Search PubMed⌕ Search

Biomedical subjects

Ryuzo Kawamori

Publications and source records attributed to Ryuzo Kawamori.

At least 19 recordsLinked to original sources
PubMed2006

Acarbose, an alpha-glucosidase inhibitor, improves endothelial dysfunction in Goto-Kakizaki rats exhibiting repetitive blood glucose fluctuation.

Several epidemiological studies have revealed that subjects with postprandial hyperglycemia are at increased risk of cardiovascular disease. However, the impact of postprandial hyperglycemia and its treatment on endothelial function has not been clarified yet. In this study, Goto-Kakizaki (GK) rats, a non-obese type 2 diabetes model, fed twice daily were used as a model of repetitive postprandial glucose spikes. We investigated the endothelial function in these rats treated or untreated with acarbose, an alpha-glucosidase inhibitor. Administration of acarbose for 12 weeks markedly improved postprandial hyperglycemia, postprandial insulin level, total cholesterol, triglyceride, and free fatty acid level in GK rats. Furthermore, acarbose efficiently reduced the number of monocytes adherent to aortic endothelial layer, improved acetylcholine-dependent vasodilatation, and reduced intimal thickening of the aorta. While it is generally regarded that repetitive postprandial hyperglycemia is associated with the onset of cardiovascular diseases, our data demonstrated that acarbose treatment efficiently ameliorated endothelial dysfunction and reduced intimal thickening, thus adding support to the protective effect of acarbose against the onset of cardiovascular disease.

Acarbose↗
PubMed2006

Beneficial effects of candesartan, an angiotensin II type 1 receptor blocker, on beta-cell function and morphology in db/db mice.

Several epidemiological studies suggested that treatment with angiotensin II type 1 receptor blocker (ARB) provided a risk reduction of developing type 2 diabetes. In this study, we investigated whether and how ARB treatment can improve abnormalities of pancreatic islets in diabetes state. We randomized db/db mice, a model of type 2 diabetes with obesity, at the age of 8 weeks to receive candesartan, an ARB, for 6 weeks. We also studied age-matched db/misty mice as control. Glucose tolerance test revealed that candesartan treatment improved glucose tolerance with the modest increase in serum insulin level in db/db mice. Concurrently, candesartan increased beta-cell mass, increased staining intensity of insulin, and decreased staining intensity of components of NAD(P)H oxidase, p22phox and gp91phox, and those of oxidative stress markers in beta-cells. These changes were accompanied by reduction of mitochondrial volume. Treatment with candesartan also reduced fibrosis in and around the islets and prevented the loss of endothelial cells in islets. Our results showed that candesartan partially prevented deterioration of glucose tolerance by providing protection against progressive beta-cell damage in diabetes.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2006

Eicosapentaenoic acid reduces the progression of carotid intima-media thickness in patients with type 2 diabetes.

To investigate the effect of highly purified eicosapentaenoic acid (EPA) on the progression of diabetic macroangiopathy, we performed an open-label randomized prospective trial. A total of 81 Japanese type 2 diabetes were randomly assigned to the EPA (1800 mg/day) treated group or the control group. Carotid intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV) were evaluated before and after treatment in both groups. Sixty patients (EPA group, n=30; control group, n=30) completed this study. During the study period of 2.1+/-0.2 years, the mean IMT and max IMT of the EPA treated group showed a significant annual decrease compared with that of the control group (mean IMT, -0.029+/-0.112 mm versus 0.016+/-0.109 mm, respectively, P=0.029; max IMT, -0.084+/-0.113 mm versus -0.005+/-0.108 mm, respectively, P=0.0008). The baPWV was also improved significantly in the EPA treated group compared with the control group (-22.1+/-127.9 cm/s versus 62.3+/-223 cm/s, respectively, P=0.021). Multiple regression analysis showed that the administration of EPA was a significant and independent factor associated with an annual improvement of mean IMT (R2=0.067). In summary, this is the first demonstration that administration of purified EPA improves the carotid IMT and the baPWV in patients with type 2 diabetes.

Aged↗
PubMed2006

Activin A-induced expression of PAX4 in AR42J-B13 cells involves the increase in transactivation of E47/E12.

Pax4 is a paired-homeodomain containing transcriptional factor that controls the differentiation of pancreatic beta cells. The aim of this study was to investigate the mechanism of PAX4 expression by activin A. By reporter gene analysis using AR42J-B13 cells, in which treatment with activin A induced PAX4 mRNA expression, we identified that a short sequence located approximately 1930 bp upstream of the transcriptional start site is essential for activin A induced PAX4 promoter activation. This region contains an E box and binding sites for hepatocyte nuclear factor (HNF)-1alpha. Mutation introduced in each binding site markedly reduced activin A responsiveness. It has been reported that HNF-1alpha synergizes with basic helix-loop-helix (bHLH) proteins in activating the PAX4 promoter, and we demonstrated that activin A strongly enhanced the functional activity of E47/E12 without the increase in its binding ability. In addition, suppression of E47/E12 expression in AR42J-B13 cells using siRNA oligonucleotides results in the significant decrease in the intrinsic activin A-induced PAX4 expression. Our results suggest that activin A enhances PAX4 expression by enhanced transactivation of E47/E12 proteins and might result in a cumulative transactivation of the promoter.

Activins↗
PubMed2006

Chemotactic cytokine receptor 5 (CCR5) gene promoter polymorphism (59029A/G) is associated with diabetic nephropathy in Japanese patients with type 2 diabetes: a 10-year longitudinal study.

We previously showed that polymorphisms of the promoter area of chemokine receptor 5 (CCR5) gene (59029G/A) and its agonist, regulated upon activation, normal T-cell expressed and secreted (RANTES) gene (-28C/G) were new candidates for susceptibility to diabetic nephropathy. The aim of this study was to confirm the effect of these polymorphisms on the development and progression of diabetic nephropathy. We performed a 10-year retrospective study of 191 Japanese type 2 diabetic patients with normoalbuminuria at baseline. The subjects were classified into two groups: (1) those with persistent normoalbuminuria (group N) and (2) those with progression from normoalbuminuria to microalbuminuria or overt proteinuria (group P). Then, their association with CCR5 59029G/A and RANTES -28C/G polymorphisms was assessed. The frequency of the RANTES -28G(+) genotype did nor differ between the two groups, but the CCR5 59029A(+) genotype had a significantly higher frequency in group P than in group N (83% versus 71%, p=0.04). By discriminant analysis, only the CCR5 59029A(+) genotype showed an independent positive correlation with the onset or progression of nephropathy (p=0.03, odds ratio=2.41, 95% CI=1.09-5.33). Therefore, the CCR5 59029A(+) genotype seems to be related the etiology of diabetic nephropathy in Japanese type 2 diabetics.

Aged↗
PubMed2006

Effects of portal free fatty acid elevation on insulin clearance and hepatic glucose flux.

We tested the hypothesis that, due to greater hepatic free fatty acid (FFA) load, portal delivery of FFAs, as in visceral obesity, induces hyperinsulinemia and increases endogenous glucose production to a greater extent than peripheral FFA delivery. For 5 h, 10 microeq.kg(-1).min(-1) portal oleate (n = 6), equidose peripheral oleate (n = 5), or saline (n = 6) were given intravenously to conscious dogs infused with a combination of portal and peripheral insulin to enable calculation of hepatic insulin clearance during a pancreatic euglycemic clamp. Peripheral FFAs were similar with both oleate treatments and were threefold greater than in controls. Portal FFAs were 1.5- to 2-fold greater with portal than with peripheral oleate. Peripheral insulin concentrations were greatest with portal oleate, intermediate with peripheral oleate (P < 0.001 vs. portal oleate or controls), and lowest in controls, consistent with corresponding reductions in plasma insulin clearance and hepatic insulin clearance. Although endogenous glucose production did not differ between the two routes of oleate delivery, total glucose output (endogenous glucose production plus glucose cycling) was greater with portal than with peripheral oleate (P < 0.001) despite the higher insulin levels. In conclusion, during euglycemic clamps in dogs, the main effect of short-term elevation in portal FFA is to generate peripheral hyperinsulinemia. This may, in the long term, contribute to the metabolic and cardiovascular risk of visceral obesity.

Animals↗
PubMed2006

Efficacy and adverse effects of nateglinide in early type 2 diabetes. Comparison with voglibose in a cross-over study.

An open-label prospective cross-over trial was performed to compare the efficacy and adverse effects of nateglinide with those of voglibose on Japanese early type 2 diabetes (who were oral hypoglycemic agent naïve and whose HbA(1C) levels were between 7.0 and 7.9% before treatment). Fourteen patients received 270 mg/day of nateglinide and 15 patients received 0.6 mg/day of voglibose. After 12 weeks of either therapy, the drugs were switched and treatment was continued for another 12 weeks. After 3-month treatment with each drug, HbA(1C) value decreased significantly (baseline HbA(1C) 7.24 +/- 0.42%, 6.70 +/- 0.47% with nateglinide: p<0.01, 6.93 +/- 0.62% with voglibose: p<0.05) but the difference in the effect between nateglinide and voglibose was not significant (p = 0.121). Symptoms related to hypoglycemia (e.g., increased appetite, palpitation, sweating, tremor) were scarcely observed with either voglibose or nateglinide treatments. Abdominal fullness/borborygmi was frequently reported, with variable severity, by patients on voglibose but this was absent or mild in those on nateglinide. After completion of both arms of the study, more patients favored nateglinide than voglibose. Our results suggest that nateglinide is an effective and safe drug in the treatment of early type 2 diabetes, similar to voglibose.

Aged↗
PubMed2006

Strict glycemic control ameliorates the increase of carotid IMT in patients with type 2 diabetes.

The aim of this study was to investigate the effect of strict glycemic control on the carotid artery intima-media thickness (IMT) in type 2 diabetic patients who initially had good glycemic control (HbA1c between 5.8 and 6.4 %). The subjects were 67 patients showing deterioration of the mean HbA1c over 3 years by more than 0.2% from baseline (D group) and 33 subjects showing improvement of the mean HbA1c by more than 0.2% from baseline (A group). The clinical characteristics and annual change of IMT during the observation period were compared between the two groups in a 3-year retrospective longitudinal study. The baseline characteristics and the mean values of BMI, blood pressure, and serum lipids during the study period did not differ significantly between the two groups. However, the mean HbA1c of A group was significantly lower than that of D group (5.67 +/- 0.10 vs. 6.28 +/- 0.08, mean +/- SE, p<0.001). The adjusted annual increase rate of IMT was significantly less in A group than in D group (-0.035 +/- 0.019 vs. 0.036 +/- 0.015 mm, M +/- SEM, p<0.001). These results indicate that further improvement of glycemic control from a good HbA1c value can prevent an increase of IMT in type 2 diabetic patients.

Adult↗
PubMed2006

Therapeutic efficacy of mitiglinide combined with once daily insulin glargine after switching from multiple daily insulin regimen of aspart insulin and glargine in patients with type 2 diabetes mellitus.

Mitiglinide is novel class of rapid-acting insulin secretagogues, which have been widely used alone or in combination with other oral hypoglycemic drugs to improve postprandial hyperglycemia in early type 2 diabetes. While mitiglinide enhances postprandial requirement of insulin, the efficacy of mitiglinide combined with insulin has yet to be established. We investigated the efficacy of mitiglinide combined with insulin glargine, the first soluble insulin analog that has a flat and prolonged effect. After control with the intensive regimen (daily aspart insulin and glargine), 30 inpatients with type 2 diabetes were switched to premeal mitiglinide combined with once daily insulin glargine (mitiglinide regimen), and daily profiles of blood glucose level were compared under each regimen. Fifteen patients showed similar control of hyperglycemia with mitiglinide regimen and intensive insulin regimen, assessed by M value (<32), while the remaining 15 showed worsening under the mitiglinide regimen. The patients who were well controlled with mitiglinide regimen were significantly younger (51.9 +/- 16.0 years, p<0.005) and heavier (body mass index: 25.7 +/- 3.3 kg/m(2), p<0.05) than those who were not (67.9 +/- 8.7 and 23.0 +/- 3.1, respectively). Moreover, insulin doses of aspart per body weight were significantly fewer in effective group than in ineffective group. Duration of diabetes was shorter in the effective group, albeit insignificantly. Previous treatment before starting intensive insulin regimen, such as insulin and sulfonylurea, was not different between the two groups. Our results suggest that mitiglinide plus insulin glargine combination therapy is useful for lowering both fasting and postprandial hyperglycemia in a subpopulation of type 2 diabetes. The long-term effects of such treatment need to be established in future studies.

Adult↗
PubMed2006

[Treatment policy for elderly diabetic patients in preparation for the super-aged society].

Recently in Japan, as the elderly population has increased remarkably, the number of elderly patients with diabetes is rapidly increasing. Among the elderly diabetic patients, there are much differences in the physical, mental, and society viewpoints. Therefore the restrictions they suffer in daily life are multifarious. In the treatment policy of elderly diabetic patients, it is important that we evaluate their various backgrounds and so on synthetically and then provide the treatment which is suitable and tailored for each of them. We have to cure with the aim of not only prevention of being taken and progress of complications but also support and improvement of elderly diabetic patient's quality of life.

Aged↗
PubMed2005

Intronic polymorphisms within TFAP2B regulate transcriptional activity and affect adipocytokine gene expression in differentiated adipocytes.

We have identified a gene encoding transcription factor activating enhancer binding protein-2beta (TFAP2B) as a candidate for conferring susceptibility to type 2 diabetes. Although we have also found that TFAP2B was preferentially expressed in adipose cells in a differentiation-dependent manner, the mechanisms by which the gene and gene polymorphisms contribute to conferring susceptibility to the disease have not yet been elucidated. The aim of this study was to evaluate the impact of the polymorphisms within the TFAP2B gene on conferring susceptibility to type 2 diabetes. We identified that a 300-bp DNA fragment in intron 1 of TFAP2B had significant enhancer activity, and the variations of this region affected this enhancer activity in differentiated adipocytes. In an experiment using adenovirus vectors encoding TFAP2B, the expression of TNF-alpha gene was shown to be elevated in the TFAP2B overexpressing cells compared with those in control cells. Furthermore, we demonstrated that the expression of TFAP2B was increased in the adipose tissues of subjects with the disease-susceptibility allele, and the plasma levels of TNF-alpha and high sensitivity C-reactive peptide were significantly elevated in the patients with the disease-susceptibility allele. These results suggest that TFAP2B may contribute to the pathogenesis of type 2 diabetes through regulation of adipocytokine gene expression, and that TFAP2B may be a promising target for treatment or prevention of this disease.

3T3-L1 Cells↗
PubMed2005

Overexpression of Kruppel-like factor 7 regulates adipocytokine gene expressions in human adipocytes and inhibits glucose-induced insulin secretion in pancreatic beta-cell line.

We have identified Kruppel-like factor 7 (KLF7) as a new candidate for conferring susceptibility to type 2 diabetes. To ascertain the possible involvement of KLF7 in the pathogenesis of type 2 diabetes, we examined the functional roles of KLF7 in various types of cells. In human adipocytes overexpressing KLF7, the expression of adiponectin and leptin was decreased compared with that in control cells, whereas expression of IL-6 was increased. In the insulin-secreting cell line (HIT-T15 cells), the expression and glucose-induced secretion of insulin were significantly suppressed in KLF7-overexpressed cells compared with control cells, accompanied by the reduction in the expression of glucose transporter 2, sulfonylurea receptor 1, Kir6.2, and pancreatic-duodenal homeobox factor 1. We also found that the overexpression of KLF7 resulted in the decrease of hexokinase 2 expression in smooth muscle cells, and of glucose transporter 2 expression in the HepG2 cells. These results suggest that KLF7 may contribute to the pathogenesis of type 2 diabetes through an impairment of insulin biosynthesis and secretion in pancreatic beta-cells and a reduction of insulin sensitivity in peripheral tissues. Therefore, we suggest that KLF7 plays an important role in the pathogenesis of type 2 diabetes, and may be a useful target for new drugs to aid in the prevention and treatment of this disease.

Adipocytes↗
PubMed2005

Genetic variations in the gene encoding TFAP2B are associated with type 2 diabetes mellitus.

To search a gene(s) conferring susceptibility to type 2 diabetes mellitus, we genotyped nearly 60,000 gene-based SNPs for Japanese patients and found evidence that the gene at chromosome 6p12 encoding transcription-factor-activating protein 2beta (TFAP2B) was a likely candidate in view of significant association of polymorphism in this gene with type 2 diabetes. Extensive analysis of this region identified that several variations within TFAP2B were significantly associated with type 2 diabetes [a variable number of tandem repeat locus: chi(2)=10.9, P=0.0009; odds ratio=1.57, 95% CI 1.20-2.06, intron 1+774 (G/T); chi(2)=11.6, P=0.0006; odds ratio=1.60, 95% CI 1.22-2.09, intron 1+2093 (A/C); chi(2)=12.2, P=0.0004; odds ratio=1.61, 95% CI 1.23-2.11]. The association of TFAP2B with type 2 diabetes was also observed in the UK population. These results suggest that TFAP2B might be a new candidate for conferring susceptibility to type 2 diabetes and contribute to the pathogenesis of type 2 diabetes.

Base Sequence↗
PubMed2005

Prevalence and risk factors for erectile dysfunction in Japanese diabetics.

We evaluated the prevalence and risk factors for erectile dysfunction (ED) and interest in ED treatment among Japanese men being treated for type 2 diabetes mellitus. Patients (40-79 years; n=1118) completed the 5-item version of the International Index of Erectile Function (IIEF-5), and questions related to interest in ED pharmacotherapy, subjective symptoms of diabetes, and general quality of life. A separate survey completed by physicians examined the relationships between age, diabetic treatments (insulin or oral), symptoms of diabetes (poor glycemic control, microangiopathy), complications of diabetes (hypertension, ischemic heart disease, cerebrovascular disease), and ED. The prevalence of ED in patients with diabetes was 90%, a rate double that of non-diabetic individuals. Multivariate analyses revealed that age, insulin therapy, microangiopathy, hypertension, history of cerebrovascular or cardiovascular disease, leg dysesthesia, dysuria, insomnia, and anorexia all represented significant risk factors for ED. Half of all respondents were interested (29%) or would consider pharmacotherapy for ED (21%). These findings suggest that ED is a significant problem in Japanese men with diabetes, and that specific risk factors increase the prevalence of ED. Furthermore, the survey results expose national attitudes toward treatment of ED.

Adult↗
PubMed2005

N-(carboxymethyl)valine residues in hemoglobin (CMV-Hb) reflect accumulation of oxidative stress in diabetic patients.

While carboxymethylated proteins are considered to be advanced glycation end products (AGE), they can also be induced by reactive oxygen species (ROS) independently of the AGE-forming process. To clarify whether N-(carboxymethyl)valine residues in hemoglobin (CMV-Hb) were a useful marker of the accumulation of ROS in diabetes, we evaluated CMV-Hb formation in vitro and in vivo. For the in vitro studying, purified human hemoglobin was incubated with D-glucose or D-glucose and hydrogen peroxide. For the in vivo study, CMV-Hb was extracted from peripheral red blood cells in diabetic patients and compared with that from non-diabetic subjects. Furthermore, the effect of antioxidants was evaluated after 6 months in 15 diabetic patients showing very high CMV-Hb levels. In vitro CMV-Hb formation increased in a glucose concentration and time-dependent manner. Co-incubation with glucose and hydrogen peroxide synergistically increased CMV-Hb formation. The CMV-Hb level was higher in the diabetic group than the non-diabetic group, and CMV-Hb was correlated with the plasma total cholesterol and serum creatinine levels. The CMV-Hb level was decreased by antioxidant therapy, whereas HbA1c did not change. These results demonstrate that CMV-Hb may be a useful marker for accumulation of oxidative stress in diabetic patients.

Diabetes Mellitus, Type 2↗
PubMed2005

Effects of diet and exercise on muscle and liver intracellular lipid contents and insulin sensitivity in type 2 diabetic patients.

Insulin resistance is associated with the circulating free fatty acid (FFA) level and intracellular lipid content in muscle and liver. We investigated the effect of 2-wk diet and exercise therapy on total adiposity, circulating FFA, intracellular lipid content in muscle and liver, and peripheral insulin sensitivity. Type 2 diabetic patients were divided into a diet group (n = 7) and a diet plus exercise group (n = 7). We performed a hyperinsulinemic-euglycemic clamp study before and after treatment. Intramyocellular lipid (IMCL) in the tibialis anterior muscle and intrahepatic lipid (IHL) were evaluated by (1)H-magnetic resonance spectroscopy. Fasting FFA were not altered, and total body fat showed a slight, but significant, decrease in both groups after treatment. IMCL was decreased by 19%, and the glucose infusion rate was increased by 57% in the diet plus exercise group, whereas neither IMCL nor glucose infusion rate was significantly altered in the diet group. However, IHL showed a significant decrease in both groups. In summary, we found that 2 wk of diet and exercise decreased IMCL and increased muscle insulin-mediated glucose uptake, whereas diet with or without exercise decreased IHL. These effects were evident despite a small decrease in body fat and were observed independently of fasting FFA levels.

Blood Glucose↗
PubMed2005

Diabetes in Japan.

In this article, we introduce the increasing prevalence of type 2 diabetes in the Japanese population and discuss the reasons for such an explosive increase. Diabetes has been brought into prominence in Japan by enhanced insulin resistance, through the change of lifestyle against the background of fragile beta-cell function and thrifty genotypes.

Diabetes Mellitus, Type 2↗