Hirotaka Watada
Juntendo University
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Featured researches published by Hirotaka Watada.
Diabetes | 2010
Masayuki Arakawa; Tomoya Mita; Kosuke Azuma; Chie Ebato; Hiromasa Goto; Takashi Nomiyama; Yoshio Fujitani; Takahisa Hirose; Ryuzo Kawamori; Hirotaka Watada
OBJECTIVE Exogenous administration of glucagon-like peptide-1 (GLP-1) or GLP-1 receptor agonists such as an exendin-4 has direct beneficial effects on the cardiovascular system. However, their effects on atherosclerogenesis have not been elucidated. The aim of this study was to investigate the effects of GLP-1 on accumulation of monocytes/macrophages on the vascular wall, one of the earliest steps in atherosclerogenesis. RESEARCH DESIGN AND METHODS After continuous infusion of low (300 pmol · kg−1 · day−1) or high (24 nmol · kg−1 · day−1) dose of exendin-4 in C57BL/6 or apolipoprotein E–deficient mice (apoE−/−), we evaluated monocyte adhesion to the endothelia of thoracic aorta and arteriosclerotic lesions around the aortic valve. The effects of exendin-4 were investigated in mouse macrophages and human monocytes. RESULTS Treatment with exendin-4 significantly inhibited monocytic adhesion in the aortas of C57BL/6 mice without affecting metabolic parameters. In apoE−/− mice, the same treatment reduced monocyte adhesion to the endothelium and suppressed atherosclerogenesis. In vitro treatment of mouse macrophages with exendin-4 suppressed lipopolysaccharide-induced mRNA expression of tumor necrosis factor-α and monocyte chemoattractant protein-1, and suppressed nuclear translocation of p65, a component of nuclear factor-κB. This effect was reversed by either MDL-12330A, a cAMP inhibitor or PKI14-22, a protein kinase A–specific inhibitor. In human monocytes, exendin-4 reduced the expression of CD11b. CONCLUSIONS Our data suggested that GLP-1 receptor agonists reduced monocyte/macrophage accumulation in the arterial wall by inhibiting the inflammatory response in macrophages, and that this effect may contribute to the attenuation of atherosclerotic lesion by exendin-4.
Nature Medicine | 2010
Hail Kim; Yukiko Toyofuku; Francis C. Lynn; Eric Chak; Toyoyoshi Uchida; Hirok i Mizukami; Yoshio Fujitani; Ryuzo Kawamori; Takeshi Miyatsuka; Yasuhiro Kosaka; Katherine Yang; Gerard Honig; Marieke van der Hart; Nina Kishimoto; Juehu Wang; Soroku Yagihashi; Laurence H. Tecott; Hirotaka Watada; Michael S. German
During pregnancy, the energy requirements of the fetus impose changes in maternal metabolism. Increasing insulin resistance in the mother maintains nutrient flow to the growing fetus, whereas prolactin and placental lactogen counterbalance this resistance and prevent maternal hyperglycemia by driving expansion of the maternal population of insulin-producing beta cells. However, the exact mechanisms by which the lactogenic hormones drive beta cell expansion remain uncertain. Here we show that serotonin acts downstream of lactogen signaling to stimulate beta cell proliferation. Expression of serotonin synthetic enzyme tryptophan hydroxylase-1 (Tph1) and serotonin production rose sharply in beta cells during pregnancy or after treatment with lactogens in vitro. Inhibition of serotonin synthesis by dietary tryptophan restriction or Tph inhibition blocked beta cell expansion and induced glucose intolerance in pregnant mice without affecting insulin sensitivity. Expression of the Gαq-linked serotonin receptor 5-hydroxytryptamine receptor-2b (Htr2b) in maternal islets increased during pregnancy and normalized just before parturition, whereas expression of the Gαi-linked receptor Htr1d increased at the end of pregnancy and postpartum. Blocking Htr2b signaling in pregnant mice also blocked beta cell expansion and caused glucose intolerance. These studies reveal an integrated signaling pathway linking beta cell mass to anticipated insulin need during pregnancy. Modulators of this pathway, including medications and diet, may affect the risk of gestational diabetes.
Nature Genetics | 2010
Toshimasa Yamauchi; Kazuo Hara; Shiro Maeda; Kazuki Yasuda; Atsushi Takahashi; Momoko Horikoshi; Masahiro Nakamura; Hayato Fujita; Niels Grarup; Stéphane Cauchi; Daniel P.K. Ng; Ronald C.W. Ma; Tatsuhiko Tsunoda; Michiaki Kubo; Hirotaka Watada; Hiroshi Maegawa; Miki Okada-Iwabu; Masato Iwabu; Nobuhiro Shojima; Hyoung Doo Shin; Gitte Andersen; Daniel R. Witte; Torben Jørgensen; Torsten Lauritzen; Annelli Sandbæk; Torben Hansen; Toshihiko Ohshige; Shintaro Omori; Ikuo Saito; Kohei Kaku
We conducted a genome-wide association study of type 2 diabetes (T2D) using 459,359 SNPs in a Japanese population with a three-stage study design (stage 1, 4,470 cases and 3,071 controls; stage 2, 2,886 cases and 3,087 controls; stage 3, 3,622 cases and 2,356 controls). We identified new associations in UBE2E2 on chromosome 3 and in C2CD4A-C2CD4B on chromosome 15 at genome-wide significant levels (rs7612463 in UBE2E2, combined P = 2.27 × 10−9; rs7172432 in C2CD4A-C2CD4B, combined P = 3.66 × 10−9). The association of these two loci with T2D was replicated in other east Asian populations. In the European populations, the C2CD4A-C2CD4B locus was significantly associated with T2D, and a combined analysis of all populations gave P = 8.78 × 10−14, whereas the UBE2E2 locus did not show association to T2D. In conclusion, we identified two new loci at UBE2E2 and C2CD4A-C2CD4B associated with susceptibility to T2D.
Journal of the American College of Cardiology | 1994
Hirotaka Watada; Hiroshi Ito; Hidemasa Oh; Tohru Masuyama; Masahito Aburaya; Masatsugu Hori; Masaomi Iwakura; Yorihiko Higashino; Kenshi Fujii; Takazo Minamino
OBJECTIVES This study was designed to evaluate dobutamine stress echocardiography in identifying reversible dysfunction and assessing the extent of irreversibly damaged myocardium early in acute myocardial infarction. BACKGROUND Several experimental and clinical studies have suggested that dobutamine enhances contractile function of stunned or hibernating, or both, myocardium. It is important for clinical strategy to predict the magnitude of improvement in myocardial function early in acute myocardial infarction. METHODS We studied 21 patients with a reperfused first anterior myocardial infarction. Two-dimensional echocardiography was performed before and during dobutamine infusion (10 micrograms/kg body weight per min) at a mean of 3 days after the infarction. Follow-up echocardiography was performed at a mean of 25 days later. To assess segmental wall motion, we divided the left ventricle into 17 segments and assigned a wall motion abnormality score: 3 = dyskinesia or akinesia; 0 = normal. Improvement in wall motion was indicated by a decrease of at least one grade in segmental score. For quantitative assessment, the ratio of endocardial length showing dyskinesia or akinesia to a left ventricular endocardial length (akinetic length ratio) was determined in the apical long-axis view at each stage. RESULTS Sensitivity and specificity of dobutamine infusion in detecting improvement in wall motion at follow-up echocardiography were 83% (55 of 66 segments) and 86% (43 of 50 segments), respectively. Excellent correlation was found (r = 0.93, p < 0.001; absolute difference [mean +/- SD] 0.03 +/- 0.05) between the akinetic length ratios measured during dobutamine infusion and in the late convalescent stage. CONCLUSIONS In the early stage of acute myocardial infarction, low dose dobutamine stress echocardiography provides a useful method for predicting reversible dysfunction with excellent sensitivity and specificity and can also be used to quantitate the extent of irreversibly damaged myocardium.
Autophagy | 2011
Claudio Gonzalez; Myung-Shik Lee; Piero Marchetti; Massimo Pietropaolo; Roberto Towns; Maria I. Vaccaro; Hirotaka Watada; John W. Wiley
An emerging body of evidence supports a role for autophagy in the pathophysiology of type 1 and type 2 diabetes mellitus. Persistent high concentrations of glucose lead to imbalances in the antioxidant capacity within the cell resulting in oxidative stress-mediated injury in both disorders. An anticipated consequence of impaired autophagy is the accumulation of dysfunctional organelles such as mitochondria within the cell. Mitochondria are the primary site of the production of reactive oxygen species (ROS), and an imbalance in ROS production relative to the cytoprotective action of autophagy may lead to the accumulation of ROS. Impaired mitochondrial function associated with increased ROS levels have been proposed as mechanisms contributing to insulin resistance. In this article we review and interpret the literature that implicates a role for autophagy in the pathophysiology of type 1 and type 2 diabetes mellitus as it applies to β-cell dysfunction, and more broadly to organ systems involved in complications of diabetes including the cardiovascular, renal and nervous systems.
Journal of Clinical Investigation | 2013
Motoyuki Tamaki; Yoshio Fujitani; Akemi Hara; Toyoyoshi Uchida; Yoshifumi Tamura; Kageumi Takeno; Minako Kawaguchi; Takahiro Watanabe; Takeshi Ogihara; Ayako Fukunaka; Tomoaki Shimizu; Tomoya Mita; Akio Kanazawa; Mica Ohara Imaizumi; Takaya Abe; Hiroshi Kiyonari; Shintaro Hojyo; Toshiyuki Fukada; Takeshi Kawauchi; Shinya Nagamatsu; Toshio Hirano; Ryuzo Kawamori; Hirotaka Watada
Recent genome-wide association studies demonstrated that common variants of solute carrier family 30 member 8 gene (SLC30A8) increase susceptibility to type 2 diabetes. SLC30A8 encodes zinc transporter-8 (ZnT8), which delivers zinc ion from the cytoplasm into insulin granules. Although it is well known that insulin granules contain high amounts of zinc, the physiological role of secreted zinc remains elusive. In this study, we generated mice with β cell-specific Slc30a8 deficiency (ZnT8KO mice) and demonstrated an unexpected functional linkage between Slc30a8 deletion and hepatic insulin clearance. The ZnT8KO mice had low peripheral blood insulin levels, despite insulin hypersecretion from pancreatic β cells. We also demonstrated that a substantial amount of the hypersecreted insulin was degraded during its first passage through the liver. Consistent with these findings, ZnT8KO mice and human individuals carrying rs13266634, a major risk allele of SLC30A8, exhibited increased insulin clearance, as assessed by c-peptide/insulin ratio. Furthermore, we demonstrated that zinc secreted in concert with insulin suppressed hepatic insulin clearance by inhibiting clathrin-dependent insulin endocytosis. Our results indicate that SLC30A8 regulates hepatic insulin clearance and that genetic dysregulation of this system may play a role in the pathogenesis of type 2 diabetes.
Arteriosclerosis, Thrombosis, and Vascular Biology | 2006
Kosuke Azuma; Ryuzo Kawamori; Yukiko Toyofuku; Yoshiro Kitahara; Fumihiko Sato; Tomoaki Shimizu; Kyoko Miura; Tomoyuki Mine; Yasushi Tanaka; Masako Mitsumata; Hirotaka Watada
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. Conclusion—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.
Journal of Biological Chemistry | 2003
Stuart Smith; Rosa Gasa; Hirotaka Watada; Juehu Wang; Steven C. Griffen; Michael S. German
During fetal development, paired/homeodomain transcription factor Pax4 controls the formation of the insulin-producing β cells and the somatostatin-producing δ cells in the islets of Langerhans in the pancreas. Targeting of Pax4 expression to the islet lineage in the fetal pancreas depends on a short sequence located ∼2 kb upstream of the transcription initiation site of the PAX4 gene. This short sequence contains binding sites for homeodomain transcription factors PDX1 and hepatic nuclear factor (HNF)1, nuclear receptor HNF4α, and basic helix-loop-helix factor Neurogenin3. In the current study we demonstrate that the HNF1α and Neurogenin3 binding sites are critical for activity of the region through synergy between the two proteins. Synergy involves a physical interaction between the factors and requires the activation domains of both factors. Furthermore, exogenous expression of Neurogenin3 is sufficient to induce expression of the endogenous pax4 gene in the mouse pancreatic ductal cell line mPAC, which already expresses HNF1α, whereas expression of both Neurogenin3 and HNF1α are necessary to activate the pax4 gene in the fibroblast cell line NIH3T3. These data demonstrate how Neurogenin3 and HNF1α activate the pax4 gene during the cascade of gene expression events that control pancreatic endocrine cell development.
Endocrinology | 2013
Nasib Ervinna; Tomoya Mita; Eisuke Yasunari; Kosuke Azuma; Rica Tanaka; Satoshi Fujimura; Dewi Sukmawati; Takashi Nomiyama; Akio Kanazawa; Ryuzo Kawamori; Yoshio Fujitani; Hirotaka Watada
Dipeptyl peptidase-4 (DPP-4) inhibitors modulate the progression of atherosclerosis. To gain insights into their mechanism of action, 9-wk-old male apolipoprotein E (apoE)-deficient mice were fed a DPP-4 inhibitor, anagliptin-containing diet. The effects of anagliptin were investigated in, a monocyte cell line, human THP-1 cells, and rat smooth muscle cells (SMCs). Treatment with anagliptin for 16 wk significantly reduced accumulation of monocytes and macrophages in the vascular wall, SMC content in plaque areas, and oil red O-stained area around the aortic valve without affecting glucose tolerance or body weight. Serum DPP-4 concentrations were significantly higher in apoE-deficient mice than control mice, and the levels increased with aging, suggesting the involvement of DPP-4 in the progression of atherosclerosis. Indeed, soluble DPP-4 augmented cultured SMC proliferation, and anagliptin suppressed the proliferation by inhibiting ERK phosphorylation. In THP-1 cells, anagliptin reduced lipopolysaccharide-induced TNF-α production with inhibiting ERK phosphorylation and nuclear translocation of nuclear factor-κB. Quantitative analysis also showed that anagliptin reduced the area of atherosclerotic lesion in apoE-deficient mice. These results indicated that the anti-atherosclerotic effect of anagliptin is mediated, at least in part, through its direct inhibition of SMC proliferation and inflammatory reaction of monocytes.
Human Molecular Genetics | 2014
Kazuo Hara; Hayato Fujita; Todd A. Johnson; Toshimasa Yamauchi; Kazuki Yasuda; Momoko Horikoshi; Chen Peng; Cheng Hu; Ronald C.W. Ma; Minako Imamura; Minoru Iwata; Tatsuhiko Tsunoda; Takashi Morizono; Nobuhiro Shojima; Wing Yee So; Ting F. Leung; Patrick Kwan; Rong Zhang; Jie Wang; Weihui Yu; Hiroshi Maegawa; Hiroshi Hirose; Kohei Kaku; Chikako Ito; Hirotaka Watada; Yasushi Tanaka; Kazuyuki Tobe; Atsunori Kashiwagi; Ryuzo Kawamori; Weiping Jia
Although over 60 loci for type 2 diabetes (T2D) have been identified, there still remains a large genetic component to be clarified. To explore unidentified loci for T2D, we performed a genome-wide association study (GWAS) of 6 209 637 single-nucleotide polymorphisms (SNPs), which were directly genotyped or imputed using East Asian references from the 1000 Genomes Project (June 2011 release) in 5976 Japanese patients with T2D and 20 829 nondiabetic individuals. Nineteen unreported loci were selected and taken forward to follow-up analyses. Combined discovery and follow-up analyses (30 392 cases and 34 814 controls) identified three new loci with genome-wide significance, which were MIR129-LEP [rs791595; risk allele = A; risk allele frequency (RAF) = 0.080; P = 2.55 × 10(-13); odds ratio (OR) = 1.17], GPSM1 [rs11787792; risk allele = A; RAF = 0.874; P = 1.74 × 10(-10); OR = 1.15] and SLC16A13 (rs312457; risk allele = G; RAF = 0.078; P = 7.69 × 10(-13); OR = 1.20). This study demonstrates that GWASs based on the imputation of genotypes using modern reference haplotypes such as that from the 1000 Genomes Project data can assist in identification of new loci for common diseases.