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Biomedical subjects

R Kikkawa

Publications and source records attributed to R Kikkawa.

At least 55 records · Page 3Linked to original sources
PubMed2000

The sera from GM1 ganglioside antibody positive patients with Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy blocks Na+ currents in rat single myelinated nerve fibers.

OBJECTIVE: To determine the possible role of anti-GM1 ganglioside antisera from patients with Gullain-Barr*e syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP) in the development of nerve dysfunction. METHODS: The effect of the anti-GM1 antibody positive antisera obtained from 4 GBS patients and 1 CIDP patient on membrane potential and ionic currents in rat single myelinated nerve fibers was investigated using the voltage clamp technique and compared with that of the anti-GM1 negative antisera obtained from 3 healthy controls and 2 GBS patients. RESULTS: In the presence of active complement, anti-GM1 positive antisera from 5 patients including 4 GBS patients and 1 CIDP patient significantly suppressed Na+ current more than anti-GM1 negative antisera. CONCLUSION: This study supports the notion that anti-GM1 antibody is one of the causative factors of conduction abnormality in GBS patients.

Adult↗
PubMed2000

Evaluation of a new care system provided to diabetic patients in the outpatient clinic.

OBJECTIVE: Evaluation of metabolic states and chronic complications is essential for maintaining a high quality of care for diabetic patients. We have assessed the quality of care in routine outpatient clinics for diabetic subjects in our university hospital, and compared with those in a newly introduced standardized clinic to evaluate the new care system. METHODS: The quality of care was assessed by the chart review in 1995, and compared with those from 1996-1997 in the "Diabetes Follow-up Clinic" which is systematically designed for the standardized care. PATIENTS: The subjects were recruited among 860 patients who visited the outpatient clinic in July and August of 1995 with a diagnosis of diabetes or glucose intolerance. Six hundred seventy-two patients whose follow-up period had been more than 6 months with clinically diagnosed diabetes were used for the analysis. RESULTS: Laboratory tests such as determination of HbA1c, and serum levels of lipids and creatinine were performed in more than 90% of the patients in the routine outpatient clinics. However, ophthalmology referral, 24-hour urine collection for the determination of creatinine clearance and albumin excretion, and electrocardiograms were not well performed and were incompletely documented (40-60% of the patients within a previous year and 70-80% in the last 2 years). In the standardized "Diabetes Follow-up Clinic", only four out of 555 diabetic patients failed to collect their 24-hour urine, and all participants had ankle blood pressure measurements, nerve conduction study, and nylon monofilament tests, etc. Furthermore, more than 95% of the patients had funduscopic examinations by ophthalmologists as well as records of electrocardiogram. CONCLUSION: Introduction of the standardized "Diabetes Follow-up Clinic" may be one of the choices for increasing the quality of outpatient care and for the prevention of chronic diabetic complications.

Adult↗
PubMed2000

Thiazolidinedione compounds ameliorate glomerular dysfunction independent of their insulin-sensitizing action in diabetic rats.

Thiazolidinedione (TZD) compounds are widely used as oral hypoglycemic agents. Herein, we provide evidence showing that troglitazone, one of the TZD compounds, is able to prevent glomerular dysfunction in diabetic rats through a novel mechanism independent of its insulin-sensitizing action. We examined the effect of troglitazone on functional and biochemical parameters of glomeruli in streptozotocin-induced diabetic rats. Troglitazone was able to prevent not only diabetic glomerular hyperfiltration and albuminuria, but an increase in mRNA expression of extracellular matrix proteins and transforming growth factor-beta1 in glomeruli of diabetic rats, without changing blood glucose levels. Biochemically, an increase in diacylglycerol (DAG) contents and the activation of the protein kinase C (PKC)-extracellular signal-regulated kinase (ERK) pathway in glomeruli of diabetic rats were abrogated by troglitazone. The activation of DAG-PKC-ERK pathways in vitro in mesangial cells cultured under high glucose conditions was also inhibited by troglitazone. Troglitazone enhanced the activities of DAG kinase, which could metabolize DAG to phosphatidic acid, in both glomeruli of diabetic rats and mesangial cells cultured under high glucose conditions. Surprisingly, pioglitazone, another TZD compound without alpha-tocopherol moiety in its structure, also prevented the activation of the DAG-PKC pathway and activated DAG kinase in mesangial cells cultured under high glucose conditions. These results may identify the TZDs as possible new therapeutic agents for diabetic nephropathy that prevent glomerular dysfunction through the inhibition of the DAG-PKC-ERK pathway.

Albuminuria↗
PubMed2000

[Kidney disease and insulin resistance--clinical impact of thiazolidinedione compounds for kidney disease].

The thiazolidinedione compounds are well known hypoglycemic agents via increasing insulin-sensitivity. Herein, we provide the possibility that thiazolidinedione compounds could be useful for renal dysfunction through mechanism dependent or independent of its insulin-sensitizing action. In type 2 diabetes, troglitazone could reduce urinary albumin-creatinine ratio compared to metformin. Furthermore, we have shown that troglitazone was able to prevent diabetic glomerular dysfunction through inhibition of diacylglycerol-protein kinase C-extracellular signal-regulated kinase pathway in type 1 diabetic rats. Thus, thiazolidinediones might be effective agents for treating insulin-resistant diabetes as well as diabetes-induced kidney disease.

Animals↗
PubMed1999

Expression of a dominant negative SHP-2 in transgenic mice induces insulin resistance.

To elucidate the roles of SHP-2, we generated transgenic (Tg) mice expressing a dominant negative mutant lacking protein tyrosine phosphatase domain (DeltaPTP). On examining two lines of Tg mice identified by Southern blot, the transgene product was expressed in skeletal muscle, liver, and adipose tissues, and insulin-induced association of insulin receptor substrate 1 with endogenous SHP-2 was inhibited, confirming that DeltaPTP has a dominant negative property. The intraperitoneal glucose loading test demonstrated an increase in blood glucose levels in Tg mice. Plasma insulin levels in Tg mice after 4 h fasting were 3 times greater with comparable blood glucose levels. To estimate insulin sensitivity by a constant glucose, insulin, and somatostatin infusion, steady state blood glucose levels were higher, suggesting the presence of insulin resistance. Furthermore, we observed the impairment of insulin-stimulated glucose uptake in muscle and adipocytes in the presence of physiological concentrations of insulin. Moreover, tyrosine phosphorylation of insulin receptor substrate-1 and stimulation of phosphatidylinositol 3-kinase and Akt kinase activities by insulin were attenuated in muscle and liver. These results indicate that the inhibition of endogenous SHP-2 function by the overexpression of a dominant negative mutant may lead to impaired insulin sensitivity of glucose metabolism, and thus SHP-2 may function to modulate insulin signaling in target tissues.

Animals↗
PubMed1999

Impaired regeneration and no amelioration with aldose reductase inhibitor in crushed unmyelinated nerve fibers of diabetic rats.

The regenerative ability of unmyelinated nerve fibers (UNFs) in diabetes and the effect of aldose reductase inhibitor (ARI) on it were ultrastructurally evaluated after sciatic nerve crush in control and untreated and tolrestat-treated streptozocin-induced diabetic rats. The density and number of UNFs were significantly increased in all groups at 5 weeks after the injury. The increase returned to the baseline level in control rats, but not in diabetic rats at 24 weeks. Although the axon size showed a marked decrease at 5 weeks and an incomplete recovery at 24 weeks in all groups, the recovery was significantly worse in diabetic than in control groups. Tolrestat did not have any effect on regeneration of UNFs in diabetes. These results suggest impaired regeneration of UNFs after nerve crush injury in diabetes and less therapeutic effect of ARI on it.

Aldehyde Reductase↗
PubMed1999

Mitogen-activated protein kinase phosphatase: a negative regulator of the mitogen-activated protein kinase cascade.

Mitogen-activated protein kinases (MAPKs) are activated by various stimuli, such as growth factors, cytokines, or stress, and are considered to be important mediators in intracellular signal transduction networks. The dual-specificity kinases, MAPK kinases (MKKs), which phosphorylate the TXY motif in the catalytic domain of MAPKs, can cause the activation of MAPKs. Recently, a family of dual-specificity phosphatases has been identified, members of which are able to dephosphorylate and inactivate MAPKs. The studies cited in this review have revealed that these MAPK phosphatases might play an important role in various cellular functions by downregulating the MAPK cascade.

Animals↗
PubMed1999

A new antidiabetic agent (JTT-501) rapidly stimulates glucose disposal rates by enhancing insulin signal transduction in skeletal muscle.

A newly synthesized antidiabetic agent, JTT-501 is an isoxazolidinedione rather than a thiazolidinedione. An oral dose of JTT-501 (100 mg x kg(-1) x day(-1)) given to 12-week-old male Zucker fatty rats for 7 days led to the amelioration of both hyperinsulinaemia (40% of non-treated) and hypertriglyceridaemia (23% of non-treated) as well as a 2.4-fold increased insulin sensitivity as determined by a euglycaemic insulin clamp. In our study, we further evaluated the acute effect of JTT-501 on both the glucose infusion rates (GIR) and insulin signalling in skeletal muscle. Male Sprague-Dawley (SD) rats aged 10 weeks were injected intravenously with JTT-501 (5 mg/kg) and then a euglycaemic insulin clamp was initiated and glucose infusion rates monitored for 150 min. We found that this treatment increased the glucose infusion rate by 33% during the last 30 min in SD rats. After the clamp had been initiated for 30 min, the insulin-stimulated phosphatidylinositol 3-kinase (PI3-kinase) activities co-immunoprecipitated with insulin receptor substrate 1 (IRS-1) were also enhanced, resulting in increased glycogen synthase activities in the soleus muscles. Treatment with JTT-501 also enhanced the phosphorylation of insulin receptors and insulin receptor-substrate 1 rapidly as well as the phosphatidylinositol 3-kinase activities, which were stimulated by a bolus injection of insulin. Similarly, JTT-501 stimulated the glucose infusion rate by 30% and enhanced insulin signalling in Zucker fatty rats. In conclusion, a newly developed isoxazolidinedione, JTT-501, rapidly potentiates the insulin sensitivity of skeletal muscle by enhancing insulin signalling and could be useful for the treatment of insulin-resistant diabetic subjects.

Animals↗
PubMed1999

Role of PDGF B-chain and PDGF receptors in rat tubular regeneration after acute injury.

Various polypeptide growth factors are generally considered to be involved in the regulation of the nephrogenic process both after acute renal injury and during renal development. Because platelet-derived growth factor B-chain (PDGF-B) has been reported to be expressed in immature tubulus of the developing kidney, PDGF-B could play a role in the process of tubulogenesis. We examined the expression of PDGF-B and PDGF receptors alpha and beta and their localization in kidneys after ischemia/reperfusion injury. The mRNA expressions of PDGF-B, PDGFR-alpha, and PDGFR-beta were enhanced after injury. In the immunohistochemical analysis and/or in situ hybridization, PDGF-B and PDGFR-alpha, beta were expressed after reperfusion in the S3 segment of the proximal tubuli, where they were not expressed normally. The expressions of proliferating cell nuclear antigen and vimentin were concomitantly observed with PDGF-B and PDGFRs in the tubular cells of injured S3 segment at 48 hours after injury. Next, the inhibition of the PDGF-B/PDGFRs axis with either Trapidil or Ki6896, which was found to inhibit the phosphorylation of PDGFR-beta selectively, resulted in a rise of serum creatinine, higher mortality rate, abnormal regenerating process, and suppressed proliferation of tubular epithelial cells. These findings suggest that the PDGF-B/PDGFRs axis is involved in the proliferation of injured tubular cells and plays an important role in the regeneration of tubular cells from acute ischemic injury.

Animals↗
PubMed1999

Effect of glycemic control on plasma plant sterol levels and post-heparin diamine oxidase activity in type 1 diabetic patients.

We examined the effect of glycemic control on the plasma plant sterol levels (a measure of cholesterol absorption efficacy) and the plasma post-heparin diamine oxidase (DAO) activity (a measure of intestinal mucosal mass) in type 1 diabetes. The plasma plant sterol levels (mmol/mol of cholesterol) and the DAO activities after 30 U/kg of intravenous heparin were determined in age- and sex-matched three groups (12 type 1 diabetic patients undergoing conventional insulin therapy, ten patients undergoing intensive insulin therapy, and ten normal subjects). All patients continued their indicated insulin regimen for 14 days with a weight-maintaining energy restricted diet. The conventional group showed a significant higher (p < 0.001) level of the fasting plasma glucose (FPG) or the glycated albumin (GA), a higher (P < 0.01) DAO activity (2-fold of the peak level), which was observed 10-30 min after the heparin injection, and a higher (P < 0.01) plasma plant sterol levels (1.5-fold) compared with those in the other two groups, respectively. The DAO activity 30 min after the heparin injection significantly correlated with either the glycated albumin (GA) concentration or the plant sterol levels in all subjects. Furthermore, the acute glycemic control by the changes of insulin regimen from conventional to intensive showed a significant reduction of the DAO activity and plant sterols in the same patients. These results suggest that glycemic control in part relates to the intestinal adaptation to cholesterol absorption efficacy in type 1 diabetes.

Adolescent↗
PubMed1999

Effects of cholesterol-lowering treatments on oxidative modification of plasma intermediate density lipoprotein plus low density lipoprotein fraction in Type 2 diabetic patients.

To investigate the normalization of enhanced oxidative modification of the lipoprotein such as increased lysophosphatidylcholine (LPC) and lipid hydroperoxide (LPO) contents in diabetic subjects, we studied the effect of cholesterol-lowering treatment on those parameters in 24 hypercholesterolemic Type 2 diabetic patients. Those patients were randomly assigned to two treatment groups, such as 12 patients treated with pravastatin 10 mg daily and 12 patients treated with probucol 500 mg daily for 8 weeks. Characteristics of the patients including age, gender, body mass index (BMI), smoking habit, modality of diabetic treatment and the glycemic control state were comparable between the two groups. LPC content in the lipoprotein fractions obtained from 24 patients with Type 2 diabetes mellitus was significantly higher than that of non-diabetic control subjects. The abnormality was improved to the control level after a significant improvement of serum cholesterol levels following 8 week-treatments with either probucol or pravastatin without any change in glycemic control (P < 0.025). Furthermore, increased LPO content in the lipoprotein fraction in those diabetics was also significantly (P < 0.0025) improved by the probucol treatment and tended to be improved by pravastatin treatment (P = 0.06). LPC contents in the lipoprotein fraction was positively correlated with LPO contents before cholesterol-lowering treatments (r = 0.41, P < 0.05). These results indicate that cholesterol-lowering treatments effectively reduce oxidative modification of the lipoprotein fraction containing intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) in hypercholesterolemic Type 2 diabetic patients.

Anticholesteremic Agents↗
PubMed1999

Free radical production in endothelial cells as a pathogenetic factor for vascular dysfunction in the insulin resistance state.

Impairment of nitric oxide-dependent vascular relaxation is a characteristic feature of the insulin-resistant state. To understand those mechanisms, we examined imbalance of O2-/NO production in aortic endothelial cells obtained from high fructose-fed, exogenous hyperinsulinemic, and control rats. Aortic segments from both high fructose-fed and insulin-treated rats produced a 4-fold more O2- than control rats evaluated by a chemiluminescence method. The O2- production in the aortas of both high fructose-fed and insulin-treated rats was mediated through activation of NADH/NADPH oxidase. In isometric tension studies, high fructose vessels with endothelium elicited impaired relaxation in response to acetylcholine or a calcium ionophore A23187 when compared with control rats, whereas these impaired vascular responses were not found in insulin-treated rats. Furthermore, endothelial constitutive NO synthase activity was increased in vessels from insulin-treated rats, but decreased in vessels from high fructose-fed rats. These results indicate that relative excess of O2- production through activation of NADH/NADPH oxidase over NO generation in endothelial cells may contribute to impaired endothelial-dependent relaxation in insulin-resistant state.

Acetylcholine↗
PubMed1999

Tetrodotoxin-resistant sodium channels of dorsal root ganglion neurons are readily activated in diabetic rats.

To clarify the mechanism of hyperalgesia in diabetic neuropathy, we investigated the effects of streptozocin-induced hyperglycemia on tetrodotoxin-resistant Na+ channel activity of dorsal root ganglion neurons. Experiments were performed on enzymatically isolated neurons of dorsal root ganglia dissected from streptozocin-induced diabetic and their age-matched control rats. Membrane currents were recorded using the whole-cell patch-clamp technique. Mean current density of tetrodotoxin-resistant Na+ channels was significantly larger in neurons prepared from diabetic rats than in control neurons. Tetrodotoxin-resistant Na+ channels were activated at more negative potentials in diabetic than in control neurons. Curves representing the steady-state inactivation and the peak Na+ conductance as a function of membrane potential shifted to the negative side. The changes in gating property of the Na+ channel were observed six weeks after the injection of streptozocin, and still after eight months, indicating that tetrodotoxin-resistant Na+ channel abnormality starts to develop early and persists during the whole period of diabetes. These results suggest that neurons participating in nociception are highly excitable in diabetic animals. The present results may provide an important clue to the elucidation of hyperalgesia in diabetes.

Animals↗
PubMed1999

TGF-beta 1 stimulates glucose uptake by enhancing GLUT1 expression in mesangial cells.

BACKGROUND: An increase in the expression of transforming growth factor-beta 1 (TGF-beta 1) has been proposed to play an important role in the excessive production of extracellular matrix (ECM) proteins seen in diabetes. Because the linkage between glucose metabolism and ECM protein production was found in mesangial cells overexpressed with the brain-type glucose transporter (GLUT1), we hypothesized that TGF-beta 1 could affect glucose metabolism. METHODS: To prove this hypothesis, we examined the effect of TGF-beta 1 on glucose uptake, the first step of glucose metabolism, in mesangial cells. 2-Deoxy-D-glucose (2DOG) uptake and the expression of GLUT1 were measured in mesangial cells exposed to various concentrations of TGF-beta 1. The kinetic constants were determined using 2DOG and 3-O-methyl-D-glucose (3OMG). The effect of anti-TGF-beta neutralizing antibody on 2DOG uptake and GLUT1 mRNA was also examined in mesangial cells cultured under high-glucose (22.2 mM) conditions for 72 hours. RESULTS: TGF-beta 1 stimulated 2DOG uptake in mesangial cells by approximately 2.5-fold in a dose- (1.25 ng/ml maximum) and time-dependent manner, with a peak stimulation at nine hours. The increase in 2DOG uptake by TGF-beta 1 was completely abolished by the addition of 1 microgram/ml cycloheximide, and kinetic analysis of 2DOG or 3OMG uptake revealed an increase in Vmax by TGF-beta 1. Furthermore, TGF-beta 1 enhanced the expression of GLUT1 mRNA from one hour, followed by an enhancement of the expression of GLUT1 protein at nine hours. Finally, 2DOG uptake was significantly enhanced in cells cultured under high-glucose (22.2 mM) conditions as compared with that in cells under normal glucose (5.6 mM) conditions, and this increase in 2DOG uptake in cells under high-glucose conditions was inhibited by the addition of anti-TGF-beta neutralizing antibody. CONCLUSIONS: TGF-beta 1 stimulates glucose uptake by enhancing the expression of GLUT1 in mesangial cells, which leads to the acceleration of intracellular metabolic abnormalities in diabetes.

3-O-Methylglucose↗
PubMed1999

Endothelium-specific activation of NAD(P)H oxidase in aortas of exogenously hyperinsulinemic rats.

To examine the effects of chronic hyperinsulinemia on vascular tissues, we examined the production of superoxide anion (O(-2)) in the aortic tissues of control and exogenously hyperinsulinemic rats performed by the implantation of an insulin pellet for 4 wk. O(-2) production by aortic segments from hyperinsulinemic rats was 2. 4-fold (lucigenin chemiluminescence method) and 1.7-fold (cytochrome c method) of that of control rats without any differences in O(-2) degrading activities in aortic tissues, respectively (P < 0.025). The increment was completely abolished in the presence of either 100 micromol/l apocynin (an inhibitor of NADPH oxidase) or 10 micromol/l diphenyleneiodonium (an inhibitor of flavin-containing enzyme) and was exclusively endothelium dependent. Consistently, NAD(P)H oxidase activities in endothelial homogenate in hyperinsulinemic rats were dose dependently stimulated above the values of control rats, although these activities in nonendothelial homogenate were not significantly stimulated by insulin. Furthermore, an insulin effect was also demonstrated 1 h after exposing aortic tissues to insulin. These results indicate that O(-2) production specifically increases in endothelium of aortic tissues in chronic hyperinsulinemic rats through the activation of NAD(P)H oxidase.

Animals↗
PubMed1999

Relationship between polymorphism in the angiotensinogen, angiotensin-converting enzyme or angiotensin II receptor and renal progression in Japanese NIDDM patients.

We determined the relationship between the gene polymorphism of angiotensinogen (AGT), angiotensin-converting enzyme (ACE), or angiotensin II receptor (AT1R) and the progression of diabetic nephropathy in a multicenter trial of ethnically homogeneous Japanese patients with non-insulin-dependent diabetes (NIDDM). Gene polymorphism of ACE I/D, AGT M235T and AT1R A1166C was determined by polymerase chain reaction amplification using allele-specific primers. Japanese NIDDM patients (n = 1,152) were selected from several diabetic clinics. All patients were divided into three groups as follows: (1) group I (n = 407): normoalbuminuric patients; (2) group II (n = 327): microalbuminuric patients, and (3) group III (n = 418): overt albuminuric patients. Clinical factors for investigation in all patients were the date of birth, gender, levels of urinary albumin excretion, findings of the ocular fundus, duration of diabetes, hemoglobin A1c and blood pressure. It appears that genetic polymorphisms in the renin-angiotensin systems, i.e. ACE or AT1R, may affect the progression to renal failure of patients (especially females) with NIDDM.

Aged↗
PubMed1999

Abnormal biopterin metabolism is a major cause of impaired endothelium-dependent relaxation through nitric oxide/O2- imbalance in insulin-resistant rat aorta.

To investigate underlying mechanisms responsible for the impaired nitric oxide (NO)-dependent vascular relaxation in the insulin-resistant state, we examined production of both NO and superoxide anion radical (O2-) and those modulating factors in aortas obtained from normal (CTR), insulin-treated (INS), or high fructose-fed (FR) rats. FR rats showed insulin resistance with endogenous hyperinsulinemia, whereas INS rats showed normal insulin sensitivity. Only FR aortic strips with endothelium elicited impaired relaxation in response to either acetylcholine or calcium ionophore A23187. Endothelial NO synthase (eNOS) activity and its mRNA levels were increased only in vessels from INS rats (P < 0.001), whereas eNOS activity in FR rats was decreased by 58% (P < 0.05) when compared with CTR rats. NO production from aortic strips stimulated with A23187 was significantly lower in FR than CTR rats. In contrast, A23187-stimulated O2- production was higher (P < 0.01) in FR than CTR rats. These differences were abolished when aortic strips were preincubated in the media including (6R)-5,6,7,8-tetrahydrobiopterin (BH4), an active cofactor for eNOS. Furthermore, as compared with CTR rats, aortic BH4 contents in FR rats were decreased (P < 0.001), whereas the levels of 7,8-dihydrobiopterin, the oxidized form of BH4, were increased, with opposite results in INS rats. These results indicate that insulin resistance rather than hyperinsulinemia itself may be a pathogenic factor for decreased vascular relaxation through impaired eNOS activity and increased oxidative breakdown of NO due to enhanced formation of O2- (NO/O2- imbalance), which are caused by relative deficiency of BH4 in vascular endothelial cells.

Acetylcholine↗