the inhibitory effect of mTNF-alpha on m-leptin secretion. mTNF-alpha significantly inhibited the expression of m-leptin messenger RNA. Agonistic polyclonal antibody directed against the mTNF-type-I receptor (mTNF-RI) significantly inhibited m-leptin secretion, but the anti-mTNF-RII antibody did not change m-leptin secretion. Moreover, human TNF-alpha (h-TNF-alpha) also inhibited human-leptin (h-leptin) secretion by cultured human adipocytes collected from the subcutaneous fat of pregnant women. These results suggest that TNF-alpha, which is secreted by adipocytes, inhibits m-leptin secretion through mTNF-RI and suggest the presence of an autocrine or paracrine regulation of leptin secretion in human and mouse adipose tissue in vivo.

Adipocytes↗

PubMed1998

Characteristics of cardiac hypertrophy in the juvenile visceral steatosis mouse with systemic carnitine deficiency.

The juvenile visceral steatosis (JVS) mouse exhibits hereditary systemic carnitine deficiency and develops cardiac hypertrophy. The aim of this study was to clarify the characteristics of cardiac hypertrophy in the JVS mouse. Total carnitine content in IVS mouse heart was about 10% of that of control mouse heart at 4 and 8 weeks of age. The heart weight/body weight ratio was bigger in JVS mice than that in control mice at 2 weeks of age, and this difference in ratio increased with age. The wall areas of both ventricles and septum in JVS mice were larger than those of the control mice at 2 and 8 weeks. The myocyte diameter in both ventricular walls and septum in JVS mice was longer than that of the control mice. On electron microscopy, the percent of mitochondria in the myocyte was 66% in JVS mice, and 37% in control mice. The percent of lipid fraction in JVS mice was six-fold higher than that in control mice. Total content of adenine nucleotides in JVS mouse heart was about 60% of that in control mouse heart. Adenylate energy charge in JVS mouse heart was 63 and 45% of that in the control mouse heart at 4 and 8 weeks, respectively. Overall, the cardiac enlargement observed in this animal model could be accounted for by a proportional increase in the myocyte diameter in the ventricles and septum, accompanied by an increase in mitochondria. Furthermore, this cellular growth is associated with decreases in the levels of ATP and ADP, and adenylate energy charge.

Adenosine Diphosphate↗

PubMed1998

Selective hippocampal damage to hypoxia after mild closed head injury in the rat.

Our previous studies have shown selective neuronal damage in the CA3 region after mild closed head injury (CHI) combined with hypoxia. In the present studies, we examined (1) extracellular concentrations of neuroactive amino acids using in vivo microdialysis technique and (2) neuroactive amino acid binding to their receptors using quantitative autoradiography. Male SD rats were divided into five groups; sham control, mild CHI (sacrificed at 1 h or 24 h after CHI), mild CHI followed by hypoxia (1 h or 24 h). [3H]-Glutamate binding to NMDA receptors, [3H]-muscimol binding to GABAA receptors and [3H]-kainate binding to KA receptors were measured in hippocampus and cortex by quantitative autoradiography. With CHI alone, GLU and TAU levels were transiently increased by 15 min posttrauma. In the CHI with hypoxia, increases in GLU and TAU levels were sustained until 60 min following CHI. GABA level was also increased until 75 min posttrauma Pretreatment of MK-801 significantly diminished the prolonged elevation in GLU and TAU levels. (2) CHI alone did not produce prominent change in the measured receptor binding. When hypoxia was combined with CHI, significant increase in [3H] GLU binding to NMDA receptors and significant decrease in [3H]-muscimol binding to GABAA receptors were observed in CA1 and CA3 at 1 h and 24 h post-insult. These results demonstrate that selective hippocampal damage to hypoxia after mild CHI may be mediated through an increase in NMDA receptor activation and the further release of GLU and that NMDA antagonist may be beneficial in preventing secondary neuronal damage by hypoxia.

Animals↗

PubMed1998

Association of distal chromosome 2q with IDDM in Japanese subjects.

An insulin-dependent diabetes mellitus (IDDM)-susceptibility gene (IDDM13) has recently been mapped to a region of distal chromosome 2q, which is syntenic to the region of mouse chromosome 1 containing a murine susceptibility gene for IDDM, Idd5. To determine the contribution of this region to IDDM disease susceptibility further and to narrow the region for positional cloning of susceptibility genes, we have studied the association of distal chromosome 2q with IDDM in the genetically distinct Japanese population. A 137 mobility unit (mu) allele at D2S137 locus was significantly associated with IDDM (odds ratio 1.92, p = 0.0016). Other markers, D2S301 and D2S143, located in the same region were not associated with IDDM, indicating that IDDM13 is in linkage disequilibrium with D2S137, but not with D2S301 or D2S143. The association of D2S137 with IDDM was observed in patients lacking one of two high risk HLA alleles, DQBI*0303 and DQBI*0401, but not in patients with either of these alleles. The frequency of high risk HLA alleles was significantly lower in patients with the susceptible allele at D2S137, suggesting that IDDMI3 contributes to IDDM susceptibility in subjects without high risk genotypes at IDDM1. Demonstration of allelic association of D2S137 with IDDM localizes IDDM13 in the close vicinity (<2 centiMorgans) of D2S137, greatly facilitating fine structure mapping and positional cloning of IDDM13.

Adolescent↗

PubMed1998

Ovarian hormone-induced beta-cell hypertrophy contributes to the homeostatic control of beta-cell mass in OLETF female rat, a model of Type II diabetes.

A sexual dimorphism regarding the incidence of diabetes mellitus in OLETF rat, a model of Type II diabetes, has been reported. As a result, the effects of ovarian hormones on beta cells per se was examined by comparing the capacity of beta-cell proliferation and changes in blood glucose and plasma insulin concentrations after a 70% pancreatectomy. All female animals were randomly assigned to two protocols. The rats involved in protocol I received either a 70% pancreatectomy (Px) or a sham pancreatectomy (sham) at 6 weeks of age, along with their diabetes-resistant counterparts, female LETO rats, which served as normal controls. The rats belonging to protocol II were given an ovariectomy (Ox) at 5 weeks of age, and one week later, they were subjected to either Px or the sham operation, with/without hormone (estradiol, 50 microg/kg; testosterone, 1 mg/kg) replacement. The findings indicate that the capacity for compensatory growth of beta cells after Px was affected by both sex hormonal and genetic components, since a 70% Px resulted in sustained hyperglycaemia within the first week after surgery, but was ameliorated by an increase in beta-cell mass thereafter in the non-Ox Px OLETF rats. The Ox also caused a decline in beta-cell mass which could be improved by replacement with ovarian hormones. Not only endogenous but also replacement ovarian hormones, led to a beneficial effect on beta cells per se in OLETF female rats. This was reflected by an increased beta-cell mass accompanied by a parallel increase in plasma immunoreactive insulin concentration. The effects of ovarian hormones, however, contributed to the beta-cell hypertrophy rather than expansion of the beta-cell population to achieve glucose homeostasis, as evidenced by an increased area of individual beta-cell after Px rather than an increased BrdU-labelling index for the beta cells. The present study suggests that ovarian hormone-induced beta-cell hypertrophy may typically occur, to compensate for changes in functional demand as the results of a 70% Px in female OLETF rats.

Animals↗

PubMed1998

A major quantitative trait locus co-localizing with cholecystokinin type A receptor gene influences poor pancreatic proliferation in a spontaneously diabetogenic rat.

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese-type, non-insulin-dependent diabetes mellitus (NIDDM) in humans. The OLETF rat has poor capacity for pancreatic proliferation, which may be the critical pathogenetic event in NIDDM development. Our investigation was designed to identify quantitative trait loci (QTLs) responsible for poor pancreatic proliferation by examining compensatory proliferation of the pancreatic remnant after partial pancreatectomy and performing a genome-wide scan in an F2 intercross obtained by mating the OLETF and the Fischer-344 (F344) rats. We identified a highly significant QTL on rat Chromosome 14 with a maximum lod score of 16.7, which accounts for 55% of the total variance. The QTL co-localizes with the gene encoding cholecystokinin type A receptor (CCKAR) which is likely to mediate the trophic effect of cholecystokinin on pancreas and is defective in the OLETF rat.

Animals↗

PubMed1998

A role of nicotinamide-induced increase in pancreatic beta-cell mass on blood glucose control after discontinuation of the treatment in partially pancreatectomized OLETF rats.

Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of NIDDM, is normoglycemic at a young age. However, they become hyperglycemic, even at a young age as a result of a 70% pancreatectomy, which is associated with insufficient proliferation of beta-cells. Administration of nicotinamide ameliorates the sustained hyperglycemia by increasing beta-cell proliferation. In order to further understand its mode of action, we studied how long nicotinamide is effective, in terms of ameliorating hyperglycemia, as evidenced by an increase in beta-cell mass, after its administration, in partially pancreatectomized OLETF rats. Male rats, 6 weeks of age, were allocated at random to two groups, 70% pancreatectomy (Px) and sham-pancreatectomy (sham). The Px group was divided into three subgroups, based on treatment with either nicotinamide (350 mg/kg), phlorizin (400 mg/kg) or saline, which continued until 4 weeks after surgery, and were sacrificed at 4, 6, or 8 weeks after surgery. A 70% Px resulted in sustained hyperglycemia in the saline-treated Px rats, which was ameliorated by administration of either phlorizin or nicotinamide, showing the non-fasting blood glucose levels reached to or near the levels found in the sham rats. After cessation of phlorizin injection, non-fasting blood glucose level increased rapidly, reaching the level of the saline-treated Px rats at the end of the experiment, whereas after cessation of nicotinamide injection, non-fasting blood glucose increased gradually to a level which was significantly lower than that observed in the saline-treated Px rats. An increased beta-cell mass, 62.7 +/- 7.8% of total beta-cell mass induced by nicotinamide at 4 weeks, decreased gradually, reaching the level of pretreatment, 30.3 +/- 4.0% 4 weeks after cessation of the treatment. The findings in this study suggest that ameliorated hyperglycemia as a result of proliferated beta-cells during the administration of nicotinamide may results in showing beta-cell exhaustion (a majority of beta-cell degranulation) once stopping injection, as compared with phlorizin treated group in this model rat.

Animals↗

PubMed1998

The influence of ovariectomy on ob gene expression in rats.

Ovarian steroid hormones exert major influences on eating behaviour and body weight regulation of female rats. Ovariectomy (OVX) results in an increase in food intake and a concomitant increase in body weight, while estradiol (E2) replacement reverses these effects. In this study, we examined the influence of OVX on obese (ob) gene expression in rat adipose tissues and serum leptin concentration. Female Wistar rats, 10 weeks old, were divided into three groups: sham-operated control rats receiving corn oil (group 1, n = 4), ovariectomized rats receiving corn oil (group 2, n = 5), and ovariectomized rats receiving 17beta-E2 (10 microg/kg/day) replacement (group 3, n = 4). After 4 weeks, the rats and food consumption were weighed and serum E2 and leptin levels were measured by radioimmunoassays. Furthermore, the expression levels of ob mRNA obtained from the bilateral perimetric fat pads were estimated by Northern blot analysis. The mean weight and food consumption in group 2 were significantly (p < 0.01) heavier than those in group 1. But there were no significant differences between group 1 and group 3. The expression levels of ob mRNA in group 2 were lower than those in group 1, however, the levels of group 3 were restored to the level of group 1. On the other hand, no significant differences among the 3 groups as to serum levels of leptin were observed. The data herein clearly indicate that ovarian steroid hormones may be one of the factors involved in the regulation of ob gene.

Adipose Tissue↗

PubMed1998

Successful surgical removal of a large arteriovenous malformation in a patient with hemophilia: case report.

OBJECTIVE AND IMPORTANCE: This is the first reported case of the successful surgical removal of a large arteriovenous malformation (AVM) in a patient with hemophilia A. CLINICAL PRESENTATION: A 19-year-old male patient was admitted to our department with intracranial hemorrhage. He had previously been diagnosed with hemophilia A and a cerebral AVM. Carotid angiography revealed a large AVM in the right temporal and parietal lobes. The neurological and neuroradiological findings, especially those of single photon emission computed tomography, identified an area of devitalization around the lesion, which was thought to reduce the risk of new deficits resulting from surgical manipulation. INTERVENTION: We resected the AVM in conjunction with supplemental infusions of Factor VIII before, during, and after the operation. A slight cerebral hemorrhage on the 7th postoperative day was observed despite control with Factor VIII, but the patient was discharged without any new deficits. CONCLUSION: We evaluated and managed all problems of a patient with multiple complications and achieved a medical cure.

Adult↗

PubMed1998

Both supplementary and presupplementary motor areas are crucial for the temporal organization of multiple movements.

Both supplementary and presupplementary motor areas are crucial for the temporal organization of multiple movements. J. Neurophysiol. 80: 3247-3260, 1998. To study the involvement of the supplementary (SMA) and presupplementary (pre-SMA) motor areas in performing sequential multiple movements that are individually separated in time, we injected muscimol, a gamma-aminobutyric acid agonist, bilaterally into the part of each area that represents the forelimb. Two monkeys were trained to perform three different movements, separated by a waiting time, in four or six different orders. First, each series of movements was learned during five trials guided by visual signals that indicated the correct movements. The monkeys subsequently executed the three movements in the memorized order, without the visual signals. After the injection of muscimol (3 microliter, 5 micrograms/microliters in 10 min) into either the SMA or pre-SMA bilaterally, the animals started making errors in performing the sequence of movements correctly from memory. However, when guided with a visual signal, they could select and perform the three movements correctly. The impaired memory-based sequencing of movements worsened progressively with time until the animals could not perform the task. Yet they still could associate the visual signals with the different movements at that stage. In control experiments on two separate monkeys, we found that injections of the same amount of muscimol into either the SMA or pre-SMA did not cause problems with nonsequential reaching movement regardless of whether it was visually triggered or self-initiated. These results support the view that both the SMA and pre-SMA are crucially involved in sequencing multiple movements over time.

Animals↗

PubMed1998

Task-dependent selectivity of movement-related neuronal activity in the primate prefrontal cortex.

Task-dependent selectivity of movement-related neuronal activity in the primate prefrontal cortex. J. Neurophysiol. 80: 3392-3397, 1998. We studied movement-related neuronal activity in the dorsolateral prefrontal cortex from the perspective of a general role for the prefrontal cortex in controlling motor behavior to achieve a specific goal according to the requirements of a given task. Monkeys were trained to perform two delayed motor tasks. The first task involved reaching for a target that matched the shape of a cue. The second task involved reaching for a target that matched the location of the cue. A majority (54%) of 175 movement-related prefrontal neurons exhibited preference for either the target shape or the type of task requirements. Sixty-four neurons (36%) were selectively active while reaching for a circle or a triangle. On the other hand, the activity of 59 neurons (34%) depended on whether the task required matching the shape or the location. These properties, characterizing the movement-related neuronal activity in the prefrontal cortex, rarely were found in the arm area of the primary motor cortex. Only 1 of 130 movement-related neurons (0.8%) showed task selectivity, and none showed target-shape selectivity.

Animals↗

PubMed1998

Upregulation of retinal vascular endothelial growth factor mRNAs in spontaneously diabetic rats without ophthalmoscopic retinopathy. A possible participation of advanced glycation end products in the development of the early phase of diabetic retinopathy.

Vascular endothelial growth factor (VEGF) has recently been shown to be involved in the pathogenesis of proliferative diabetic retinopathy. However, its involvement in the development of the early phase of diabetic retinopathy is not fully understood. In this study we investigated the retinal VEGF mRNA level in spontaneously diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats, a model of non-insulin-dependent diabetes, without overt retinopathy, using quantitative reverse-transcription polymerase chain reaction. The retinal VEGF mRNA level was 2.2 times higher (p < 0.0005) in OLETF rats than in control rats at the age of 60 weeks. Moreover, their retinal mRNA level was positively correlated with serum concentration of advanced glycation end products (AGEs) but not to serum glucose concentration. Furthermore, the peak latency of the oscillatory potentials in the electroretinogram, one of the most sensitive markers for the early phase of diabetic retinopathy, was significantly prolonged in OLETF rats (p < 0.05), being also correlated with the serum AGE concentration. The results thus suggest that AGEs, which are formed acceleratedly in diabetic conditions, are involved in the development of the early phase of diabetic retinopathy probably through the induction of retinal VEGF mRNAs.

Animals↗