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Mitsuhiko Noda

Publications and source records attributed to Mitsuhiko Noda.

At least 19 recordsLinked to original sources
PubMed2006

Diabetes mellitus and the risk of cancer: results from a large-scale population-based cohort study in Japan.

BACKGROUND: An association between diabetes mellitus (DM) and cancer has long been speculated, but no conclusive evidence has been obtained. METHODS: We prospectively examined the association between a history of DM and subsequent risk of cancer in the Japan Public Health Center-Based Prospective Study. A total of 97 771 general Japanese persons (46 548 men and 51 223 women) aged 40 to 69 years who responded to the baseline questionnaire, from January 1990 to December 1994, were followed up for cancer incidence through December 31, 2003. At baseline, 6.7% of men and 3.1% of women had a history of DM. RESULTS: A total of 6462 cases of newly diagnosed cancer were identified. In men, a 27% increase in the risk of total cancer incidence was observed in those with a history of DM (n = 3907 [366 with DM]; hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.14-1.42). The HR was especially high for those with cancer of the liver (n = 312 [52 with DM]; HR, 2.24; 95% CI, 1.64-3.04), pancreas (n = 118 [16 with DM]; HR, 1.85; 95% CI, 1.07-3.20), and kidney (n = 99 [13 with DM]; HR, 1.92; 95% CI, 1.06-3.46). We also observed a moderately increased risk of colon cancer (n = 491 [46 with DM]; HR, 1.36; 95% CI, 1.00-1.85) and of stomach cancer with borderline significance (n = 977 [87 with DM]; HR, 1.23; 95% CI, 0.98-1.54). In women, a borderline significant increase in risk was observed for the incidence of total cancer (n = 2555 [104 with DM]; HR, 1.21; 95% CI, 0.99-1.47), while statistical significance was observed for the incidence of stomach cancer (n = 362 [20 with DM]; HR, 1.61; 95% CI, 1.02-2.54) and liver cancer (n = 120 [10 with DM]; HR, 1.94; 95% CI, 1.00-3.73) and borderline significance was observed for the incidence of ovarian cancer (n = 74 [5 with DM]; HR, 2.42; 95% CI, 0.96-6.09). CONCLUSION: Patients with DM drawn from the general Japanese population may be at increased risk of total cancer and of cancer in specific sites.

Adult↗
PubMed2006

Hepatocyte nuclear factor-4alpha P2 promoter haplotypes are associated with type 2 diabetes in the Japanese population.

Hepatocyte nuclear factor (HNF)-4alpha is a transcription factor known as a key molecule in the development and functions of the beta-cells. In a previously performed genome-wide scan of Japanese type 2 diabetic sibpairs, we observed linkage of type 2 diabetes to chromosome 20q12-q13, a region in which the HNF4A gene is located. Recent studies have reported associations between type 2 diabetes and polymorphisms in the P2 promoter region specific to beta-cells. In this study, we attempted to assess whether the HNF4A gene plays a role in the genetic susceptibility to type 2 diabetes in the Japanese population by analyzing polymorphisms and haplotypes of the HNF4A gene. Linkage disequilibrium across the P2 promoter region was preserved in the Japanese population, consistent with previous reports. Although none of the individual polymorphisms examined showed any significant association with type 2 diabetes, we found very strong evidence of the association between type 2 diabetes and the haplotype consisting of two polymorphisms in the P2 promoter region of the HNF4A gene (P = 3.82 x 10(-4)). In contrast, there was no association between type 2 diabetes and haplotypes consisting of polymorphisms not located in the P2 promoter region, suggesting that the type 2 diabetes susceptibility loci are localized in the P2 promoter region of the HNF4A gene. The association was replicated using two additional cohorts (P = 1.51 x 10(-4) and 0.019, respectively). The results of the present analysis revealed that the HNF4A gene might be a type 2 diabetes susceptibility gene common to different ethnic groups. The study also suggested the possible existence of an as-yet-unidentified but functional polymorphism in the P2 promoter region of the HNF4A gene that directly influences susceptibility to type 2 diabetes.

Chromosome Mapping↗
PubMed2004

Role of uncoupling protein-2 up-regulation and triglyceride accumulation in impaired glucose-stimulated insulin secretion in a beta-cell lipotoxicity model overexpressing sterol regulatory element-binding protein-1c.

Triglyceride (TG) accumulation in pancreatic beta-cells is thought to be associated with impaired insulin secretory response to glucose (lipotoxicity). To better understand the mechanism of the impaired insulin secretory response to glucose in beta-cell lipotoxicity, we overexpressed a constitutively active form of the sterol regulatory element-binding protein- 1c (SREBP-1c), a master transcriptional factor of lipogenesis, in INS-1 cells with an adenoviral vector. This treatment was associated with strong activation of transcription of the genes involved in fatty acid biosynthesis, increased cellular TG content, severely blunted glucose-stimulated insulin secretion, and enhanced expression of the uncoupling protein-2 (UCP-2), which supposedly dissipates the mitochondrial electrochemical potential. To decrease the up-regulated UCP-2 expression, small interfering RNA for UCP-2 was used. Introduction of the small interfering RNA increased the ATP/ADP ratio and partially rescued the glucose-stimulated insulin secretion in the cells overexpressing SREBP-1c, but did not affect the cellular TG content. Next, the effect of the AMP-activated protein kinase (AMPK) agonist, 5-amino-4-imidazolecarboxamide riboside, was examined in the lipotoxicity model. Exposure of the cells with lipotoxicity to 5-amino-4-imidazolecarboxamide riboside increased free fatty acid oxidation, partially reversed the TG accumulation, phosphorylated AMPK and acetyl-coenzyme A carboxylase, and improved the impaired glucose-stimulated insulin secretion. These results suggest that UCP-2 down-regulation and AMPK activation could be candidate targets for releasing beta-cells from lipotoxicity.

AMP-Activated Protein Kinase Kinases↗
PubMed2004

Chronological characterization of diabetes development in male Spontaneously Diabetic Torii rats.

To characterize the underlying mechanisms of diabetes development in males of the Spontaneously Diabetic Torii (SDT) rat, a novel spontaneous model for diabetes, we chronologically examined them, focusing on their diabetic features and the pathological changes in the pancreatic islets. Male SDT rats exhibited glucose intolerance with impaired insulin secretion after 14 weeks and developed diabetes with remarkable hyperglycemia and marked hypoinsulinemia after 20 weeks. At prediabetic stage (10-20 weeks), they were normoglycemic, but had significantly lower insulin levels of plasma and pancreas than the normal rats. Their beta-cell volume was already smaller significantly at 10 weeks than that of normal rats. The primary changes of the pancreatic islets were microvascular events such as congestion and hemorrhage at 8-10 weeks. Thereafter, the SDT rat islets were affected with inflammation and progressive fibrosis (at 10-20 weeks), and eventually atrophied with a loss of beta-cells (at 38 weeks). These results indicate that the male SDT rats develop spontaneous diabetes with an absolute decrease in the insulin secretory capacity of the islets.

Animals↗
PubMed2004

Pioglitazone reduces islet triglyceride content and restores impaired glucose-stimulated insulin secretion in heterozygous peroxisome proliferator-activated receptor-gamma-deficient mice on a high-fat diet.

Heterozygous peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-deficient (PPARgamma(+/-)) mice were protected from high-fat diet-induced insulin resistance. To determine the impact of systemic reduction of PPAR-gamma activity on beta-cell function, we investigated insulin secretion in PPARgamma(+/-) mice on a high-fat diet. Glucose-induced insulin secretion in PPARgamma(+/-) mice was impaired in vitro. The tissue triglyceride (TG) content of the white adipose tissue, skeletal muscle, and liver was decreased in PPARgamma(+/-) mice, but it was unexpectedly increased in the islets, and the increased TG content in the islets was associated with decreased glucose oxidation. Administration of a PPAR-gamma agonist, pioglitazone, reduced the islet TG content in PPARgamma(+/-) mice on a high-fat diet and ameliorated the impaired insulin secretion in vitro. Our results demonstrate that PPAR-gamma protects islets from lipotoxicity by regulating TG partitioning among tissues and that a PPAR-gamma agonist can restore impaired insulin secretion under conditions of islet fat accumulation.

Animals↗
PubMed2003

Glucose metabolism and glutamate analog acutely alkalinize pH of insulin secretory vesicles of pancreatic beta-cells.

We studied acute changes of secretory vesicle pH in pancreatic beta-cells with a fluorescent pH indicator, lysosensor green DND-189. Fluorescence was decreased by 0.66 +/- 0.10% at 149 +/- 16 s with 22.2 mM glucose stimulation, indicating that vesicular pH was alkalinized by approximately 0.016 unit. Glucose-responsive pH increase was observed when cytosolic Ca2+ influx was blocked but disappeared when an inhibitor of glycolysis or mitochondrial ATP synthase was present. Glutamate dimethyl ester (GME), a plasma membrane-permeable analog of glutamate, potentiated glucose-stimulated insulin secretion at 5 mM without changing cellular ATP content or cytosolic Ca2+ concentration ([Ca2+]). Application of GME at basal glucose concentration decreased DND-189 fluorescence by 0.83 +/- 0.19% at 38 +/- 2 s. These results indicated that the acutely alkalinizing effect of glucose on beta-cell secretory vesicle pH was dependent on glucose metabolism but independent of modulations of cytosolic [Ca2+]. Moreover, glutamate derived from glucose may be one of the mediators of this alkalinizing effect of glucose, which may have potential relevance to the alteration of secretory function by glutamate.

Adenosine Triphosphate↗
PubMed2003

[Not Available].

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Journal Article↗
PubMed2002

Switch to anaerobic glucose metabolism with NADH accumulation in the beta-cell model of mitochondrial diabetes. Characteristics of betaHC9 cells deficient in mitochondrial DNA transcription.

To elucidate the mechanism underlying diabetes caused by mitochondrial gene mutations, we created a model by applying 0.4 microg/ml ethidium bromide (EtBr) to the murine pancreatic beta cell line betaHC9; in this model, transcription of mitochondrial DNA, but not that of nuclear DNA, was suppressed in association with impairment of glucose-stimulated insulin release (Hayakawa, T., Noda, M., Yasuda, K., Yorifuji, H., Taniguchi, S., Miwa, I., Sakura, H., Terauchi, Y., Hayashi, J.-I., Sharp, G. W. G., Kanazawa, Y., Akanuma, Y., Yazaki, Y., and Kadowaki, T. (1998) J. Biol. Chem. 273, 20300-20307). To elucidate fully the metabolism-secretion coupling in these cells, we measured glucose oxidation, utilization, and lactate production. We also evaluated NADH autofluorescence in betaHC9 cells using two-photon excitation laser microscopy. In addition, we recorded the membrane potential and determined the ATP and ADP contents of the cells. The results indicated 22.2 mm glucose oxidation to be severely decreased by EtBr treatment compared with control cells (by 63% on day 4 and by 78% on day 6; both p < 0.01). By contrast, glucose utilization was only marginally decreased. Lactate production under 22.2 mm glucose was increased by 2.9- and 3.5-fold by EtBr treatment on days 4 and 6, respectively (both p < 0.01). Cellular NADH at 2.8 mm glucose was increased by 35 and 43% by EtBr on days 4 and 6 (both p < 0.01). These data suggest that reduced expression of the mitochondrial electron transport system causes NADH accumulation in beta cells, thereby halting the tricarboxylic acid cycle on one hand, and on the other hand facilitating anaerobic glucose metabolism. Glucose-induced insulin secretion was lost rapidly along with the EtBr treatment with concomitant losses of membrane potential depolarization and the [Ca(2+)](i) increase, whereas glibenclamide-induced changes persisted. This is the first report to demonstrate the connection between metabolic alteration of electron transport system and that of tricarboxylic acid cycle and its impact on insulin secretion.

Anaerobiosis↗
PubMed2002

A link between Cdc42 and syntaxin is involved in mastoparan-stimulated insulin release.

Mastoparan, a hormone receptor-mimetic peptide isolated from wasp venom, stimulates insulin release from pancreatic beta-cells in a Ca(2+)-independent but GTP-dependent manner. In this report, the role of the Rho family GTP-binding protein Cdc42, in the mastoparan stimulus-secretion pathway, was examined. Overexpression of wild-type Cdc42 in beta HC-9 cells, an insulin-secreting mouse-derived cell line, resulted in a 2-fold increase in mastoparan-stimulated insulin release over vector-transfected beta HC-9 cells. This effect was not seen with secretagogues such as glucose that stimulate secretion via Ca(2+)-dependent pathways. GDP/GTP exchange assay data and studies with pertussis (PTX) toxin suggest that mastoparan may work directly to activate Cdc42 and not via PTX-sensitive heterotrimeric GTP-binding proteins. Using bacterial glutathione S-transferase-Cdc42 fusion proteins and co-immunoprecipitation and transient transfection studies, Cdc42 was shown to be an upstream regulator of the exocytotic protein, syntaxin. These results suggest that the GTP-dependent signal underlying the mastoparan effect acts at a "distal site" in stimulus-secretion coupling on one of the SNARE proteins essential for exocytosis. In vitro binding assays, using purified Cdc42 and syntaxin proteins, show that Cdc42 mediates the GTP signal through an indirect association with syntaxin. The H3 domain at the C-terminus of syntaxin, which participates in the formation of the ternary SNARE complex with the core proteins, SNAP-25 and synaptobrevin, is also required for the association with Cdc42. Thus, these studies indicate that Cdc42 could be a putative GTP-binding protein thought to be involved in the mastoparan-stimulated GTP-dependent pathway of insulin release.

Animals↗
PubMed2002

Maturity-onset diabetes of the young resulting from a novel mutation in the HNF-4alpha gene.

A 52-year-old woman with early-onset diabetes mellitus, severe diabetic retinopathy, and a family history of a dominant inheritance pattern was referred to our hospital. Direct sequencing revealed a novel mutation in the HNF-4alpha gene (R244Q). The position of the mutation in the amino-acid sequence of the gene is well conserved among species and transcriptional activity of the mutant gene was significantly reduced. Therefore, a diagnosis of maturity-onset diabetes of the young (MODY)-1 was made. Genetic testing enabled early diagnosis of diabetes in the patient's 20-year-old daughter, which we consider to be important for the prevention of diabetic complications.

Adult↗
PubMed2002

Phosphatidylinositol 3-kinase suppresses glucose-stimulated insulin secretion by affecting post-cytosolic [Ca(2+)] elevation signals.

The role of phosphatidylinositol (PI) 3-kinase in the regulation of pancreatic beta-cell function was investigated. PI 3-kinase activity in p85 alpha regulatory subunit-deficient (p85 alpha(-/-)) islets was decreased to approximately 20% of that in wild-type controls. Insulin content and mass of rough endoplasmic reticula were decreased in beta-cells from p85 alpha(-/-) mice with increased insulin sensitivity. However, p85 alpha(-/-) beta-cells exhibited a marked increase in the insulin secretory response to higher concentrations of glucose. When PI 3-kinase in wild-type islets was suppressed by wortmannin or LY294002, the secretion was also substantially potentiated. Wortmannin's potentiating effect was not due to augmentation in glucose metabolism or cytosolic [Ca(2+)] elevation. Results of p85 alpha(-/-) islets and wortmannin-treated wild-type islets stimulated with diazoxide and KCl showed that inhibition of PI 3-kinase activity exerted its effect on secretion, at least in part, distal to a cytosolic [Ca(2+)] elevation. These results suggest that PI 3-kinase activity normally plays a crucial role in the suppression of glucose-stimulated insulin secretion.

Androstadienes↗
PubMed2002

Genetic manipulations of fatty acid metabolism in beta-cells are associated with dysregulated insulin secretion.

Triacylglyceride (TG) accumulation in pancreatic beta-cells is associated with impaired insulin secretion, which is called lipotoxicity. To gain a better understanding of the pathophysiology of lipotoxicity, we generated three models of dysregulated fatty acid metabolism in beta-cells. The overexpression of sterol regulatory element binding protein-1c induced lipogenic genes and TG accumulation. Under these conditions, we observed a decrease in glucose oxidation and upregulation of uncoupling protein-2, which might be causally related to the decreased glucose-stimulated insulin secretion. The overexpression of AMP-activated protein kinase was accompanied by decreased lipogenesis, increased fatty acid oxidation, and decreased glucose oxidation; insulin secretions to glucose and depolarization stimuli were decreased, probably because of the decrease in glucose oxidation and cellular insulin content. It was notable that the secretory response to palmitate was blunted, which would suggest a role of the fatty acid synthesis pathway, but not its oxidative pathway in palmitate-stimulated insulin secretion. Finally, we studied islets of PPAR-gamma(+/-) mice that had increased insulin sensitivity and low TG content in white adipose tissue, skeletal muscle, and liver. On a high-fat diet, glucose-stimulated insulin secretion was decreased in association with increased TG content in the islets, which might be mediated through the elevated serum free fatty acid levels and their passive transport into beta-cells. These results revealed some aspects about the mechanisms by which alterations of fatty acid metabolism affect beta-cell functions.

Adenylate Kinase↗
PubMed2002

[Tailor-made medicine for diabetes].

Several genes are implicated to be the cause for diabetes, such as genes of PPAR gamma (peroxisome proliferator-activated receptor-gamma), adiponectin, beta 3-adrenergic receptor, etc., and their polymorphisms may have significant impact on the treatment and prevention of diabetes. Detection and analysis of such susceptibility genes will provide an enormous benefit for the future tailor-made medicine of diabetes, which include choosing the most effective treatment policy for each individual and developing novel drugs based on the genetic information that are applicable for corresponding individuals. Tailor-made medicine will be an efficient tool for treatment and prevention of lifestyle diseases, especially type 2 diabetes, along with further identification of its disease-causing genes.

Acetates↗