Biomedical subjects

Ryuzo Kawamori

Publications and source records attributed to Ryuzo Kawamori.

At least 19 recordsLinked to original sources

PubMed2006

Long-term effect of combination therapy with mitiglinide and once daily insulin glargine in patients who were successfully switched from intensive insulin therapy in short-term study.

We have previously reported the therapeutic efficacy of mitiglinide combined with once daily insulin glargine (mitiglinide regimen) after switching from multiple daily insulin regimen of aspart insulin and glargine (intensive insulin regimen) in inpatients with type 2 diabetes mellitus in two consecutive days. In the present study, we followed up 9 of the 15 responsive patients with these novel regimens for 6 months after discharge. The data collected from these patients were compared to those of 15 randomly chosen patients who had well matched background and received intensive insulin regimen during hospitalization which was continued after discharge. The average HbA1c level of these 9 patients with mitiglinide regimen at 6 months was 6.7 +/- 0.8% and was comparable to that of the patients with intensive insulin regimen (HbA1c = 7.0 +/- 1.0%). In conclusion, mitiglinide and insulin glargine combination therapy maintained fair glycemic control for as long as 6 months in subpopulation of Japanese patients with type 2 diabetes.

Diabetes Mellitus, Type 2↗

PubMed2006

Comparison of glycated albumin (GA) and glycated hemoglobin (HbA1c) in type 2 diabetic patients: usefulness of GA for evaluation of short-term changes in glycemic control.

We studied the cross-sectional relationship between GA and HbA1c in 142 type 2 diabetic patients who had an HbA1c level < 7.5% for at least one year without fluctuation by more than 0.5%. We also followed the changes of GA and HbA1c in 18 type 2 diabetic patients for 16 weeks as they progressed from untreated severe hyperglycemia (HbA1c > or = 9.0%) to good glycemic control (HbA1c < or = 6.5%) by intensive insulin treatment. The annual mean levels of GA and HbA1c in the stably controlled patients showed a weak, but significant, correlation (r = 0.23, p<0.001) in the 142 diabetic patients. However, the GA/HbA1c ratio ranged widely from 2.0 to 4.0 showing a normal distribution (2.9 +/- 0.34, M +/- SE), although patients with conditions affecting albumin turnover or RBC lifespan were excluded from the study. The GA/HbA1c ratio was significantly higher when patients were in hyperglycemic than when glycemic control was good (3.5 +/- 0.15 vs. 2.9 +/- 0.07, M +/- SE, p<0.01). GA decreased more rapidly than HbA1c during intensive insulin therapy, but the percent reduction of HbA1c eventually corresponded with that of GA by 16 weeks after the start of treatment. These results demonstrate that, although unknown influences on GA or HbA1c may exist, GA may be a useful marker for monitoring short-term variations of glycemic control during treatment of diabetic patients.

Aged↗

PubMed2006

Protein kinase Cdelta plays a non-redundant role in insulin secretion in pancreatic beta cells.

Protein kinase C (PKC) is considered to modulate glucose-stimulated insulin secretion. Pancreatic beta cells express multiple isoforms of PKCs; however, the role of each isoform in glucose-stimulated insulin secretion remains controversial. In this study we investigated the role of PKCdelta, a major isoform expressed in pancreatic beta cells on beta cell function. Here, we showed that PKCdelta null mice manifested glucose intolerance with impaired insulin secretion. Insulin tolerance test showed no decrease in insulin sensitivity in PKCdelta null mice. Studies using islets isolated from these mice demonstrated decreased glucose- and KCl-stimulated insulin secretion. Perifusion studies indicated that mainly the second phase of insulin secretion was decreased. On the other hand, glucose-induced influx of Ca2+ into beta cells was not altered. Immunohistochemistry using total internal reflection fluorescence microscopy and electron microscopic analysis showed an increased number of insulin granules close to the plasma membrane in beta cells of PKCdelta null mice. Although PKC is thought to phosphorylate Munc18-1 and facilitate soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors complex formation, the phosphorylation of Munc18-1 by glucose stimulation was decreased in islets of PKCdelta null mice. We conclude that PKCdelta plays a non-redundant role in glucose-stimulated insulin secretion. The impaired insulin secretion in PKCdelta null mice is associated with reduced phosphorylation of Munc18-1.

Animals↗

PubMed2006

Hepatic safety profile and glycemic control of pioglitazone in more than 20,000 patients with type 2 diabetes mellitus: postmarketing surveillance study in Japan.

The prospective observational study was designed to identify factors affecting glycemic control with pioglitazone and to confirm the hepatic safety of the drug in patients with type 2 diabetes. Baseline patient characteristics, changes in serum hemoglobin A1c (A1c) and alanine aminotransferase (ALT), other treatments for diabetes mellitus, and hepatobiliary adverse reactions were examined. In total, 24,993 patients, representing 28,008 patient-years, were included in the safety evaluation and 20,447 patients in the efficacy evaluation. No case of hepatic failure was reported, and neither temporal nor dose relations were found between pioglitazone and ALT abnormalities. Serum A1c was clearly reduced in patients with baseline body mass index <25 kg/m(2) or baseline fasting immunoreactive insulin <5.0 microU/mL. Among the patients treated for more than 6 months, the change in A1c was -1.0% at 6 months with both monotherapy and combination therapy and remained stable up to 18 months. The overall rate of achievement of A1c<7% in patients with baseline A1c above 7% was 34.1%; notably, the achievement rate of A1c<7% was approximately 30% even in patients with high baseline A1c (mean 8.8%) taking multiple antidiabetic medications, including sulfonylurea, for whom insulin therapy is usually indicated in Japan.

Adolescent↗

PubMed2006

Amlodipine versus angiotensin II receptor blocker; control of blood pressure evaluation trial in diabetics (ADVANCED-J).

BACKGROUND: The coexistence of type 2 diabetes mellitus and hypertension increases the risk of cardiovascular diseases. The U.K. Prospective Diabetes Study has shown that blood pressure control as well as blood glucose control is efficient for prevention of complications in hypertensive patients with diabetes mellitus. However, some reports have shown that it is difficult to control the blood pressure and the concomitant use of a plurality of drugs is needed in hypertensive patients with diabetes mellitus. In recent years renin-angiotensin system depressants are increasingly used for the blood pressure control in diabetic patients. Particularly in Japan, angiotensin II (A II) antagonists are increasingly used. However, there is no definite evidence of the point of which is efficient for the control, the increase in dose of A II antagonist or the concomitant use of another drug, in hypertensive patients whose blood pressure levels are inadequately controlled with A II antagonist. METHODS/DESIGN: Hypertensive patients of age 20 years or over with type 2 diabetes mellitus who have been treated by the single use of AII antagonist at usual doses for at least 8 weeks or patients who have been treated by the concomitant use of AII antagonist and an antihypertensive drug other than calcium channel blockers and ACE inhibitors at usual doses for at least 8 weeks are included. DISCUSSION: We designed a multi-center, prospective, randomized, open label, blinded-endpoint trial, ADVANCED-J, to compare the increases in dose of A II antagonist and the concomitant use of a Ca-channel blocker (amlodipine) and A II antagonist in hypertensive patients with diabetes mellitus, whose blood pressure levels were inadequately controlled with A II antagonist. This study is different from the usual previous studies in that home blood pressures are assessed as indicators of evaluation of blood pressure. The ADVANCED-J study may have much influence on selection of antihypertensive drugs for treatment in hypertensive patients with diabetes mellitus. It is expected to give an important hint for considering the validity of selection of antihypertensive drugs from the aspects not only of the antihypertensive effect but medical cost-effectiveness.

Adult↗

PubMed2006

[IGT].

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Arteriosclerosis↗

PubMed2006

Insulin and nateglinide reduce monocyte adhesion to endothelial cells in Goto-Kakizaki rats exhibiting repetitive blood glucose fluctuation.

Epidemiological studies demonstrated the importance of postprandial hyperglycemia on the progression of atherosclerosis. However, whether treatment of postprandial hyperglycemia by insulin or insulin secretagogues has a beneficial effect on atherosclerosis has not been elucidated. To elucidate the effects of reduction of postprandial rise of blood glucose by insulin and nateglinide on monocyte adhesion to endothelial cells, we used non-obese type 2 diabetic Goto-Kakizaki (GK) rats fed twice daily, as a model of repetitive postprandial hyperglycemia. We investigated the effects of insulin injection and nateglinide administration just before each meal for 12 weeks on monocyte adhesion to endothelial cells. By setting the doses of insulin and nateglinide, both treatment significantly reduced postprandial hyperglycemia without significant reduction of HbA1c. Nateglinide also reduced serum insulin level just after 1 h meal. Both nateglinide and insulin therapy reduced the number of monocytes adherent to the aortic endothelial layer. Nateglinide, but not insulin, reduced intimal thickness of the thoracic aorta. While increased serum insulin level might be regarded as a factor responsible for the progression of atherosclerosis, our data showed that treatment with pre-meal insulin or nateglinide, which reduces postprandial hyperglycemia, reduced monocyte adhesion to endothelial cells.

Animals↗

PubMed2006

The NR4A orphan nuclear receptor NOR1 is induced by platelet-derived growth factor and mediates vascular smooth muscle cell proliferation.

Members of the nuclear hormone receptor superfamily function as key transcriptional regulators of inflammation and proliferation in cardiovascular diseases. In addition to the ligand-dependent peroxisome proliferator-activated receptors and liver X receptors, this family of transcription factors includes a large number of orphan receptors, and their role in vascular diseases remains to be investigated. The neuron-derived orphan receptor-1 (NOR1) belongs to the ligand-independent NR4A subfamily, which has been implicated in cell proliferation, differentiation, and apoptosis. In this study, we demonstrate NOR1 expression in vascular smooth muscle cells (SMC) of human atherosclerotic lesions. In response to mitogenic stimulation with platelet-derived growth factor (PDGF), SMC rapidly express NOR1 through an ERK-MAPK-dependent signaling pathway. 5'-deletion analysis, site-directed mutagenesis, and transactivation experiments demonstrate that PDGF-induced NOR1 expression is mediated through a cAMP-response element-binding protein (CREB)-dependent transactivation of the NOR1 promoter. Consequently, short interfering RNA-mediated depletion of CREB abolished PDGF-induced NOR1 expression in SMC. Furthermore, PDGF induced Ser-133 phosphorylation of CREB and subsequent binding to the CRE sites of the endogenous NOR1 promoter. Functional analysis demonstrated that PDGF induces NOR1 transactivation of its consensus NGFI-B-response elements (NBRE) in SMC. We finally demonstrate that SMC isolated from NOR1-deficient mice exhibit decreased cell proliferation and characterize cyclin D1 and D2 as NOR1 target genes in SMC. These experiments indicate that PDGF-induced NOR1 transcription in SMC is mediated through CREB-dependent transactivation of the NOR1 promoter and further demonstrate that NOR1 functions as a key transcriptional regulator of SMC proliferation.

Animals↗

PubMed2006

Association of C-reactive protein with early-stage carotid atherosclerosis in Japanese patients with early-state type 2 diabetes mellitus.

The aim of this study was to assess the association between high sensitivity-C-reactive protein (hs-CRP), a sensitive marker of inflammation, and early-stage carotid atherosclerosis, in patients with early-state type 2 diabetes mellitus. The study subjects were 75 patients with type 2 diabetes mellitus without obvious diabetic vascular complications, who were not on any medication, and whose HbA(1c) level was less than 6.5%. We evaluated the mean intima-media thickness (IMT) of the common carotid artery (CCA) by ultrasound B-mode imaging. Then, we investigated various factors associated with CCA-IMT including hs-CRP. Serum hs-CRP levels correlated well with factors strongly associated with insulin resistance such as homeostasis model assessment of insulin resistance (HOMA-IR), fasting insulin level, and body mass index. Serum hs-CRP also correlated with mean CCA-IMT and serum levels of soluble intercellular adhesion molecule-1. Multivariate regression analysis using mean CCA-IMT as the dependent variable identified only age, hs-CRP, and diastolic blood pressure as independent determinants of mean CCA-IMT. While hs-CRP associates with insulin resistance and subclinical atherosclerosis in ealy-state type 2 diabetes, our data suggest that hs-CRP is a useful marker of subclinical atherosclerosis in early-state type 2 diabetes mellitus independent of factors that directly reflect insulin resistance.

Aged↗

PubMed2006

Rationale and protocol of a trial for prevention of diabetic atherosclerosis by using antiplatelet drugs: study of Diabetic Atherosclerosis Prevention by Cilostazol (DAPC study).

BACKGROUND: Secondary treatment of arteriosclerosis may be applicable for the primary prevention of atherosclerosis in diabetic patients. This prospective, 2-year follow-up study was designed to determine the efficacy and safety of antiplatelet therapy in the prevention of atherosclerosis of diabetic subjects. METHODS: Patients with type 2 diabetes and arteriosclerosis obliterans from the Eastern Asian countries were registered online and randomly assigned either to the aspirin group (81-100 mg/day) or the cilostazol group (100-200 mg/day) in this international, 2-year, prospective follow-up interventional study. RESULTS: The primary study endpoint was changes in right and left maximum intima-media thickness of the common carotid artery. Secondary endpoints include changes in right and left maximum intima-media thickness of the internal carotid artery; semiquantitative evaluation of cerebral infarction by magnetic resonance imaging; cardiovascular events including sudden death, stroke, transient cerebral ischemic attacks, acute myocardial infarction, angina, and progression of arteriosclerosis obliterans; overall death; withdrawal; and change in ankle-brachial pressure index. CONCLUSION: This is the first study to use an online system that was developed in Asian countries for pooling data from an international clinical trial. These findings are expected to help in the prevention of diabetic atherosclerosis and subsequent cardiovascular and cerebrovascular disease.

Atherosclerosis↗

PubMed2006

Repetitive fluctuations in blood glucose enhance monocyte adhesion to the endothelium of rat thoracic aorta.

BACKGROUND: The aim of this study was to elucidate the effect of repetitive fluctuations in blood glucose concentrations on monocyte adhesion to the aortic endothelium. METHODS AND RESULTS: Nonobese type 2 diabetes, Goto-Kakizaki (GK) rats were fed twice daily to induce repetitive postprandial glucose spikes. Then, we compared the number of monocytes adherent to the endothelium of thoracic aorta in these rats with that in rats fed ad libitum. To suppress the glucose spikes, rats were injected with an inhibitor of sodium-glucose transporter, phloridzin, just before each meal for 12 weeks. GK rats fed twice daily showed significantly lower HbA1c than GK rats fed ad libitum. However, the former group showed markedly higher number of monocytes adherent to the endothelium than the latter, together with increased arterial intimal thickening. Phloridzin significantly reduced the number of adherent monocytes in GK rats fed twice daily. CONCLUSIONS: Our data demonstrated that repetitive postprandial fluctuation in glucose concentration evokes monocyte adhesion to endothelial cells that was worse than that induced by stable hyperglycemia in vivo. Suppression of such fluctuations efficiently suppressed monocyte adhesion to the aortic endothelium.

Animals↗

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↗