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1. One year follow-up after a randomized controlled trial of a 130 g/day low-carbohydrate diet in patients with type 2 diabetes mellitus and poor glycemic control.

Author: Junko Sato, Akio Kanazawa, Chie Hatae, Sumiko Makita, Koji Komiya, Tomoaki Shimizu, Fuki Ikeda, Yoshifumi Tamura, Takeshi Ogihara, Tomoya Mita, Hiromasa Goto, Toyoyoshi Uchida, Takeshi Miyatsuka, Chie Ohmura, Takehito Watanabe, Kiyoe Kobayashi, Yoshiko Miura, Manami Iwaoka, Nao Hirashima, and Hirotaka Watada
Subjects: Medicine, Science
Abstract: Recently, we conducted a prospective randomized controlled trial (RCT) showing that a 6-month 130g/day low-carbohydrate diet (LCD) reduced HbA1c and BMI more than a calorie restricted diet (CRD). [1] To assess whether the benefits of the LCD persisted after the intensive intervention, we compared HbA1c and BMI between the LCD and CRD groups at 1 year after the end of the 6-month RCT.Following the end of the 6-month RCT, patients were allowed to manage their own diets with periodic outpatient visits. One year later, we analyzed clinical and nutrition data.Of the 66 participants in the original study, 27 in the CRD group and 22 in the LCD group completed this trial. One year after the end of the original RCT, the carbohydrate intake was comparable between the groups (215 [189-243]/day in the CRD group and 214 (176-262) g/day in the LCD group). Compared with the baseline data, HbA1c and BMI were decreased in both groups (CRD: HbA1c -0.4 [-0.9 to 0.3] % and BMI -0.63 [-1.20 to 0.18] kg/m2; LCD: HbA1c -0.35 [-1.0 to 0.35] % and BMI -0.77 [-1.15 to -0.12] kg/m2). There were no significant differences in HbA1c and BMI between the groups.One year after the diet therapy intervention, the beneficial effect of the LCD on reduction of HbA1c and BMI did not persist in comparison with CRD. However, combining the data of both groups, significant improvements in HbA1c and BMI from baseline were observed. Although the superiority of the LCD disappeared 1 year after the intensive intervention, these data suggest that well-constructed nutrition therapy programs, both CRD and LCD, were equally effective in improving HbA1c for at least 1 year.University Hospital Medical Information Network (UMIN) ID000010663.
Published: 2017
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2. Relationships between lifestyle patterns and cardio-renal-metabolic parameters in patients with type 2 diabetes mellitus: A cross-sectional study.

Author: Takeshi Ogihara, Tomoya Mita, Yusuke Osonoi, Takeshi Osonoi, Miyoko Saito, Atsuko Tamasawa, Shiho Nakayama, Yuki Someya, Hidenori Ishida, Masahiko Gosho, Akio Kanazawa, and Hirotaka Watada
Subjects: Medicine, Science
Abstract: INTRODUCTION:While individuals tend to show accumulation of certain lifestyle patterns, the effect of such patterns in real daily life on cardio-renal-metabolic parameters remains largely unknown. This study aimed to assess clustering of lifestyle patterns and investigate the relationships between such patterns and cardio-renal-metabolic parameters. PARTICIPANTS AND METHODS:The study participants were 726 Japanese type 2 diabetes mellitus (T2DM) outpatients free of history of cardiovascular diseases. The relationship between lifestyle patterns and cardio-renal-metabolic parameters was investigated by linear and logistic regression analyses. RESULTS:Factor analysis identified three lifestyle patterns. Subjects characterized by evening type, poor sleep quality and depressive status (type 1 pattern) had high levels of HbA1c, alanine aminotransferase and albuminuria. Subjects characterized by high consumption of food, alcohol and cigarettes (type 2 pattern) had high levels of γ-glutamyl transpeptidase, triglycerides, HDL-cholesterol, blood pressure, and brachial-ankle pulse wave velocity. Subjects characterized by high physical activity (type 3 pattern) had low uric acid and mild elevation of alanine aminotransferase and aspartate aminotransferase. In multivariate regression analysis adjusted by age, gender and BMI, type 1 pattern was associated with higher HbA1c levels, systolic BP and brachial-ankle pulse wave velocity. Type 2 pattern was associated with higher HDL-cholesterol levels, triglycerides, aspartate aminotransferase, ɤ- glutamyl transpeptidase levels, and diastolic BP. CONCLUSIONS:The study identified three lifestyle patterns that were associated with distinct cardio-metabolic-renal parameters in T2DM patients. TRIAL REGISTRATION:UMIN000010932.
Published: 2017
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3. Switching from Twice-Daily Basal Insulin Injections to Once-Daily Insulin Degludec Injection for Basal-Bolus Insulin Regimen in Japanese Patients with Type 1 Diabetes: A Pilot Study

Author: Yuka Tosaka, Akio Kanazawa, Fuki Ikeda, Mayu Iida, Junko Sato, Kazuhisa Matsumoto, Toyoyoshi Uchida, Yoshifumi Tamura, Takeshi Ogihara, Tomoya Mita, Tomoaki Shimizu, Hiromasa Goto, Chie Ohmura, Yoshio Fujitani, and Hirotaka Watada
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: The aim of this study was to investigate the efficacy of insulin degludec used for basal-bolus insulin regimen after switching from twice-daily basal insulin in Japanese patients with type 1 diabetes mellitus. The subjects were 22 type 1 diabetes patients treated with basal-bolus insulin regimen with twice-daily basal insulin. Basal insulin was switched to once-daily injection of insulin degludec with 10% dose reduction. HbA1c and fasting plasma glucose (FPG) were measured before and 12 weeks after switching. The frequency of hypoglycemic episodes, standard deviation (SD) of blood glucose, and mean of daily difference (MODD) were evaluated by continuous glucose monitoring (CGM) before and 4 weeks after switching. HbA1c and FPG before and 12 weeks after switching were comparable (HbA1c 8.5 ± 1.4 versus 8.7 ± 1.6%, P=0.28; FPG 203.2 ± 81.2 versus 206.5 ± 122.4 mg/dL, P=0.91). The frequency of hypoglycemia during nighttime was not significantly different at 4 weeks after switching (14.4 ± 17.0 versus 11.1 ± 15.0%, P=0.45). In addition, SD and MODD before and 4 weeks after switching were also comparable. In conclusion, glycemic control under once-daily insulin degludec injection was almost comparable to that under twice-daily basal insulin injections in Japanese type 1 diabetes patients. This study was registered with ID: UMIN000010474.
Published: 2015
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4. Empagliflozin in Patients with Chronic Kidney Disease

Author: Herrington, William G, Staplin, Natalie, Wanner, Christoph, Green, Jennifer B, Hauske, Sibylle J, Emberson, Jonathan R, Preiss, David, Judge, Parminder, Mayne, Kaitlin J, Ng, Sarah Y A, Sammons, Emily, Zhu, Doreen, Hill, Michael, Stevens, Will, Wallendszus, Karl, Brenner, Susanne, Cheung, Alfred K, Liu, Zhi-Hong, Li, Jing, Hooi, Lai Seong, Liu, Wen, Kadowaki, Takashi, Nangaku, Masaomi, Levin, Adeera, Cherney, David, Maggioni, Aldo P, Pontremoli, Roberto, Deo, Rajat, Goto, Shinya, Rossello, Xavier, Tuttle, Katherine R, Steubl, Dominik, Petrini, Michaela, Massey, Dan, Eilbracht, Jens, Brueckmann, Martina, Landray, Martin J, Baigent, Colin, Haynes, Richard, The EMPA-KIDNEY Collaborative Group: Colin Baigent, Martin J Landray, Christoph Wanner, William G Herrington, Richard Haynes, Jennifer B Green, Sibylle J Hauske, Martina Brueckmann, Mark Hopley, Maximillian von-Eynatten, Jyothis George, Susanne Brenner, Alfred K Cheung, David Preiss, Zhi-Hong Liu, Jing Li, Laiseong Hooi, Wen Liu, Takashi Kadowaki, Masaomi Nangaku, Adeera Levin, David Cherney, Roberto Pontremoli, Aldo P Maggioni, Natalie Staplin, Jonathan Emberson, Stefan Hantel, Shinya Goto, Rajat Deo, Katherine R Tuttle, Michael Hill, Parminder Judge, Kaitlin J Mayne, Sarah Y A Ng, Xavier Rossello, Emily Sammons, Doreen Zhu, Peter Sandercock, Rudolf Bilous, Charles Herzog, Paul Whelton, Janet Wittes, Derrick Bennett, Patricia Achiri, Chrissie Ambrose, Cristina Badin, Jill Barton, Richard Brown, Andy Burke, Sebastian Butler, Rejive Dayanandan, Pia Donaldson, Robert Dykas, Lucy Fletcher, Kate Frederick, Hannah Kingston, Mo Gray, Emily Harding, Akiko Hashimoto, Lyn Howie, Susan Hurley, Ryonfa Lee, Nik Luker, Kevin Murphy, Mariko Nakahara, John Nolan, Michelle Nunn, Sorcha Mulligan, Akiko Omata, Sandra Pickworth, YanRu Qiao, Shraddha Shah, Karen Taylor, Alison Timadjer, Monique Willett, Liz Wincott, Qin Yan, Hui Yu, Louise Bowman, Fang Chen, Robert Clarke, Michelle Goonasekera, Waseem Karsan, Marion Mafham, Christina Reith, Mohammed Zayed, Ritva Ellison, Rowan Moys, Will Stevens, Kevin Verdel, Karl Wallendszus, Chris Bowler, Anna Brewer, Andy Measor, Guanguo Cui, Charles Daniels, Angela Field, Bob Goodenough, Ashley Lawson, Youcef Mostefai, Dheeptha Radhakrishnan, Samee Syed, Shuang Xia, Ruth Adewuyi-Dalton, Thomas Arnold, Anne-Marie Beneat, Anoushka Bhatt, Chloe Bird, Andrew Breach, Laura Brown, Mark Caple, Tatyana Chavagnon, Karen Chung, Sarah Clark, Luminita Condurache, Katarzyna Eichstadt, Marta Espino Obrero, Scarlett Forest, Helen French, Nick Goodwin, Andrew Gordon, Joanne Gordon, Cat Guest, Tina Harding, Michal Hozak, Matthew Lacey, David MacLean, Louise Messinger, Stewart Moffat, Martin Radley, Claire Shenton, Sarah Tipper, Jon Tyler, Lesley Weaving, James Wheeler, Elissa Williams, Tim Williams, Hamish Woodhouse, Angela Chamberlain, Jo Chambers, Joanne Davies, Denise Donaldson, Pati Faria-Shayler, Denise Fleming-Brown, Jennifer Ingell, Carol Knott, Anna Liew, Helen Lochhead, Juliette Meek, Isabel Rodriguez-Bachiller, Andrea Wilson, Patrick Zettergren, Rach AitSadi, Ian Barton, Alex Baxter, Yonghong Bu, Lukasz Danel, Sonja Grotjahn, Rijo Kurien, Michael Lay, Archie Maskill, Aleksandra Murawska, Rachel Raff, Allen Young, Rebecca Sardell, Vladimir Cejka, Marcela Fajardo-Moser, Christian Hartner, Doris Poehler, Janina Renner, Franziska Scheidemantel, Miya Bryant, Anita Hepditch, Cassandra Johnson, Erin Latore, Yolanda Miller, Lauren Price, Merilee Whalen, Ashleigh Wheeler, Jenny Ingell, Yu An, Yinghua Chen, Peiling Chen, Hao Dai, Hong Du, Fang Feng, Qing Guo, Libo Hou, Wuhanbilige Hundei, Binbin Jin, Yan Li, Jiamin Liu, Xia Song, Yanping Wang, Yanwu Yu, Ning Zhang, Lingshan Zhao, Hui Zhong, Cheng Beng Goh, Ye Mun Low, Soon Yi Sor, Farah Hanis Zulkipli, Sarojini Sivanandam, Natsuki Arai, Ai Fukasawa, Mizue Furukawa, Keisuke Habuki, Shoko Hayashi, Wakako Isari, Saki Kanegae, Maria Kawai, Reiki Kobayashi, Takako Kuramae, Chika Kuribayashi, Sawako Maeno, Satoshi Masumoto, Tomoko Morisaki, Minoru Oda, Kazue Sawada, Kenta Sugamori, Ayana Tatsuzawa, Aiko Tomita, Kazuyuki Yuasa, Hiroko Inazawa, Amanda Axler, Kerri Gallo, Ester Baldini, Barbara Bartolomei Mecatti, Francesca Bianchini, Martina Ceseri, Laura Cipressa, Gianna Fabbri, Andrea Lorimer, Donata Lucci, Sharang Ghavampour, Anja Knoppe, Hans Schmidt-Gurtler, Hubert Dumann, Sybille Merscher, Margret Patecki, Georg Rainer Schlieper, Anke Torp, Bianca Weber, Maja Zietz, Bernd Hohenstein, Urs Benck, Diliana Draganova, Thomas Weinreich, Lothar Wolf, Jasmine Gaidu, Hanna Reiner, Mandy Visnjic, Daniel Steffl, Marie Breitenfeldt, Annette Kraemer-Guth, Christine Braun, Simone Hagge, Michael Schomig, Stephan Matthias, Dominik Stoffler, Beate Schumacher, Thomas Sitter, Louise Fuessl, Julia Krappe, Jerome Loutan, Volker Vielhauer, Luciano Andriaccio, Magdalena Maurer, Bernhard Winkelmann, Martin Dursch, Linda Seifert, Linda Tenbusch, Julia Weinmann-Menke, Simone Boedecker, Wiebke Kaluza-Schilling, Daniel Kraus, Carina Krieger, Margit Schmude, Anne Schreiber, Ewelina Eckrich, Diethelm Tschope, Abdulwahab Arbi, Young Lee-Barkey, Bernd Stratmann, Natalie Prib, Sina Rolfsmeier, Irina Schneider, Lars Rump, Johannes Stegbauer, Christine Pötz, Mara Schemmelmann, Claudia Schmidt, Michael Koch, Sendogan Aker, Annika Küpper, Manuela Martin, Thiemo Pfab, Christian Albert, Michael Haase, Barbara Zander, Claudia Schneider-Danwitz, Wolfgang Seeger, Wolf-Adam Seeger, Britta Zemann, Christoph Stellbrink, Kristin Marx, Ekaterina Stellbrink, Britta Brettschneider, Stephanie Watson, Marion Iselt, Gerhard Klausmann, Inga-Nadine Kummer, Auguste Kutschat, Simone Streitenberger, Matthias Girndt, Silke Markau, Ina Girakossyan, Claudia Hanf, Joachim Beige, Ralph Wendt, Ulrike Schmidt, Andreas Schneider, Roland Veelken, Claudia Donhauser, Luis Becker, Nexhat Miftari, Ricarda Wolfling, Sarah Morlok, Christian Hugo, Alexander Paliege, Jens Passauer, Julian Stumpf, Annegret Fleischer, Kerstin Haaser, Bernhard Kraemer, Jan Jochims, Bernd Kruger, Claudia Foellinger, Anastassiya Reisler, Frank Strutz, Stefan Haack, Ursula Hohenstatt, Martin Busch, Konstantin Herfurth, Gunter Wolf, Rainer Paul, Hermann Haller, Jessica Kaufeld, Jan Menne, Elisabeth Bahlmann-Kroll, Angela Bergner, Horst Weihprecht, Aydin Er, Florian Sonntag, Elif Turan, Michael Wittmann, Franziska Klauser, Eva Voigt, Volker Schettler, Egbert Schulz, Madlen Rohnstock, Elke Schettler, Bernd Schroppel, Rene van Erp, Martin Kachele, Ulla Ludwig, Lena Schulte-Kemna, Waltraud Kmietschak, Elke Preiss, Martina Ruocco, Gunnar Heine, Martin Brzoska, Sebastian Gabel, Christina Büttner, Asma Sabarai, Bernhard Banas, Tobias Bergler, Yvonne Ehrl, Franz Putz, Antonia Schuster, Stefanie Kuhn, Torsten Schramm, Stefan Degenhardt, Gerhard Schmidt, Lea Weiland, Ulrike Giebeln-Hudnell, Jan Kielstein, Gabriele Eden, Brigitte Fuchs, Gina Morig, Manuela Winkler, Harald Darius, Charalampos Kriatselis, Carl-Philipp Roesch, Astrid Maselli, Dominik Alscher, Markus Ketteler, Moritz Schanz, Severin Schricker, Bianka Rettenmaier, Andrea Schwab, Pablo Pergola, Irene Leal, Melissa Cagle, Anna Romo, Anthony Torres, Sucharit Joshi, Kulli Barrett, Alexis Africano, Vicki Dodds, Dorleena Gowen, Ashlee Morris, Juan Fernandez, Guillermo Jimenez, Ricardo Viera, Kendaling Bruce, Ryan Barrios, Maylin Garcia, Kerelyn Garcia, Iradis Leal, David Tietjen, David Bains, Carlo Castillo, Genielle Brewer, Justin Davis, Natalie Freking, Brittany Golson, Sally Ham, Jesslyn Roesch, Pusadee Suchinda, Shameem Beigh, Usah Lilavivat, Joyce Bilton, Kim Bocchicchia, Jeffrey Turner, Neera Dahl, Aldo Peixoto, Yasemin Kavak, Lauren Liberti, Hari Nair, Nicolas Page, Stephanie Rosenberg, Kathryn Simmons, Tamara Isakova, Rebecca Frazier, Rupal Mehta, Anand Srivastava, Patrick Fox, Jonathan Hecktman, Alexander Hodakowski, Carlos Martinez, Rachel Phillips, Alexis Stevenson, Reem Mustafa, Kyle Jansson, Cassandra Kimber, Jason Stubbs, Ahmad Tuffaha, Sri Yarlagadda, Debbie Griffin, Elisabeth Laundy, Zhuo Tang, Radica Alicic, Ann Cooper, Lisa Davis, Ashwini Gore, Rebecca Goldfaden, Leslie Harvill, Lisa Hichkad, Barry Johns, Thomas Jones, Kayla Merritt, Jennifer Sheldon, Jennifer Stanfield, Lindsay Alexander, Kaitlyn Preston, Lindsey Wood, Rajesh Pradhan, Roger DeRaad, Kelli McIntosh, Louis Raymond, Michael Shepperd, Susan McLaughlin, Mary Seifert, Andrew Shepherd, Joseph Aiello, William Durham, Laurie Loudermilk, John Manley, Sabrina Burnette, Stephanie Evans, Tara Johnson, Lance Sloan, Judy Ann Acosta, Stacy Gillham, Katia Sloan, SueAnn Squyres, Michael Rocco, Amret Hawfield, Ben Bagwell, Lauren Richmond, Joseph Soufer, Subha Clarke, Amanda Aliu, Kristine Calabrese, Amanda Davis, Veronica Poma, Tracy Spinola, James Magee, Ricardo Silva, Rushab Choksi, Lorraine Dajani, John Evans, Anil George, Prasanth Krish, Gerard Martins, Mae Sheikh-Ali, David Sutton, Freda Driver, Abraham Hanburry, Laura Hume, Amber Hurst, Matthew Taddeo, Marla Turner, Veronica Yousif, Srinivasan Beddhu, Laith Al-Rabadi, Nikita Abraham, Amalia Caamano, Judy Carle, Victoria Gonce, Kaitlyn Staylor, Na Zhou, Shweta Bansal, Manoj Bhattarai, Kumar Sharma, Subrata Debnath, Aliseiya Garza, Chakradhar Velagapudi, Sergio Rovner, Javier Almeida, Pablo Casares, Verlaine Stewart-Ray, Rene Almaraz, Renata Dayrell, Ana Moncada, Ricardo Pulido, Roxana Rodriquez, Wasim Deeb, Kathryn DeGoursey, Rodel Gloria, Trevor Greene, Robert Miller, Edward Pereira, Miguel Roura, Debbie Domingo, Sasha Dorestin, William Hodge, Cathy Jackson, Deborah Lund, Katrina Taylor, Kenneth Boren, Brittany Cleveland, Sandra Gaiser, Mandeep Sahani, Logan Aldrich, Exodus Edmerson, Edmond Limon, Cole Valletta, Patricia Vasquez, Christopher Provenzano, Navkiranjot Brar, Heather Henderson, Bellovich Keith, Qur Khai, Quresh Khairullah, Gail Makos, Joel Topf, Sherry Gasko, Rosemarie Henschel, Kaitlin Knapp, Teresa Kozlowski, Paula LaFleur, Ashwathy Varughese, Hui Xue, Patricia Wu, Olga Arechiga, Shan Darbeau, Michael Fechter, Stephanie Martinez, Lenita Hanson, Nyla Cooper, Arelis Madera, Jay Cadorna, Rita Sheridan, Helen Sparks, Bradley Eilerman, Susanne Bodine, Wael Eid, Rebecca Flora, Amber Avery, Cashmere Hardy, Mihaela Biscoveanu, Steven Nagelberg, Tracey Cummins, Frederic Rahbari-Oskoui, Anju Oommen, Zohreh Forghani, Stacie Hitchcock, Darya Hosein, Diane Watkins, Minesh Patel, Anthony Lambert, Elizabeth Newman, Autumn Wood, Tammy Ross, Stephany Topping, Jeffrey Mulhern, Lorna Murphy, Ann Vasseur, Gregory Greenwood, Alexander Hadley, Denise Laurienti, Christopher Marshall, Nicholas McLean, Scott Satko, Brandy Caudill, Jacob Maris, Janice Rogers, Cindy Vanhoy, George Thomas, Georges Nakhoul, John O'Toole, Jonathan Taliercio, Leslie Cooperman, Marina Markovic, Barbara Tucky, Devasmita Dev, Alia Hasan, Hima Yalamanchili, Namita Jain, Lesley McNeil, Eric Wines, Jean Park, Adline Ghazi, Mia Hamm, Tejas Patel, Amy Mottl, Emily Chang, Vimal Derebail, Emmie Cole, Anne Froment, Sara Kelley, Jordan Osmond Foster, Vahid Mahabadi, Golriz Jafari, Anita Kamarzarian, Wendy Arriaga, Daisy Arteaga, Rosario Machicado, Genesis Naverrete, Prashant Kumar, Imran Nazeer, Karina Urquia, Tammi Glider, Vickie Jones, Savannah Rucker, Jennifer Wiley, Rahul Pandey, Jesus Arroyo, Harish Pariani, Mohammad Ahmad, Shahin Mozaffari, Erika Perez, Matthew Budoff, Sion Roy, Divya Birudaraju, Ahmed Ghanem, Sajad Hamal, Stephen Aronoff, Elisa Joye Petr, Richard Sachson, Jaime Wiebel, Sana Akram, Laurie Jones, Curtis Knight, Maurie Tarlac, Shahbaz Ahmed, Harold Szerlip, Akinwande Akinfolarin, Ankit Mehta, Shana Camp, Cindy Castro, Zanaida Cooper, Jessica Terry, Ahmed Awad, Bhavya Kothapalli, Ryan Lustig, Serine Alfaress, Hyder Jasim, Mary Parrigon, Dennis Karounos, Sadiq Ahmed, Maggie Berry, Ruth Oremus, Carlos Hernandez-Cassis, Elias Ugwu, Nazia Junejo, Nancy Suazo, Mark Segal, Amir Kazory, Sherry Brown, Tristan Daniels, Sofia Dayi, Renee Hogan, Kathy McCray, Jennifer Stickley, Mahboob Rahman, Mirela Dobre, Lavinia Negrea, Aparna Padiyar, Nishigandha Pradhan, Arash Rashidi, Nagaraju Sarabu, Vicki Donley, Tricia Young, Godson Oguchi, Judepatricks Onyema, Kahla Damianik, Jack Dienes, Judith Plummer-Morgan, Marilyn Roman, Mauver Skipper, Stacey-Ann Villaruel, Krystle Williams, Danny Sugimoto, Jeffrey Dugas, Ismeal Ahmed, Jamie Bhairoo, Dolores Rijos, Huzaifa Salim, Madita Gavrila, Kathryn Lafferty, Ria Rabara, Sally Ruse, Maria Weetman, James Bushnell, Albert Power, Alison Jenkins, Stefanie Jones, Amanda Scott, Cath Byrne, Mark Jesky, Alison Cowley, Emma McHaffie, Holly Waterfall, Jo Taylor, Laura Bough, Thomas Phillips, Barbara Winter-Goodwin, Sui Phin Kon, Iain MacDougall, Eirini Lioudaki, Sapna Shah, Claire Sharpe, Francisco Aguilar, Abegail Hernandez Pena, Conception Pugay, Amelia Te, Hugh Finn, Wasim Hanif, Samiul Mostafa, Alice Aitken, Katharine Draxlbauer, Evelina Grobovaite, Jennifer Kearney, Theresa McCarthy, Giorgio Gentile, Duncan Browne, Palanichamy Chellamuthu, Tabinda Dugal, Terri Chant, Laura Jones, Emily Laity, Megan Miners, James Muir, Elizabeth Swanson, Andrew Frankel, James Tomlinson, Marlon Alegata, Rashid Almasarwah, Anthoula Apostolidi, Maria Vourvou, Thomas Walters, Maarten Taal, Hari Dukka, Nitin Kolhe, Carly McDonald, Kelly White, Shiva Ugni, Smita Gunda, Rotimi Oluyombo, Vicki Brindle, Ping Coutts, Tracy Fuller, Evelyn Nadar, Suresh Ramadoss, Nichola Motherwell, Susannah Pajak, Louise Tonks, Sunil Bhandari, Richard Bodington, Adil Hazara, Dominic Fellowes, Christopher Wong, Christopher Goldsmith, Sherald Barnes, Ann Bennett, Claire Burston, Samantha Hope, Nicola Hunt, Lini Kurian, Richard Fish, Daniela Farrugia, Judy Lee, Emma Sadler, Hannah Turner, Christopher Hill, Henry Brown, Agnes Masengu, Peter Maxwell, Nina Bleakley, Hugh Murtagh, William Petchey, Vivian Yiu, Joanne Kellett, Angharad Williams, Helen Clarke, Victoria Carnall, Sarah Benyon, Caroline Blake, Stephanie Estcourt, Jane Piper, Neal Morgan, Carolyn Hutchinson, Teresa McKinley, Alastair Woodman, Judi Graham, Niall Leonard, John Smyth, Vicki Adell, Samantha Hagan, Ben Caplin, Amin Oomatia, Eleanor Damian, Toluleyi Sobande, Tim Doulton, Michael Delaney, Mahmoud Montasser, Jenny Hansen, David Loader, Angela Moon, Frances Morris, Smeeta Sinha, Chukwuma Chukwu, Amy Hudson, Diane Campbell, Melanie Kershaw, Stephanie Whittaker, Ayesha Irtiza-Ali, Farid Ghalli, Heba Nosseir, Allison Leslie, Kate Trivedi, Donald Fraser, Mohammad Alhadj Ali, Sian Griffin, Farah Latif, Justyna Witczak, Alexa Wonnacott, Lynda Jeffers, Yvette Webley, Paul Phelan, Eve Miller-Hodges, Ailsa Geddes, Margaret Glenwright, Amy Hunter, Thomas Pickett, Jim Moriarty, Linda Hill, Amanda Tyler, Waqar Ayub, Gail Evans, Sue Hewins, Davina Hewitt, Kerry Read, Samira Bell, Leanne Cosgrove, Rachel Craik, Shona Murray, Nitin Bhandary, Holly Coles, Rashmi Easow, Maya Joseph, Arif Khwaja, Yvonne Jackson, Angeline Mbuyisa, Rachel Sellars, Nihil Chitalia, Cynthia Mohandas, Anca Gherman, Charlotte Kamundi, Olumide Olufuwa, Kieran McCafferty, Adedolapo Adeleke, Cara Healy, Damini Jeyarajah, Edward Kinsella-Perks, Richard Smith, Brian Camilleri, Carol Buckman, Jenny Finch, Vanessa Rivers, Andrew Connor, Sheila Carr, Lisa Shainberg, Andrew Lewington, Richard Baker, Suzannah Dorey, Kay Tobin, Rosalyn Wheatley, Debasish Banerjee, Richard Hull, Sharirose Abat, Riny Paul, Mahzuz Karim, Zay Htet, Saad Tufail, Ravi Varma, Karen Convery, Deirdre Fottrell-Gould, Lisa Hudig, Emily Tropman, Thahir Abdul-Samad, Anne Grace, Marie Phipps, Rebecca Suckling, Subash Somalanka, Bhrigu Sood, Pauline Swift, Sarah Acheampong, Kwame Ansu, Martia Augustin, Anna Sampson, Lynn Vinall, Kim Wren, Shamila Wanninayake, Nicholas Wooding, Heather Edwards, Lydia Owen, Stephanie Bolton, Marion Carson, Michael Matthews, Nigel Brunskill, Jorge Jesus-Silva, Alex Howson, Mary Quashie-Akponeware, Hilary Tindall, Chidambaram Nethaji, Helen Eldon, Rajan Patel, Patrick Mark, Alastair Rankin, Michael Sullivan, Kirsty Forsyth, Rowan McDougall, Tanaji Dasgupta, Louisa Davies, Maggie Ryder, Philip Grimmer, Clare Macdonald, Mary Webster, Newcastle Newcastle, Timothy Ellam, Edwin Wong, Christine Meshykhi, Andrea Webster, Peter Wilson, Enric Vilar, Jocelyn Berdeprado, Eunice Doctolero, Lily Wilkinson, Frank McCarroll, Hesham Ammar, Ying Kuan, Conor Moran, Girish Shivashankar, Ryan Campbell, Deborah Glowski, Paula McDermott, Amar Ali, Zuber Patel, Christine Bond, Gillian Whalley, Haitao Zhang, Liu Yang, Lihua Zhang, Tingting Kan, Ling Zhu, Jinghong Zhao, Weiping Hou, Jing Wu, Hong Cheng, Weijing Bian, Zhirui Zhao, Fengmin Shao, Huixia Cao, Xiaojing Jiao, Peiyuan Niu, Jianying Niu, Yu Chen, Lihong Zhang, Shenglang Zhu, Haiyan Lin, Shaopeng Yao, Jiehui Chen, Ying Jiang, Ying Hu, Huaying Xiao, Fuye Yang, Xinzhou Zhang, Baochun Guo, Qiu Jin, Lixia Liu, Xiangcheng Xiao, Yanyun Xie, Ting Meng, Chuanwen Xu, Jie Huang, Yanmei Xu, Weixin Kong, Xiaoliang Wang, Qianpan Liu, Xueying Wang, Ming Gao, Xiumei Hu, Ying Lu, Li Wang, Kun Peng, Wei Wang, Qiuhong Gong, Jianfang Cai, Xiaojue Li, Xuejiao Liu, Shuhan Zhou, Hong Liu, Yao Weng, Shuai Tang, Yao Yao, Shi Zhao, Chen Cheng, Wei Wei, Na Li, Sadanah Aqashiah Mazlan, Alia Zubaidah Bahtar, Elliyyin Katiman, Noraini Othman, Lily Mushahar, Nurdiana Mazlan, Nur Sharafina Safiee, Sarasa Ramasamy, Hin Seng Wong, Hajar Ahmad Rosdi, Esther Zhao Zhi Tan, Ju Fan Tay, Kok Seng Teng, Hasnah Yahaya, Wen Jiun Liu, Lik Wee Ee, Kenneth Kay Leong Khoo, Yuana Mohd Yusoff, Fariz Safhan Mohamad Nor, Mohd Kamil Ahmad, Mohd Ramli Seman, Clare Hui Hong Tan, Laura Lui Sian Ngu, Jaime Yoke May Chan, Javelin Peji, Chek Loong Loh, Yee Yan Lee, Sridhar Ramanaidu, Kah Mean Thong, Yik Hong Wong, Suria Junus, Chen Hua Ching, Mohammad Faisal Asmee, Ku Ruziana Ku Md Razi, Chun Leong Low, Christopher Sze Bing Sim, Zhang Duan Tham, Noor Kamila Abdullah, Tai Meng Chen, Yong Chieh Chan, Eason Chang, Huan Yean Kang, Kai Quan Lee, Sue Ann Lee, Aik Kheng Lee, Jeevika Vinathan, Rizna Abdul Cader, Ruslinda Mustafar, Lydia Kamaruzaman, Rozita Mohd, Rahimah Ismail, Chong Men Leong, Chee Koon Low, Liang Wei Wong, Norlezah Adnan, Sabariah Ibrahim, Mohamad Zaimi Abdul Wahab, Sunita Bavanandan, Yik Shen Lim, Wan Hazlina Wan Mohamad, Siti Munirah Jaafar, Nur Ashykeen Mohd Fauzi, Aziee Sudin, Soo Kun Lim, Chye Chung Gan, Albert Hing, Wan Ahmad Faizal Alaidin Razali, Yew Fong Liew, Chelsia Bao Tyng Chan, Mei Chih Cheng, Yu Chen Ong, Loke Meng Ong, Farah Amalina Mohamed Affandi, Korina Rahmat, Ban Chai Peng, Masayu Amat, Nuzaimin Hadafi Ahmad, Doo Yee Mah, Yi Loon Tye, Zaid Azhari, Siti Nabilah Mohamad Zaini, Mohd Aidil Musa, Norazinizah Ahmad Miswan, Rafizanur Ramli, Nor Aziah Ahmad, Bak Leong Goh, Nurul Izah Ahmad, Fairol Huda Ibrahim, Tze Jian Ng, Malini Shanmuganathan, Li Lian Tay, Zaiha Harun, Salmi Ramli, Nurul 'Ain Yusof, Rossenizal Abd Rahman, Muhammad Iqbal Abdul Hafidz, Nur Hidayati Mohd Sharif, Irda Yasmoon Awang, Eitaro Nakashima, Rui Imamine, Makiko Minatoguchi, Yukari Miura, Miduki Nakaoka, Yoshiki Suzuki, Hitomi Yoshikawa, Koki Shin, Kanae Fujita, Misuzu Iwasa, Haruka Sasajima, Airi Sato, Yoshiyuki Hamamoto, Yuki Fujita, Takuya Haraguchi, Takanori Hyo, Kiyohiro Izumi, Toshiyuki Komiya, Sodai Kubota, Takeshi Kurose, Hitoshi Kuwata, Susumu Nakatani, Kaori Oishi, Saki Okamoto, Kaori Okamura, Jun Takeoka, Nagaaki Tanaka, Katsuya Tanigaki, Naohiro Toda, Koin Watanabe, Hiromi Komori, Rika Kumuji, Asako Takesada, Aya Tanaka, Shoichi Maruyama, Tomonori Hasegawa, Akiko Ishiguro, Takuji Ishimoto, Kazuhiro Ito, Yutaka Kamimura, Noritoshi Kato, Sawako Kato, Hiroshi Kojima, Tomoki Kosugi, Kayaho Maeda, Masasi Mizuno, Shoji Saito, Hitomi Sato, Yuka Sato, Yasuhiro Suzuki, Akihito Tanaka, Yoshinari Yasuda, Fujiko Hasegawa, Maiko Hayashi, Shizuka Higashi, Kaho Shimamura, Momoko Sumi, Kazuki Tajima, Chimaki Unekawa, Kana Wakayama, Yukiko Wakita, Takatoshi Otani, Ayako Imai, Sayaka Kawashima, Eri Kogure, Tomoe Sato, Misato Takezawa, Shinya Yoshida, Hideo Araki, Yuko Katsuda, Masahiro Konishi, Takahiro Matsunaga, Masashi Oe, Kunihiro Ogane, Masato Sakai, Tomoko Takahashi, Takahiro Yamano, Takuya Yokoyama, Hitomi Ito, Masayo Katayama, Emi Kuroda, Toru Ikeda, Takuma Kojo, Etsuo Yoshidome, Rieko Mizumachi, Akane Yamamoto, Narihisa Yamasaki, Yoshihiko Yamasaki, Jun Wada, Jun Eguchi, Chigusa Higuchi, Akihiro Katayama, Masaru Kinomura, Masashi Kitagawa, Shinji Kitamura, Satoshi Miyamoto, Hiroshi Morinaga, Atsuko Nakatsuka, Ichiro Nojima, Kenichi Shikata, Hitoshi Sugiyama, Katsuyuki Tanabe, Kenji Tsuji, Haruhito Uchida, Mayu Watanabe, Chie Hashimoto, Takahiro Kato, Sayaka Yamamoto, Takehiko Wada, Masafumi Fukagawa, Naoto Hamano, Masahiro Koizumi, Hirotaka Komaba, Yosuke Nakagawa, Michiyo Iwamoto, Kosuke Masutani, Akane Katanosaka, Mayu Kiyota, Hikari Uchi, Yuka Ueda, Sonoka Yamamoto, Hajime Nagasu, Seiji Itano, Tsukasa Iwakura, Hiroyuki Kadoya, Eiichiro Kanda, Naoki Kashihara, Kengo Kidokoro, Megumi Kondo, Tamaki Sasaki, Minoru Satoh, Atsuyuki Tokuyama, Reina Umeno, Yoshihisa Wada, Toshiya Yamamoto, Yu Yamanouchi, Masumi Abe, Yoko Inukai, Wataru Ogawa, Shunichiro Asahara, Hideki Fujii, Shunsuke Goto, Yushi Hirota, Tetsuya Hosooka, Keiji Kono, Shinichi Nishi, Yuko Okada, Kazuhiko Sakaguchi, Kenji Sugawara, Michiko Takahashi, Tomoko Takai, Yoshikazu Tamori, Kentaro Watanabe, Miyu Kitajima, Misaki Nishi, Junko Wada, Yasuhiko Ito, Hideki Kamiya, Akimasa Asai, Nao Asai, Saeko Asano, Shogo Banno, Yohei Ejima, Hanako Hase, Tomohide Hayami, Tatsuhito Himeno, Takahiro Ishikawa, Mayumi Ito, Shiho Iwagaitsu, Rina Kasagi, Yoshiro Kato, Makoto Kato, Koichi Kato, Takayuki Katsuno, Miyuka Kawai, Hiroshi Kinashi, Masaki Kondo, Masako Koshino, Naoya Matsuoka, Yoshiaki Morishita, Mikio Motegi, Jiro Nakamura, Hiromi Shimoda, Hirokazu Sugiyama, Shin Tsunekawa, Makoto Yamaguchi, Kazuyo Takahashi, Hirotaka Watada, Takashi Funayama, Yasuhiko Furukawa, Tomohito Gohda, Hiromasa Goto, Hideyoshi Kaga, Yasuhiko Kanaguchi, Akio Kanazawa, Kayo Kaneko, Toshiki Kano, Masao Kihara, Shogo Kimura, Takashi Kobayashi, Masayuki Maiguma, Yuko Makita, Satoshi Mano, Tomoya Mita, Takeshi Miyatsuka, Maki Murakoshi, Masahiro Muto, Masami Nakata, Junichiro Nakata, Yuya Nishida, Nao Nohara, Takeshi Ogihara, Daisuke Sato, Junko Sato, Hiroaki Sato, Yusuke Suzuki, Ruka Suzuki, Hitoshi Suzuki, Miyuki Takagi, Yoshifumi Tamura, Toyoyoshi Uchida, Seiji Ueda, Miki Asawa, Minako Miyaji, Eri Nagashima, Yoshie Shibata, Eri Yanagisawa, Toshimasa Yamauchi, Yosuke Hirakawa, Hiroshi Nishi, Nobuhiro Shojima, Satoko Horikawa, Yukiko Nakayama, Naoko Yamada, Yuki Omori, Shintaro Yano, Miyabi Ioka, Nahoko Kuwabara, Remi Nagano, Megumi Nozawa, Yumi Osawa, Hiroshi Maegawa, Shinji Kume, Shinichi Araki, Itsuko Miyazawa, Katsutaro Morino, Ikuko Kawai, Masumi Sobata, Motoko Takaoka, Yasushi Iwaita, Takashi Udagawa, Ami Inamori, Aya Kawase, Aya Yamanaka, Hitoshi Shimano, Akiko Fujita, Hitoshi Iwasaki, Hirayasu Kai, Yoshinori Osaki, Chie Saito, Motohiro Sekiya, Ryoya Tsunoda, 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Teresa, Lafleur, Paula, Varughese, Ashwathy, Xue, Hui, Wu, Patricia, Arechiga, Olga, Darbeau, Shan, Fechter, Michael, Martinez, Stephanie, Hanson, Lenita, Cooper, Nyla, Madera, Areli, Cadorna, Jay, Sheridan, Rita, Sparks, Helen, Eilerman, Bradley, Bodine, Susanne, Eid, Wael, Flora, Rebecca, Avery, Amber, Hardy, Cashmere, Biscoveanu, Mihaela, Nagelberg, Steven, Cummins, Tracey, Rahbari-Oskoui, Frederic, Oommen, Anju, Forghani, Zohreh, Hitchcock, Stacie, Hosein, Darya, Watkins, Diane, Patel, Minesh, Lambert, Anthony, Newman, Elizabeth, Wood, Autumn, Ross, Tammy, Topping, Stephany, Mulhern, Jeffrey, Murphy, Lorna, Vasseur, Ann, Greenwood, Gregory, Hadley, Alexander, Laurienti, Denise, Marshall, Christopher, Mclean, Nichola, Satko, Scott, Caudill, Brandy, Maris, Jacob, Rogers, Janice, Vanhoy, Cindy, Thomas, George, Nakhoul, George, O'Toole, John, Taliercio, Jonathan, Cooperman, Leslie, Markovic, Marina, Tucky, Barbara, Dev, Devasmita, Hasan, Alia, Yalamanchili, Hima, Jain, Namita, Mcneil, Lesley, Wines, Eric, Park, Jean, Ghazi, Adline, Hamm, Mia, Patel, Teja, Mottl, Amy, Chang, Emily, Derebail, Vimal, Cole, Emmie, Froment, Anne, Kelley, Sara, Osmond Foster, Jordan, Mahabadi, Vahid, Jafari, Golriz, Kamarzarian, Anita, Arriaga, Wendy, Arteaga, Daisy, Machicado, Rosario, Naverrete, Genesi, Kumar, Prashant, Nazeer, Imran, Urquia, Karina, Glider, Tammi, Jones, Vickie, Rucker, Savannah, Wiley, Jennifer, Pandey, Rahul, Arroyo, Jesu, Pariani, Harish, Ahmad, Mohammad, Mozaffari, Shahin, Perez, Erika, Budoff, Matthew, Roy, Sion, Birudaraju, Divya, Ghanem, Ahmed, Hamal, Sajad, Aronoff, Stephen, Joye Petr, Elisa, Sachson, Richard, Wiebel, Jaime, Akram, Sana, Jones, Laurie, Knight, Curti, Tarlac, Maurie, Ahmed, Shahbaz, Szerlip, Harold, Akinfolarin, Akinwande, Mehta, Ankit, Camp, Shana, Castro, Cindy, Cooper, Zanaida, Terry, Jessica, Awad, Ahmed, Kothapalli, Bhavya, Lustig, Ryan, Alfaress, Serine, Jasim, Hyder, Parrigon, Mary, Karounos, Denni, Ahmed, Sadiq, Berry, Maggie, Oremus, Ruth, Hernandez-Cassis, Carlo, Ugwu, Elia, Junejo, Nazia, Suazo, Nancy, Segal, Mark, Kazory, Amir, Brown, Sherry, Daniels, Tristan, Dayi, Sofia, Hogan, Renee, Mccray, Kathy, Stickley, Jennifer, Rahman, Mahboob, Dobre, Mirela, Negrea, Lavinia, Padiyar, Aparna, Pradhan, Nishigandha, Rashidi, Arash, Sarabu, Nagaraju, Donley, Vicki, Young, Tricia, Oguchi, Godson, Onyema, Judepatrick, Damianik, Kahla, Dienes, Jack, Plummer-Morgan, Judith, Roman, Marilyn, Skipper, Mauver, Villaruel, Stacey-Ann, Williams, Krystle, Sugimoto, Danny, Dugas, Jeffrey, Ahmed, Ismeal, Bhairoo, Jamie, Rijos, Dolore, Salim, Huzaifa, Gavrila, Madita, Lafferty, Kathryn, Rabara, Ria, Ruse, Sally, Weetman, Maria, Bushnell, Jame, Power, Albert, Jenkins, Alison, Jones, Stefanie, Scott, Amanda, Byrne, Cath, Jesky, Mark, Cowley, Alison, Mchaffie, Emma, Waterfall, Holly, Taylor, Jo, Bough, Laura, Phillips, Thoma, Winter-Goodwin, Barbara, Phin Kon, Sui, Macdougall, Iain, Lioudaki, Eirini, Shah, Sapna, Sharpe, Claire, Aguilar, Francisco, Hernandez Pena, Abegail, Pugay, Conception, Te, Amelia, Finn, Hugh, Hanif, Wasim, Mostafa, Samiul, Aitken, Alice, Draxlbauer, Katharine, Grobovaite, Evelina, Kearney, Jennifer, Mccarthy, Theresa, Gentile, Giorgio, Browne, Duncan, Chellamuthu, Palanichamy, Dugal, Tabinda, Chant, Terri, Jones, Laura, Laity, Emily, Miners, Megan, Muir, Jame, Swanson, Elizabeth, Frankel, Andrew, Tomlinson, Jame, Alegata, Marlon, Almasarwah, Rashid, Apostolidi, Anthoula, Vourvou, Maria, Walters, Thoma, Taal, Maarten, Dukka, Hari, Kolhe, Nitin, Mcdonald, Carly, White, Kelly, Ugni, Shiva, Gunda, Smita, Oluyombo, Rotimi, Brindle, Vicki, Coutts, Ping, Fuller, Tracy, Nadar, Evelyn, Ramadoss, Suresh, Motherwell, Nichola, Pajak, Susannah, Tonks, Louise, Bhandari, Sunil, Bodington, Richard, Hazara, Adil, Fellowes, Dominic, Wong, Christopher, Goldsmith, Christopher, Barnes, Sherald, Bennett, Ann, Burston, Claire, Hope, Samantha, Hunt, Nicola, Kurian, Lini, Fish, Richard, Farrugia, Daniela, Lee, Judy, Sadler, Emma, Turner, Hannah, Hill, Christopher, Brown, Henry, Masengu, Agne, Maxwell, Peter, Bleakley, Nina, Murtagh, Hugh, Petchey, William, Yiu, Vivian, Kellett, Joanne, Williams, Angharad, Clarke, Helen, Carnall, Victoria, Benyon, Sarah, Blake, Caroline, Estcourt, Stephanie, Piper, Jane, Morgan, Neal, Hutchinson, Carolyn, Mckinley, Teresa, Woodman, Alastair, Graham, Judi, Leonard, Niall, Smyth, John, Adell, Vicki, Hagan, Samantha, Caplin, Ben, Oomatia, Amin, Damian, Eleanor, Sobande, Toluleyi, Doulton, Tim, Delaney, Michael, Montasser, Mahmoud, Hansen, Jenny, Loader, David, Moon, Angela, Morris, France, Sinha, Smeeta, Chukwu, Chukwuma, Hudson, Amy, Campbell, Diane, Kershaw, Melanie, Whittaker, Stephanie, Irtiza-Ali, Ayesha, Ghalli, Farid, Nosseir, Heba, Leslie, Allison, Trivedi, Kate, Fraser, Donald, Alhadj Ali, Mohammad, Griffin, Sian, Latif, Farah, Witczak, Justyna, Wonnacott, Alexa, Jeffers, Lynda, Webley, Yvette, Phelan, Paul, Miller-Hodges, Eve, Geddes, Ailsa, Glenwright, Margaret, Hunter, Amy, Pickett, Thoma, Moriarty, Jim, Hill, Linda, Tyler, Amanda, Ayub, Waqar, Evans, Gail, Hewins, Sue, Hewitt, Davina, Read, Kerry, Bell, Samira, Cosgrove, Leanne, Craik, Rachel, Murray, Shona, Bhandary, Nitin, Coles, Holly, Easow, Rashmi, Joseph, Maya, Khwaja, Arif, Jackson, Yvonne, Mbuyisa, Angeline, Sellars, Rachel, Chitalia, Nihil, Mohandas, Cynthia, Gherman, Anca, Kamundi, Charlotte, Olufuwa, Olumide, Mccafferty, Kieran, Adeleke, Adedolapo, Healy, Cara, Jeyarajah, Damini, Kinsella-Perks, Edward, Smith, Richard, Camilleri, Brian, Buckman, Carol, Finch, Jenny, Rivers, Vanessa, Connor, Andrew, Carr, Sheila, Shainberg, Lisa, Lewington, Andrew, Baker, Richard, Dorey, Suzannah, Tobin, Kay, Wheatley, Rosalyn, Banerjee, Debasish, Hull, Richard, Abat, Sharirose, Paul, Riny, Karim, Mahzuz, Htet, Zay, Tufail, Saad, Varma, Ravi, Convery, Karen, Fottrell-Gould, Deirdre, Hudig, Lisa, Tropman, Emily, Abdul-Samad, Thahir, Grace, Anne, Phipps, Marie, Suckling, Rebecca, Somalanka, Subash, Sood, Bhrigu, Swift, Pauline, Acheampong, Sarah, Ansu, Kwame, Augustin, Martia, Sampson, Anna, Vinall, Lynn, Wren, Kim, Wanninayake, Shamila, Wooding, Nichola, Edwards, Heather, Owen, Lydia, Bolton, Stephanie, Carson, Marion, Matthews, Michael, Brunskill, Nigel, Jesus-Silva, Jorge, Howson, Alex, Quashie-Akponeware, Mary, Tindall, Hilary, Nethaji, Chidambaram, Eldon, Helen, Patel, Rajan, Mark, Patrick, Rankin, Alastair, Sullivan, Michael, Forsyth, Kirsty, Mcdougall, Rowan, Dasgupta, Tanaji, Davies, Louisa, Ryder, Maggie, Grimmer, Philip, Macdonald, Clare, Webster, Mary, Newcastle, Newcastle, Ellam, Timothy, Wong, Edwin, Meshykhi, Christine, Webster, Andrea, Wilson, Peter, Vilar, Enric, Berdeprado, Jocelyn, Doctolero, Eunice, Wilkinson, Lily, Mccarroll, Frank, Ammar, Hesham, Kuan, Ying, Moran, Conor, Shivashankar, Girish, Campbell, Ryan, Glowski, Deborah, Mcdermott, Paula, Ali, Amar, Patel, Zuber, Bond, Christine, Whalley, Gillian, Zhang, Haitao, Yang, Liu, Zhang, Lihua, Kan, Tingting, Zhu, Ling, Zhao, Jinghong, Hou, Weiping, Wu, Jing, Cheng, Hong, Bian, Weijing, Zhao, Zhirui, Shao, Fengmin, Cao, Huixia, Jiao, Xiaojing, Niu, Peiyuan, Niu, Jianying, Chen, Yu, Zhang, Lihong, Zhu, Shenglang, Lin, Haiyan, Yao, Shaopeng, Chen, Jiehui, Jiang, Ying, Hu, Ying, Xiao, Huaying, Yang, Fuye, Zhang, Xinzhou, Guo, Baochun, Jin, Qiu, Liu, Lixia, Xiao, Xiangcheng, Xie, Yanyun, Meng, Ting, Xu, Chuanwen, Huang, Jie, Xu, Yanmei, Kong, Weixin, Wang, Xiaoliang, Liu, Qianpan, Wang, Xueying, Gao, Ming, Hu, Xiumei, Lu, Ying, Wang, Li, Peng, Kun, Wang, Wei, Gong, Qiuhong, Cai, Jianfang, Li, Xiaojue, Liu, Xuejiao, Zhou, Shuhan, Liu, Hong, Weng, Yao, Tang, Shuai, Yao, Yao, Zhao, Shi, Cheng, Chen, Wei, Wei, Li, Na, Aqashiah Mazlan, Sadanah, Zubaidah Bahtar, Alia, Katiman, Elliyyin, Othman, Noraini, Mushahar, Lily, Mazlan, Nurdiana, Sharafina Safiee, Nur, Ramasamy, Sarasa, Seng Wong, Hin, Ahmad Rosdi, Hajar, Zhao Zhi Tan, Esther, Fan Tay, Ju, Seng Teng, Kok, Yahaya, Hasnah, Jiun Liu, Wen, Wee Ee, Lik, Kay Leong Khoo, Kenneth, Mohd Yusoff, Yuana, Safhan Mohamad Nor, Fariz, Kamil Ahmad, Mohd, Ramli Seman, Mohd, Hui Hong Tan, Clare, Lui Sian Ngu, Laura, Yoke May Chan, Jaime, Peji, Javelin, Loong Loh, Chek, Yan Lee, Yee, Ramanaidu, Sridhar, Mean Thong, Kah, Hong Wong, Yik, Junus, Suria, Hua Ching, Chen, Faisal Asmee, Mohammad, Ruziana Ku Md Razi, Ku, Leong Low, Chun, Sze Bing Sim, Christopher, Duan Tham, Zhang, Kamila Abdullah, Noor, Meng Chen, Tai, Chieh Chan, Yong, Chang, Eason, Yean Kang, Huan, Quan Lee, Kai, Ann Lee, Sue, Kheng Lee, Aik, Vinathan, Jeevika, Abdul Cader, Rizna, Mustafar, Ruslinda, Kamaruzaman, Lydia, Mohd, Rozita, Ismail, Rahimah, Men Leong, Chong, Koon Low, Chee, Wei Wong, Liang, Adnan, Norlezah, Ibrahim, Sabariah, Zaimi Abdul Wahab, Mohamad, Bavanandan, Sunita, Shen Lim, Yik, Hazlina Wan Mohamad, Wan, Munirah Jaafar, Siti, Ashykeen Mohd Fauzi, Nur, Sudin, Aziee, Kun Lim, Soo, Chung Gan, Chye, Hing, Albert, Ahmad Faizal Alaidin Razali, Wan, Fong Liew, Yew, Bao Tyng Chan, Chelsia, Chih Cheng, Mei, Chen Ong, Yu, Meng Ong, Loke, Amalina Mohamed Affandi, Farah, Rahmat, Korina, Chai Peng, Ban, Amat, Masayu, Hadafi Ahmad, Nuzaimin, Yee Mah, Doo, Loon Tye, Yi, Azhari, Zaid, Nabilah Mohamad Zaini, Siti, Aidil Musa, Mohd, Ahmad Miswan, Norazinizah, Ramli, Rafizanur, Aziah Ahmad, Nor, Leong Goh, Bak, Izah Ahmad, Nurul, Huda Ibrahim, Fairol, Jian Ng, Tze, Shanmuganathan, Malini, Lian Tay, Li, Harun, Zaiha, Ramli, Salmi, 'Ain Yusof, Nurul, Abd Rahman, Rossenizal, Iqbal Abdul Hafidz, Muhammad, Hidayati Mohd Sharif, Nur, Yasmoon Awang, Irda, Nakashima, Eitaro, Imamine, Rui, Minatoguchi, Makiko, Miura, Yukari, Nakaoka, Miduki, Suzuki, Yoshiki, Yoshikawa, Hitomi, Shin, Koki, Fujita, Kanae, Iwasa, Misuzu, Sasajima, Haruka, Sato, Airi, Hamamoto, Yoshiyuki, Fujita, Yuki, Haraguchi, Takuya, Hyo, Takanori, Izumi, Kiyohiro, Komiya, Toshiyuki, Kubota, Sodai, Kurose, Takeshi, Kuwata, Hitoshi, Nakatani, Susumu, Oishi, Kaori, Okamoto, Saki, Okamura, Kaori, Takeoka, Jun, Tanaka, Nagaaki, Tanigaki, Katsuya, Toda, Naohiro, Watanabe, Koin, Komori, Hiromi, Kumuji, Rika, Takesada, Asako, Tanaka, Aya, Maruyama, Shoichi, Hasegawa, Tomonori, Ishiguro, Akiko, Ishimoto, Takuji, Ito, Kazuhiro, Kamimura, Yutaka, Kato, Noritoshi, Kato, Sawako, Kojima, Hiroshi, Kosugi, Tomoki, Maeda, Kayaho, Mizuno, Masasi, Saito, Shoji, Sato, Hitomi, Sato, Yuka, Suzuki, Yasuhiro, Tanaka, Akihito, Yasuda, Yoshinari, Hasegawa, Fujiko, Hayashi, Maiko, Higashi, Shizuka, Shimamura, Kaho, Sumi, Momoko, Tajima, Kazuki, Unekawa, Chimaki, Wakayama, Kana, Wakita, Yukiko, Otani, Takatoshi, Imai, Ayako, Kawashima, Sayaka, Kogure, Eri, Sato, Tomoe, Takezawa, Misato, Yoshida, Shinya, Araki, Hideo, Katsuda, Yuko, Konishi, Masahiro, Matsunaga, Takahiro, Oe, Masashi, Ogane, Kunihiro, Sakai, Masato, Takahashi, Tomoko, Yamano, Takahiro, Yokoyama, Takuya, Ito, Hitomi, Katayama, Masayo, Kuroda, Emi, Ikeda, Toru, Kojo, Takuma, Yoshidome, Etsuo, Mizumachi, Rieko, Yamamoto, Akane, Yamasaki, Narihisa, Yamasaki, Yoshihiko, Wada, Jun, Eguchi, Jun, Higuchi, Chigusa, Katayama, Akihiro, Kinomura, Masaru, Kitagawa, Masashi, Kitamura, Shinji, Miyamoto, Satoshi, Morinaga, Hiroshi, Nakatsuka, Atsuko, Nojima, Ichiro, Shikata, Kenichi, Sugiyama, Hitoshi, Tanabe, Katsuyuki, Tsuji, Kenji, Uchida, Haruhito, Watanabe, Mayu, Hashimoto, Chie, Kato, Takahiro, Yamamoto, Sayaka, Wada, Takehiko, Fukagawa, Masafumi, Hamano, Naoto, Koizumi, Masahiro, Komaba, Hirotaka, Nakagawa, Yosuke, Iwamoto, Michiyo, Masutani, Kosuke, Katanosaka, Akane, Kiyota, Mayu, Uchi, Hikari, Ueda, Yuka, Yamamoto, Sonoka, Nagasu, Hajime, Itano, Seiji, Iwakura, Tsukasa, Kadoya, Hiroyuki, Kanda, Eiichiro, Kashihara, Naoki, Kidokoro, Kengo, Kondo, Megumi, Sasaki, Tamaki, Satoh, Minoru, Tokuyama, Atsuyuki, Umeno, Reina, Wada, Yoshihisa, Yamamoto, Toshiya, Yamanouchi, Yu, Abe, Masumi, Inukai, Yoko, Ogawa, Wataru, Asahara, Shunichiro, Fujii, Hideki, Goto, Shunsuke, Hirota, Yushi, Hosooka, Tetsuya, Kono, Keiji, Nishi, Shinichi, Okada, Yuko, Sakaguchi, Kazuhiko, Sugawara, Kenji, Takahashi, Michiko, Takai, Tomoko, Tamori, Yoshikazu, Watanabe, Kentaro, Kitajima, Miyu, Nishi, Misaki, Wada, Junko, Ito, Yasuhiko, Kamiya, Hideki, Asai, Akimasa, Asai, Nao, Asano, Saeko, Banno, Shogo, Ejima, Yohei, Hase, Hanako, Hayami, Tomohide, Himeno, Tatsuhito, Ishikawa, Takahiro, Ito, Mayumi, Iwagaitsu, Shiho, Kasagi, Rina, Kato, Yoshiro, Kato, Makoto, Kato, Koichi, Katsuno, Takayuki, Kawai, Miyuka, Kinashi, Hiroshi, Kondo, Masaki, Koshino, Masako, Matsuoka, Naoya, Morishita, Yoshiaki, Motegi, Mikio, Nakamura, Jiro, Shimoda, Hiromi, Sugiyama, Hirokazu, Tsunekawa, Shin, Yamaguchi, Makoto, Takahashi, Kazuyo, Watada, Hirotaka, Funayama, Takashi, Furukawa, Yasuhiko, Gohda, Tomohito, Goto, Hiromasa, Kaga, Hideyoshi, Kanaguchi, Yasuhiko, Kanazawa, Akio, Kaneko, Kayo, Kano, Toshiki, Kihara, Masao, Kimura, Shogo, Kobayashi, Takashi, Maiguma, Masayuki, Makita, Yuko, Mano, Satoshi, Mita, Tomoya, Miyatsuka, Takeshi, Murakoshi, Maki, Muto, Masahiro, Nakata, Masami, Nakata, Junichiro, Nishida, Yuya, Nohara, Nao, Ogihara, Takeshi, Sato, Daisuke, Sato, Junko, Sato, Hiroaki, Suzuki, Yusuke, Suzuki, Ruka, Suzuki, Hitoshi, Takagi, Miyuki, Tamura, Yoshifumi, Uchida, Toyoyoshi, Ueda, Seiji, Asawa, Miki, Miyaji, Minako, Nagashima, Eri, Shibata, Yoshie, Yanagisawa, Eri, Yamauchi, Toshimasa, Hirakawa, Yosuke, Nishi, Hiroshi, Shojima, Nobuhiro, Horikawa, Satoko, Nakayama, Yukiko, Yamada, Naoko, Omori, Yuki, Yano, Shintaro, Ioka, Miyabi, Kuwabara, Nahoko, Nagano, Remi, Nozawa, Megumi, Osawa, Yumi, Maegawa, Hiroshi, Kume, Shinji, Araki, Shinichi, Miyazawa, Itsuko, Morino, Katsutaro, Kawai, Ikuko, Sobata, Masumi, Takaoka, Motoko, Iwaita, Yasushi, Udagawa, Takashi, Inamori, Ami, Kawase, Aya, Yamanaka, Aya, Shimano, Hitoshi, Fujita, Akiko, Iwasaki, Hitoshi, Kai, Hirayasu, Osaki, Yoshinori, Saito, Chie, Sekiya, Motohiro, Tsunoda, Ryoya, Yamagata, Kunihiro, Nakamura, Rikako, Yamada, Aiko, Ohsugi, Mitsuru, Awazawa, Motoharu, Bouchi, Ryotaro, Hashimoto, Shota, Hashimoto, Makiko, Hisatake, Tomoko, Ihana, Noriko, Ishizuka, Koko, Izumi, Kazuo, Kajio, Hiroshi, Kobayashi, Michi, Kodani, Noriko, Maruyama, Koji, Matsumoto, Michihiro, Matsushita, Maya, Nakamura, Tomoka, Sugiyama, Takehiro, Tanabe, Akiyo, Terakawa, Aiko, Ueki, Kojiro, Orimo, Yuko, Ozawa, Takako, Takahira, Eriko, Yamasaki, Yoshimitsu, Haneda, Masakazu, Tomita, Tadahiro, Akimoto, Saori, Fujimoto, Akihiro, Ishihara, Kenji, Murakami, Chiho, Nishiyama, Akiyo, Toyonaga, Yukiko, Uozumi, Kana, Yamaji, Yukihiro, Shigehara, Tetsuya, Okajyo, Jun, Shimizu, Yukihiro, Iwasaki, Shingo, Fukao, Yuki, Furusho, Megumi, Nunokawa, Shintaro, Katagiri, Hideki, Izumi, Tomohito, Kaneko, Keizo, Kodama, Shinjiro, Miyazaki, Mariko, Munakata, Yuichiro, Nagasawa, Tasuku, Oe, Yuji, Sugawara, Hiroto, Takahashi, Kei, Hirata, Kazushige, Inomata, Keiko, Otomo, Shoko, Uchida, Taeko, Yamashita, Chigusa, Kiyosue, Arihiro, Tamura, Ryota, Dube, Francoi, Bolduc, Marilene, Talbot, Marie-Christine, Cham, Leslie, Lai, Vesta, Tse, Josephine, Jolly, Shivinder, Duck, Tabbatha, Lyle, Scott, Epp, Rachel, Galloway, Camille, Haskett, Susan, Matvienko, Elizabeta, Paulsen, Liam, Moist, Louise, Lozon, Zabrina, Ramsey, Tina, Whitmore, Brittany, Al-Zeer, Bader, Macleod, Paula, O'Sullivan, Aoife, Sheriff, Zainab, Tholl, Sam, Pandey, Amritanshu, Armstrong, Samantha, Gebeyehu, Bethelihem, Toth, Patrick, Goldenberg, Ronald, Jahangiriesmaili, Mahsa, Sanguila, Shariff, Suresh, Neethi, Talsania, Tanvi, Zalunardo, Nadia, Agharazii, Mohsen, Roussel, Marie-Pier, Saillant, Annie, Samson, France, Bajaj, Harpreet, Bhavsar, Miken, Dhall, Parul, Dhillon, Gagandeep, Grewal, Bhupinder, Nimbkar, Taniya, Madore, Francoi, Marcotte, Guylaine, Steen, Oren, Bullen, Mathura, Raguwaran, Shayani, Valleteau, Andre, Langlois, Marie-France, Brown, Christine, Steele, Andrew, Garrity, Melissa, Ghate, Taneera, Robinson, Holly, Tolibas, Michael, Tailor, Chetna, Elliott, Lauren, McClary-Wright, Christine, Boreky, Fadia, Fikry, Sameh, Ali, Ayesha, Barot, Chintankumar, Basily, Wagdy, Saram, Thisun, Varad, Vinay, Khandwala, Hasnain, Aguilera, Alex, Alvarez, Patricia, Gill, Balwinder, Huda, Nazihah, Navivala, Aamir, Pinto, Daniel, Bevilacqua, Micheli, Fung, Elaine, Hernandez, Geraldine, Mann, Puneet, Saini, Jaskiran, Rabasa-Lhoret, Remi, Bovan, Danijela, Devaux, Marie, Barnini, Cecilia, Leoncini, Giovanna, Manco, Luca, Nobili, Giulia, Piemontese, Matteo, Aucella, Filippo, Grifa, Rachele, Totaro, Francesco, La Manna, Gaetano, Capelli, Irene, Cianciolo, Giuseppe, Lerario, Sarah, Zappulo, Fulvia, Rosati, Alberto, Fani, Filippo, Spatoliatore, Giuseppe, Gesualdo, Loreto, Pesce, Francesco, Russo, Maria, Zippo, Maria, Cafiero, Cesira, Motta, Daria, Bianco, Simona, Bilucaglia, Donatella, Messa, Piergiorgio, Pavone, Laura, Tripodi, Federica, Vettoretti, Simone, Fioretto, Paola, Carraro, Gianni, Farnia, Filippo, Postal, Anna, D'Amelio, Alessandro, Cardone, Antonio, Piccinni, Giovanni, Aloisi, Annalisa, Scolari, Francesco, Alberici, Federico, Guerini, Alice, Saccà, Chiara, Salviani, Chiara, Zani, Roberta, DE NICOLA, Luca, Garofalo, Carlo, Elena Liberti, Maria, Minutolo, Roberto, Pennino, Luigi, Polese, Lucio, Mené, Paolo, Barberi, Simona, Falcone, Clorinda, Russo, Francesco, Caroppo, Maurizio, Santorelli, Gennaro, Rivera, Rodolfo, Santoro, Domenico, Giuffrida, Alfio, Zirino, Fortunata, Calvi, Cristina, Estienne, Luca, Gambaro, Giovanni, Gangemi, Concetta, Ortalda, Vittorio, Pessolano, Giuseppina, Grandaliano, Giuseppe, Baccaro, Rocco, Ferraro, Pietro, Mangiacapra, Roberto, Melandri, Marco, Foligno, Nadia, Quartagno, Rita, Vezzoli, Giuseppe, Brioni, Elena, and Group, EMPA-KIDNEY Collaborative
Subjects: chronic renal disease, empagliflozin, empa-kidney, General Medicine
Abstract: Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m2 of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m2 with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; PConclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo. (Funded by Boehringer Ingelheim and others; EMPA-KIDNEY ClinicalTrials.gov number, NCT03594110. opens in new tab; EudraCT number, 2017-002971-24. opens in new tab.)
Published: 2023

5. Postprandial Plasma Glucagon Kinetics in Type 2 Diabetes Mellitus: Comparison of Immunoassay and Mass Spectrometry

Author: Atsushi Miyachi, Hirotaka Watada, Naoko Takayanagi, Takeshi Miyatsuka, Yuka Tosaka, Fuki Ikeda, Takeshi Ogihara, Tomoya Mita, Chie Ohmura, Satoko Yamashita, Koji Komiya, Mai Shinohara, Takehiro Katahira, Akio Kanazawa, Hideyoshi Kaga, Eri Mieno, Kosuke Azuma, and Mami Koshibu
Subjects: 0301 basic medicine, medicine.medical_specialty, Diabetes, Pancreatic and Gastrointestinal Hormones, Endocrinology, Diabetes and Metabolism, Incretin, 030209 endocrinology & metabolism, Dipeptidyl peptidase-4 inhibitor, Type 2 diabetes, Glucagon, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Medicine, mass spectrometry, Technical Resource, business.industry, digestive, oral, and skin physiology, Area under the curve, Type 2 Diabetes Mellitus, medicine.disease, incretin, 030104 developmental biology, Endocrinology, Postprandial, glucagon, dipeptidyl peptidase-4 inhibitor, Anagliptin, ELISA, business, medicine.drug
Abstract: Context Accurate glucagon level measurements are necessary for investigation of mechanisms for postprandial hyperglycemia in type 2 diabetes. Objective To evaluate the accuracy of postprandial glucagon level measurements using a sandwich ELISA vs a recently established liquid chromatography-high resolution mass spectrometry (LC-HRMS) method in type 2 diabetes mellitus. Design and Participants Twenty patients with type 2 diabetes treated with insulin underwent a meal test before and after administration of the dipeptidyl peptidase-4 inhibitor anagliptin for 4 weeks. Blood samples were taken serially after the meal, and glucagon levels were measured using both ELISA and LC-HRMS. We compared the change from baseline to 4 weeks (Δ0–4W) using the area under the curve for plasma glucagon during the meal test [area under the curve (AUC)0–3h] measured using ELISA and LC-HRMS. Results ELISA-based glucagon AUC0–3h was higher than LC-HRMS–based AUC0–3h at baseline and 4 weeks. However, differences in Δ0–4W-AUC0–3h measured using ELISA and LC-HRMS were not statistically significant. Additionally, Δ0–4W-AUC0–3h measured using ELISA and LC-HRMS were strongly correlated (r = 0.87, P < 0.001). Conclusions Plasma glucagon levels during a meal test in patients with type 2 diabetes measured using ELISA were consistently higher than those measured using LC-HRMS. However, given that the changes in glucagon levels measured using ELISA before and after dipeptidyl peptidase-4 inhibitor therapy were similar to those based on LC-HRMS, this ELISA seems to be useful for evaluating the effect of the drug interventions on postprandial glucagon levels.
Published: 2018
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6. Enhanced Expression of the Key Mitosis Regulator Cyclin B1 Is Mediated by PDZ-Binding Kinase in Islets of Pregnant Mice

Author: Hirotaka Watada, Yoshio Fujitani, Tadayoshi Uesato, Hitoshi Iida, Takeshi Miyatsuka, Akemi Hara, Takeshi Ogihara, and Satoru Takeda
Subjects: p53, 0301 basic medicine, endocrine system, Small interfering RNA, Diabetes, Pancreatic and Gastrointestinal Hormones, islet, Kinase, cyclin B1, Endocrinology, Diabetes and Metabolism, Cell biology, Gene expression profiling, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, chemistry, Downregulation and upregulation, Pbk, estradiol, Protein kinase A, Cyclin B1, Bromodeoxyuridine, Research Article, Regulator gene
Abstract: The proliferation of pancreatic β cells is enhanced to enable an increase in β-cell mass and to compensate for insulin resistance during pregnancy. To elucidate the mechanisms involved, we previously investigated islets from pregnant and nonpregnant mice by gene expression profiling and found that the expression of postsynaptic density-95/Discs large/zonula occludens-1 (PDZ)–binding kinase (Pbk), a member of the mitogen-activated protein kinase kinase family, is increased in pregnant mouse islets compared with control mouse islets. Among the pregnancy hormones, treatment with estradiol upregulated Pbk expression. Inhibition of Pbk expression using a small interfering RNA for Pbk reduced bromodeoxyuridine incorporation in mouse insulinoma 6 cells, which was accompanied by a decreased expression of Ccnb1, a regulatory gene involved in mitosis. Ccnb1 expression was augmented in mouse islets during pregnancy. The forced expression of Pbk using an adenovirus system in isolated mouse islets increased Ccnb1 expression, and the Pbk inhibitor HI-TOPK-032 suppressed Ccnb1 expression in islets isolated from pregnant mice. Our results suggest that Pbk contributes to the expansion of islets during pregnancy and that Ccnb1 may assist Pbk in its role in β-cell proliferation., PDZ-binding kinase is increased in islets of pregnant mice. Inhibition of Pbk expression reduces BrdU incorporation in MIN6 cells, which was accompanied by a decreased expression of Ccnb1.
Published: 2018
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7. Normal pancreatic β-cell function in mice with RIP-Cre-mediated inactivation of p62/SQSTM1

Author: Koji Komiya, Hirotaka Watada, Akira Honda, Yoshio Fujitani, Takeshi Ogihara, Akemi Hara, Takeshi Miyatsuka, Luka Suzuki, and Ayako Fukunaka
Subjects: 0301 basic medicine, Sequestosome-1 Protein, education.field_of_study, geography, medicine.medical_specialty, Cell signaling, geography.geographical_feature_category, Endocrinology, Diabetes and Metabolism, Autophagy, Biology, medicine.disease, Islet, medicine.disease_cause, Impaired glucose tolerance, 03 medical and health sciences, 030104 developmental biology, Endocrinology, Sequestosome 1, Internal medicine, medicine, education, Homeostasis, Oxidative stress
Abstract: Recent studies have suggested that decreased pancreatic β-cell function and mass are common features of patients with type 2 diabetes mellitus. Pancreatic β-cell homeostasis is regulated by various types of signaling molecules and stress responses. Sequestosome 1/p62 (SQSTM1, hereafter referred to as p62) is a ubiquitin-binding adaptor protein involved in cell signaling, oxidative stress, and autophagy. Because p62 appears to play an important role in maintaining mitochondrial quality control, it is possible that the loss of p62 in pancreatic β cells contributes to mitochondrial dysfunction, and thus leading to impaired glucose tolerance. In this study we investigated the physiological roles of p62 by inactivating p62 in a β-cell specific manner. We found that firstly, rat insulin-2 promoter-Cre (RIP-Cre)-mediated p62 inactivation did not cause body weight gain, although ubiquitous inactivation of p62 was previously shown to result in severe obesity. Secondly, we found no gross structural disorganization of the islets of p62-deficient mice. Consistent with normal islet morphology, no impairment in glucose tolerance was observed in mice with RIP-Cre-mediated p62 deletion. These results suggest that p62 is dispensable for normal islet organization and β-cell function.
Published: 2018
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8. Effect of treatment guidance using a retrospective continuous glucose monitoring system on glycaemic control in outpatients with type 2 diabetes mellitus: A randomized controlled trial

Author: Toyoyoshi Uchida, Nayumi Shigihara, Hirotaka Watada, Junko Sato, Tomoya Mita, Takeshi Ogihara, Koji Komiya, Tomoaki Shimizu, Fuki Ikeda, Akio Kanazawa, Minako Kawaguchi, and Yoshio Fujitani
Subjects: Blood Glucose, Male, medicine.medical_specialty, endocrine system diseases, medicine.medical_treatment, 030209 endocrinology & metabolism, Type 2 diabetes, Biochemistry, law.invention, 03 medical and health sciences, 0302 clinical medicine, Patient satisfaction, Randomized controlled trial, law, Surveys and Questionnaires, Internal medicine, Blood Glucose Self-Monitoring, Outpatients, medicine, Humans, 030212 general & internal medicine, Continuous glucose monitoring, Demography, Retrospective Studies, Glycated Hemoglobin, business.industry, Insulin, Biochemistry (medical), nutritional and metabolic diseases, Type 2 Diabetes Mellitus, Retrospective cohort study, Cell Biology, General Medicine, Middle Aged, medicine.disease, Surgery, Research Note, Diabetes Mellitus, Type 2, Hyperglycemia, insulin therapy, Practice Guidelines as Topic, Female, type 2 diabetes, business
Abstract: Objectives To assess the effect of treatment guidance based on data from a continuous glucose monitoring (CGM) device on glycaemic control, and patient satisfaction, in patients with type 2 diabetes mellitus (T2DM). Methods Patients with poorly-controlled T2DM treated with insulin were randomly assigned to the intervention or nonintervention group. Continuous blood-glucose levels were recorded for 4–5 days using a CGM device on three separate occasions during the 8-month study period. The intervention group received treatment guidance based on the CGM data; the nonintervention group received advice based on blood glucose and glycosylated haemoglobin (HbA1c) levels. Results A total of 34 patients were enrolled in the study. The mean ± SD baseline HbA1c was 8.2 ± 1.2% in the intervention group and 8.2 ± 0.9% in the nonintervention group. At the study end, there was no significant difference in the change from baseline of HbA1c between the two groups. There was also no significant difference in the change from baseline in the Diabetes Treatment Satisfaction Questionnaire score between the two groups. Conclusions The present study did not demonstrate that treatment guidance using retrospective CGM data was effective for improving glycaemic control and therapeutic satisfaction in Japanese patients with T2DM.
Published: 2015
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9. Switching from Twice-Daily Basal Insulin Injections to Once-Daily Insulin Degludec Injection for Basal-Bolus Insulin Regimen in Japanese Patients with Type 1 Diabetes: A Pilot Study

Author: Yoshifumi Tamura, Kazuhisa Matsumoto, Akio Kanazawa, Toyoyoshi Uchida, Tomoya Mita, Fuki Ikeda, Junko Sato, Tomoaki Shimizu, Yoshio Fujitani, Chie Ohmura, Hirotaka Watada, Takeshi Ogihara, Hiromasa Goto, Yuka Tosaka, and Mayu Iida
Subjects: Insulin degludec, medicine.medical_specialty, Type 1 diabetes, lcsh:RC648-665, Basal bolus insulin, Article Subject, endocrine system diseases, Endocrine and Autonomic Systems, business.industry, Endocrinology, Diabetes and Metabolism, Basal insulin, Hypoglycemia, medicine.disease, lcsh:Diseases of the endocrine glands. Clinical endocrinology, Regimen, Endocrinology, Internal medicine, Clinical Study, medicine, Once daily, business, Glycemic
Abstract: The aim of this study was to investigate the efficacy of insulin degludec used for basal-bolus insulin regimen after switching from twice-daily basal insulin in Japanese patients with type 1 diabetes mellitus. The subjects were 22 type 1 diabetes patients treated with basal-bolus insulin regimen with twice-daily basal insulin. Basal insulin was switched to once-daily injection of insulin degludec with 10% dose reduction. HbA1c and fasting plasma glucose (FPG) were measured before and 12 weeks after switching. The frequency of hypoglycemic episodes, standard deviation (SD) of blood glucose, and mean of daily difference (MODD) were evaluated by continuous glucose monitoring (CGM) before and 4 weeks after switching. HbA1c and FPG before and 12 weeks after switching were comparable (HbA1c 8.5 ± 1.4 versus 8.7 ± 1.6%,P=0.28; FPG 203.2 ± 81.2 versus 206.5 ± 122.4 mg/dL,P=0.91). The frequency of hypoglycemia during nighttime was not significantly different at 4 weeks after switching (14.4 ± 17.0 versus 11.1 ± 15.0%,P=0.45). In addition, SD and MODD before and 4 weeks after switching were also comparable. In conclusion, glycemic control under once-daily insulin degludec injection was almost comparable to that under twice-daily basal insulin injections in Japanese type 1 diabetes patients. This study was registered with ID:UMIN000010474.
Published: 2015
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10. Normal pancreatic β-cell function in mice with RIP-Cre-mediated inactivation of p62/SQSTM1

Author: Akira, Honda, Koji, Komiya, Akemi, Hara, Ayako, Fukunaka, Luka, Suzuki, Takeshi, Miyatsuka, Takeshi, Ogihara, Yoshio, Fujitani, and Hirotaka, Watada
Subjects: Blood Glucose, Male, Mice, Knockout, Gene Expression, Reproducibility of Results, Mice, Transgenic, Weight Gain, Immunohistochemistry, Specific Pathogen-Free Organisms, Islets of Langerhans, Organ Specificity, Insulin-Secreting Cells, Insulin Secretion, Sequestosome-1 Protein, Autophagy, Animals, Insulin, RNA, Messenger, Promoter Regions, Genetic, Crosses, Genetic, Cell Proliferation
Abstract: Recent studies have suggested that decreased pancreatic β-cell function and mass are common features of patients with type 2 diabetes mellitus. Pancreatic β-cell homeostasis is regulated by various types of signaling molecules and stress responses. Sequestosome 1/p62 (SQSTM1, hereafter referred to as p62) is a ubiquitin-binding adaptor protein involved in cell signaling, oxidative stress, and autophagy. Because p62 appears to play an important role in maintaining mitochondrial quality control, it is possible that the loss of p62 in pancreatic β cells contributes to mitochondrial dysfunction, and thus leading to impaired glucose tolerance. In this study we investigated the physiological roles of p62 by inactivating p62 in a β-cell specific manner. We found that firstly, rat insulin-2 promoter-Cre (RIP-Cre)-mediated p62 inactivation did not cause body weight gain, although ubiquitous inactivation of p62 was previously shown to result in severe obesity. Secondly, we found no gross structural disorganization of the islets of p62-deficient mice. Consistent with normal islet morphology, no impairment in glucose tolerance was observed in mice with RIP-Cre-mediated p62 deletion. These results suggest that p62 is dispensable for normal islet organization and β-cell function.
Published: 2017

11. Gut Dysbiosis and Detection of 'Live Gut Bacteria' in Blood of Japanese Patients With Type 2 Diabetes

Author: Takuya Takahashi, Hiroshi Fukuda, Yuko Sakurai, Tomoaki Shimizu, Yoshifumi Tamura, Tomoaki Yoshihara, Akio Kanazawa, Risako Yamamoto, Takeshi Ogihara, Takahisa Hirose, Hiroko Abe, Hirotaka Watada, Tomoya Mita, Koji Komiya, Yuichiro Yamashiro, Koji Nomoto, Fuki Ikeda, Minako Kawaguchi, Junko Sato, Yoshio Fujitani, Hiromasa Goto, Takashi Asahara, and Satoru Nagata
Subjects: Adult, Male, Atopobium, Endocrinology, Diabetes and Metabolism, Bacteremia, Gut flora, Microbiology, Feces, Japan, Lactobacillus, Internal Medicine, Prevotella, Humans, Medicine, Aged, Advanced and Specialized Nursing, biology, business.industry, Microbiota, Obligate anaerobe, Middle Aged, biology.organism_classification, Lactobacillus reuteri, Intestines, Blood, Diabetes Mellitus, Type 2, Case-Control Studies, Immunology, Dysbiosis, Female, business, Bacteria
Abstract: OBJECTIVE Mounting evidence indicates that the gut microbiota are an important modifier of obesity and diabetes. However, so far there is no information on gut microbiota and “live gut bacteria” in the systemic circulation of Japanese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Using a sensitive reverse transcription–quantitative PCR (RT-qPCR) method, we determined the composition of fecal gut microbiota in 50 Japanese patients with type 2 diabetes and 50 control subjects, and its association with various clinical parameters, including inflammatory markers. We also analyzed the presence of gut bacteria in blood samples. RESULTS The counts of the Clostridium coccoides group, Atopobium cluster, and Prevotella (obligate anaerobes) were significantly lower (P < 0.05), while the counts of total Lactobacillus (facultative anaerobes) were significantly higher (P < 0.05) in fecal samples of diabetic patients than in those of control subjects. Especially, the counts of Lactobacillus reuteri and Lactobacillus plantarum subgroups were significantly higher (P < 0.05). Gut bacteria were detected in blood at a significantly higher rate in diabetic patients than in control subjects (28% vs. 4%, P < 0.01), and most of these bacteria were Gram-positive. CONCLUSIONS This is the first report of gut dysbiosis in Japanese patients with type 2 diabetes as assessed by RT-qPCR. The high rate of gut bacteria in the circulation suggests translocation of bacteria from the gut to the bloodstream.
Published: 2014
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12. Exendin-4 Improves β-Cell Function in Autophagy-Deficient β-Cells

Author: Yasuo Uchiyama, Hirotaka Watada, Hiroki Mizukami, Yukiko Toyofuku, Koji Komiya, Hiroko Abe, Masato Koike, Takeshi Ogihara, Nayumi Shigihara, Soroku Yagihashi, Akemi Hara, Toyoyoshi Uchida, and Yoshio Fujitani
Subjects: Blood Glucose, Male, endocrine system, medicine.medical_specialty, Programmed cell death, medicine.medical_treatment, Apoptosis, Type 2 diabetes, Biology, Autophagy-Related Protein 7, Glucagon, Mice, Endocrinology, Mice, Inbred NOD, Insulin-Secreting Cells, Internal medicine, Diabetes mellitus, Glucose Intolerance, Autophagy, medicine, Animals, Receptor, Venoms, Insulin, Type 2 Diabetes Mellitus, medicine.disease, Diabetes Mellitus, Type 2, Gene Expression Regulation, Exenatide, Peptides, Microtubule-Associated Proteins, Transcription Factor TFIIH, Transcription Factors
Abstract: Autophagy is cellular machinery for maintenance of β-cell function and mass. The implication of autophagy failure in β-cells on the pathophysiology of type 2 diabetes and its relation to the effect of treatment of diabetes remains elusive. Here, we found increased expression of p62 in islets of db/db mice and patients with type 2 diabetes mellitus. Treatment with exendin-4, a glucagon like peptide-1 receptor agonist, improved glucose tolerance in db/db mice without significant changes in p62 expression in β-cells. Also in β-cell-specific Atg7-deficient mice, exendin-4 efficiently improved blood glucose level and glucose tolerance mainly by enhanced insulin secretion. In addition, we found that exendin-4 reduced apoptotic cell death and increased proliferating cells in the Atg7-deficient islets, and that exendin-4 counteracted thapsigargin-induced cell death of isolated islets augmented by autophagy deficiency. Our results suggest the potential involvement of reduced autophagy in β-cell dysfunction in type 2 diabetes. Without altering the autophagic state in β-cells, exendin-4 improves glucose tolerance associated with autophagy deficiency in β-cells. This is mainly achieved through augmentation of insulin secretion. In addition, exendin-4 prevents apoptosis and increases the proliferation of β-cells associated with autophagy deficiency, also without altering the autophagic machinery in β-cells.
Published: 2013
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13. Identification and comparison of insulin pharmacokinetics injected with a new 4‐mm needle vs 6‐ and 8‐mm needles accounting for endogenous insulin and C‐peptide secretion kinetics in non‐diabetic adult males

Author: Shusaku Tozaka, Takahisa Hirose, Hirotaka Watada, Takeshi Ogihara, and Sami Kanderian
Subjects: medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Bioequivalence, Body fat percentage, chemistry.chemical_compound, Pharmacokinetics, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Insulin lispro, Insulin, C-peptide, business.industry, Area under the curve, General Medicine, Articles, medicine.disease, Endocrinology, Clinical Science and Care, chemistry, Needle length, Original Article, business, medicine.drug
Abstract: Aims/Introduction Many patients with diabetes now use 5-, 6- or 8-mm needles for insulin injection. However, it is unclear whether needle length, particularly for shorter needles, affects the pharmacokinetic properties of insulin. Materials and Methods This was a three-way, randomized, cross-over, single-center study involving 12 healthy Japanese adult males (age 27.4 ± 4.14 years; weight 64.2 ± 5.2 kg; body fat percentage 18.2 ± 1.5%). Participants received a subcutaneous (abdomen) dose of insulin lispro (1.5 U for participants weighing 55 to
Published: 2013

14. Efficacy and Safety of Vildagliptin as an Add-On Therapy in Inadequately Controlled Type 2 Diabetes Patients Treated With Basal Insulin

Author: Junko Sato, Fuki Ikeda, Hirotaka Watada, Toyoyoshi Uchida, Fumihiko Sato, Takeshi Miyatsuka, Hiromasa Goto, Takeshi Ogihara, Chie Ohmura, Akio Kanazawa, Nayumi Shigihara, and Daisuke Saito
Subjects: medicine.medical_specialty, 030209 endocrinology & metabolism, Type 2 diabetes, 030204 cardiovascular system & hematology, Hypoglycemia, Gastroenterology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, DPP-4 inhibitor, Vildagliptin, Basal insulin, 1,5-anhydroglucitol, Glycemic, business.industry, Type 2 Diabetes Mellitus, General Medicine, medicine.disease, Add on therapy, Endocrinology, chemistry, 1,5-Anhydroglucitol, Original Article, business, medicine.drug
Abstract: Background: The aim of this study was to investigate the efficacy and safety of vildagliptin as an add-on therapy for patients with type 2 diabetes mellitus inadequately controlled with basal insulin. Methods: Twenty-four patients treated with basal insulin and oral anti-diabetes drugs were randomly allocated into two groups: the control group (did not receive any add-on drugs) and vildagliptin group (received vildagliptin 100 mg/day for 6 months). The primary outcome was changes in hemoglobin A1c (HbA1c) from baseline to end of study. Results: Treatment with vildagliptin significantly reduced HbA1c from 8.1±0.7% at baseline to 7.1±0.7% (P < 0.01), while there was no significant change of HbA1c in the control group. Vildagliptin group showed significant reduction of HbA1c compared with control group (-1.0±0.3% vs. 0.2±0.8%, P < 0.01). In addition, vildagliptin group showed a significant increase in 1,5-anhydroglucitol compared with the control group (4.5 ± 3.4 vs. 0.5 ± 4.1 μg/mL, P < 0.05). Mild hypoglycemia was reported in one patient of the vildagliptin group and two patients of the control group. Conclusion: Vildagliptin improved glycemic control without increasing hypoglycemia in Japanese type 2 diabetes inadequately controlled with basal insulin treatment and other oral anti-diabetes drugs. This study was registered with UMIN (University Hospital Medical Information Network ID#000010849). J Clin Med Res. 2017;9(3):193-199 doi: https://doi.org/10.14740/jocmr2874w
Published: 2016

15. PPAR-γ Activation Restores Pancreatic Islet SERCA2 Levels and Prevents β-Cell Dysfunction under Conditions of Hyperglycemic and Cytokine Stress

Author: Angel Zarain-Herzberg, Dan R. Moss, Takeshi Ogihara, Liann Gann, Carmella Evans-Molina, Tatsuyoshi Kono, Patrick T. Fueger, Yurika Nishiki, and Geonyoung Ahn
Subjects: Blood Glucose, Male, Peroxisome proliferator-activated receptor, Mice, Transactivation, Endocrinology, Insulin-Secreting Cells, Insulin Secretion, Insulin, Phosphorylation, Receptor, Original Research, chemistry.chemical_classification, Cell Cycle, General Medicine, Isoenzymes, Cytokines, Protein Binding, medicine.drug, medicine.medical_specialty, SERCA, Molecular Sequence Data, Down-Regulation, Biology, Response Elements, Diabetes Mellitus, Experimental, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Proinflammatory cytokine, Islets of Langerhans, Downregulation and upregulation, Stress, Physiological, Internal medicine, medicine, Animals, Humans, Hypoglycemic Agents, Molecular Biology, Binding Sites, Base Sequence, Pioglitazone, Cyclin-dependent kinase 5, Cyclin-Dependent Kinase 5, Rats, Mice, Inbred C57BL, PPAR gamma, chemistry, Calcium, Thiazolidinediones
Abstract: The maintenance of intracellular Ca2+ homeostasis in the pancreatic β-cell is closely regulated by activity of the sarco-endoplasmic reticulum Ca2+ ATPase (SERCA) pump. Our data demonstrate a loss of β-cell SERCA2b expression in several models of type 2 diabetes including islets from db/db mice and cadaveric diabetic human islets. Treatment of 832/13 rat INS-1-derived cells with 25 mm glucose and the proinflammatory cytokine IL-1β led to a similar loss of SERCA2b expression, which was prevented by treatment with the peroxisome proliferator-activated receptor (PPAR)-γ agonist, pioglitazone. Pioglitazone was able to also protect against hyperglycemia and cytokine-induced elevations in cytosolic Ca2+ levels, insulin-secretory defects, and cell death. To determine whether PPAR-γ was a direct transcriptional regulator of the SERCA2 gene, luciferase assays were performed and showed that a −259 bp region is sufficient to confer PPAR-γ transactivation; EMSA and chromatin immunoprecipitation experiments confirmed that PPAR-γ directly binds a PPAR response element in this proximal region. We next sought to characterize the mechanisms by which SERCA2b was down-regulated. INS-1 cells were exposed to high glucose and IL-1β in time course experiments. Within 2 h of exposure, activation of cyclin-dependent kinase 5 (CDK5) was observed and correlated with increased serine-273 phosphorylation of PPAR-γ and loss of SERCA2 protein expression, findings that were prevented by pioglitazone and roscovitine, a pharmacological inhibitor of CDK5. We conclude that pioglitazone modulates SERCA2b expression through direct transcriptional regulation of the gene and indirectly through prevention of CDK5-induced phosphorylation of PPAR-γ.
Published: 2012
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16. Inhibition of Deoxyhypusine Synthase Enhances Islet β Cell Function and Survival in the Setting of Endoplasmic Reticulum Stress and Type 2 Diabetes

Author: Bernhard Maier, Sarah A. Tersey, Raghavendra G. Mirmira, Takeshi Ogihara, Krister Bokvist, Reiesha D. Robbins, Thomas B. Farb, James Ficorilli, and Dhananjay Gupta
Subjects: Cell Survival, Peptide Chain Elongation, Translational, Apoptosis, Biology, CHOP, Endoplasmic Reticulum, Biochemistry, Mice, chemistry.chemical_compound, Peptide Initiation Factors, Insulin-Secreting Cells, Enhancer binding, Animals, Deoxyhypusine synthase, Enzyme Inhibitors, Molecular Biology, Transcription Factor CHOP, Hypusine, Oxidoreductases Acting on CH-NH Group Donors, Caspase 3, Endoplasmic reticulum, RNA-Binding Proteins, Molecular Bases of Disease, Cell Biology, Molecular biology, Mice, Mutant Strains, Diabetes Mellitus, Type 2, chemistry, Unfolded Protein Response, biology.protein, Unfolded protein response, Thapsigargin, Translational elongation
Abstract: Islet β cell dysfunction resulting from inflammation, ER stress, and oxidative stress is a key determinant in the progression from insulin resistance to type 2 diabetes mellitus. It was recently shown that the enzyme deoxyhypusine synthase (DHS) promotes early cytokine-induced inflammation in the β cell. DHS catalyzes the conversion of lysine to hypusine, an amino acid that is unique to the translational elongation factor eIF5A. Here, we sought to determine whether DHS activity contributes to β cell dysfunction in models of type 2 diabetes in mice and β cell lines. A 2-week treatment of obese diabetic C57BLKS/J-db/db mice with the DHS inhibitor GC7 resulted in improved glucose tolerance, increased insulin release, and enhanced β cell mass. Thapsigargin treatment of β cells in vitro induces a picture of ER stress and apoptosis similar to that seen in db/db mice; in this setting, DHS inhibition led to a block in CHOP (CAAT/enhancer binding protein homologous protein) production despite >30-fold activation of Chop gene transcription. Blockage of CHOP translation resulted in reduction of downstream caspase-3 cleavage and near-complete protection of cells from apoptotic death. DHS inhibition appeared to prevent the cytoplasmic co-localization of eIF5A with the ER, possibly precluding the participation of eIF5A in translational elongation at ER-based ribosomes. We conclude that hypusination by DHS is required for the ongoing production of proteins, particularly CHOP, in response to ER stress in the β cell.
Published: 2010
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17. Islet β-Cell-Specific MafA Transcription Requires the 5′-Flanking Conserved Region 3 Control Domain

Author: Chad S. Hunter, Eva Henderson, Roland Stein, Min Guo, Takeshi Ogihara, Isabella Artner, Lori Sussel, Raghavendra G. Mirmira, Beatriz Sosa-Pineda, Jeffrey C. Raum, and Lynda Elghazi
Subjects: Maf Transcription Factors, Large, PAX6 Transcription Factor, Transcription, Genetic, 5' Flanking Region, Molecular Sequence Data, 5' flanking region, Repressor, Mice, Transgenic, Nerve Tissue Proteins, Regulatory Sequences, Nucleic Acid, Biology, Mice, Transcription (biology), Insulin-Secreting Cells, Basic Helix-Loop-Helix Transcription Factors, Animals, Humans, Paired Box Transcription Factors, Eye Proteins, Molecular Biology, Cells, Cultured, Homeodomain Proteins, Base Sequence, Articles, Cell Biology, Transfection, Molecular biology, Repressor Proteins, Glucose, Regulatory sequence, Mutation, NEUROD1, PAX6, Chromatin immunoprecipitation, Protein Binding
Abstract: MafA is a key transcriptional activator of islet beta cells, and its exclusive expression within beta cells of the developing and adult pancreas is distinct among pancreatic regulators. Region 3 (base pairs -8118 to -7750 relative to the transcription start site), one of six conserved 5' cis domains of the MafA promoter, is capable of directing beta-cell-line-selective expression. Transgenic reporters of region 3 alone (R3), sequences spanning regions 1 to 6 (R1-6; base pairs -10428 to +230), and R1-6 lacking R3 (R1-6(DeltaR3)) were generated. Only the R1-6 transgene was active in MafA(+) insulin(+) cells during development and in adult cells. R1-6 also mediated glucose-induced MafA expression. Conversely, pancreatic expression was not observed with the R3 or R1-6(DeltaR3) line, although much of the nonpancreatic expression pattern was shared between the R1-6 and R1-6(DeltaR3) lines. Further support for the importance of R3 was also shown, as the islet regulators Nkx6.1 and Pax6, but not NeuroD1, activated MafA in gel shift, chromatin immunoprecipitation (ChIP), and transfection assays and in vivo mouse knockout models. Lastly, ChIP demonstrated that Pax6 and Pdx-1 also bound to R1 and R6, potentially functioning in pancreatic and nonpancreatic expression. These data highlight the nature of the cis- and trans-acting factors controlling the beta-cell-specific expression of MafA.
Published: 2010
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18. Liver X Receptor Agonists Augment Human Islet Function through Activation of Anaplerotic Pathways and Glycerolipid/Free Fatty Acid Cycling

Author: Xiaolun Huang, Michael O. Thorner, Takeshi Ogihara, Raghavendra G. Mirmira, James C. Garmey, Jen Chieh Chuang, Carmella Evans-Molina, R.J. Ketchum, Joyce J. Repa, George L. Vestermark, and Kenneth L. Brayman
Subjects: Adult, Male, Benzylamines, medicine.medical_specialty, Adolescent, Hydrocarbons, Fluorinated, medicine.medical_treatment, Pyruvate cycling, Fatty Acids, Nonesterified, Biology, Benzoates, Biochemistry, Glycerides, Islets of Langerhans, Internal medicine, Insulin Secretion, Pyruvic Acid, medicine, Humans, Insulin, Glucose homeostasis, Promoter Regions, Genetic, Liver X receptor, Molecular Biology, Liver X Receptors, Pyruvate Carboxylase, Cell Nucleus, Homeodomain Proteins, Sulfonamides, geography, geography.geographical_feature_category, Lipogenesis, Cell Biology, Middle Aged, Orphan Nuclear Receptors, Islet, Pyruvate carboxylase, Metabolism, Glucose, Endocrinology, Gene Expression Regulation, Sweetening Agents, Adipose triglyceride lipase, Trans-Activators, Female
Abstract: Recent studies in rodent models suggest that liver X receptors (LXRs) may play an important role in the maintenance of glucose homeostasis and islet function. To date, however, no studies have comprehensively examined the role of LXRs in human islet biology. Human islets were isolated from non-diabetic donors and incubated in the presence or absence of two synthetic LXR agonists, TO-901317 and GW3965, under conditions of low and high glucose. LXR agonist treatment enhanced both basal and stimulated insulin secretion, which corresponded to an increase in the expression of genes involved in anaplerosis and reverse cholesterol transport. Furthermore, enzyme activity of pyruvate carboxylase, a key regulator of pyruvate cycling and anaplerotic flux, was also increased. Whereas LXR agonist treatment up-regulated known downstream targets involved in lipogenesis, we observed no increase in the accumulation of intra-islet triglyceride at the dose of agonist used in our study. Moreover, LXR activation increased expression of the genes encoding hormone-sensitive lipase and adipose triglyceride lipase, two enzymes involved in lipolysis and glycerolipid/free fatty acid cycling. Chronically, insulin gene expression was increased after treatment with TO-901317, and this was accompanied by increased Pdx-1 nuclear protein levels and enhanced Pdx-1 binding to the insulin promoter. In conclusion, our data suggest that LXR agonists have a direct effect on the islet to augment insulin secretion and expression, actions that should be considered either as therapeutic or unintended side effects, as these agents are developed for clinical use.
Published: 2010
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19. Expression and function of Set7/9 in pancreatic islets

Author: Takeshi Ogihara, Bernhard Maier, Raghavendra G. Mirmira, Roland Stein, and Nathan L. Vanderford
Subjects: endocrine system, Transcription, Genetic, Endocrinology, Diabetes and Metabolism, RNA polymerase II, Biology, Article, Islets of Langerhans, Mice, Endocrinology, Transcription (biology), Histone methylation, Gene Knockdown Techniques, Animals, Transcription factor, Cells, Cultured, Homeodomain Proteins, Regulation of gene expression, Gene knockdown, Histone-Lysine N-Methyltransferase, Chromatin Assembly and Disassembly, Molecular biology, Gene Expression Regulation, Histone methyltransferase, NIH 3T3 Cells, Trans-Activators, biology.protein
Abstract: Histone tail acetylation and methylation are known to enhance accessibility of islet genes to transcription factors and the basal transcriptional machinery. In this brief report, we follow up on a recent study in which we identified the islet enriched factor Set7/9 as a potentially important histone methyltransferase in β-cells (Deering, et al. Diabetes 2009; 58:185-93). We had suggested that the methylation of H3-Lys4 by Set7/9 enhances accessibility of the insulin gene to the basal transcriptional machinery. Consistent with this hypothesis, we show here that RNA polymerase II occupancy at the insulin and IAPP genes is considerably enhanced in β-cells compared to α cells (or NIH3T3 cells), and that the converse is true for RNA polymerase II occupancy at the glucagon gene. The enrichment of Set7/9 in β-cells appears to be dependent upon Pdx1, as knockdown of Pdx1 in INS-1 β-cells using small hairpin RNAs almost completely abolishes Set7/9 expression. A LacZ expression vector driven by the -6.5 kilobase pair Set7/9 promoter that contains putative Pdx1 binding sites shows β-cell-line-specific expression. Taken together, our data support further the hypothesis that Pdx1-dependent Set7/9 expression may be crucial to enhancing chromatin accessibility and transcription of β-cell genes.
Published: 2009
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20. Methyltransferase Set7/9 Maintains Transcription and Euchromatin Structure at Islet-Enriched Genes

Author: Raghavendra G. Mirmira, Bernhard Maier, Takeshi Ogihara, Anthony P. Trace, and Tye G. Deering
Subjects: Chromatin Immunoprecipitation, endocrine system, Transcription, Genetic, Euchromatin, Endocrinology, Diabetes and Metabolism, Immunoblotting, 030209 endocrinology & metabolism, RNA polymerase II, Islets of Langerhans, Mice, 03 medical and health sciences, Histone H3, 0302 clinical medicine, Transcription (biology), Insulin-Secreting Cells, Commentaries, Internal Medicine, Animals, Protein Methyltransferases, RNA, Small Interfering, Promoter Regions, Genetic, Enhancer, 030304 developmental biology, Regulation of gene expression, 0303 health sciences, biology, Reverse Transcriptase Polymerase Chain Reaction, Promoter, Histone-Lysine N-Methyltransferase, Immunohistochemistry, Molecular biology, Mice, Inbred C57BL, Glucose, Gene Expression Regulation, DNA methylation, Histone Methyltransferases, NIH 3T3 Cells, biology.protein
Abstract: OBJECTIVE—The activation of β-cell genes, particularly of those encoding preproinsulin, requires an appropriate euchromatin (or “open”) DNA template characterized by hypermethylation of Lys4 of histone H3. We hypothesized that this modification is maintained in islet β-cells by the action of the histone methyltransferase Set7/9. RESEARCH DESIGN AND METHODS—To identify the role of Set7/9, we characterized its expression pattern and gene regulation and studied its function using RNA interference in both cell lines and primary mouse islets. RESULTS—Within the pancreas, Set7/9 protein shows striking specificity for islet cells, including α- and β-cells, as well as occasional cells within ducts. Consistent with these findings, the Set7/9 gene promoter contained an islet-specific enhancer located between −5,768 and −6,030 base pairs (relative to the transcriptional start site) that exhibited Pdx1-responsive activation in β-cells. To study Set7/9 function, we depleted insulinoma cells and primary mouse islets of Set7/9 protein using siRNA. Following siRNA treatment, we observed striking repression of genes involved in glucose-stimulated insulin secretion, including Ins1/2, Glut2, and MafA. These changes in transcription were accompanied by loss of dimethylated H3 Lys4 and RNA polymerase II recruitment, particularly at the Ins1/2 and Glut2 genes. Consistent with these data, depletion of Set7/9 in islets led to defects in glucose-stimulated Ca2+ mobilization and insulin secretion. CONCLUSIONS—We conclude that Set7/9 is required for normal β-cell function, likely through the maintenance of euchromatin structure at genes necessary for glucose-stimulated insulin secretion.
Published: 2009
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21. Impact of whole body irradiation and vascular endothelial growth factor-A on increased beta cell mass after bone marrow transplantation in a mouse model of diabetes induced by streptozotocin

Author: Takeshi Ogihara, Yoshio Fujitani, Toyoyoshi Uchida, K. Azuma, Masahiro Inoue, Hirotaka Watada, Shiho Nakayama, Hideki Mochizuki, Takahisa Hirose, Jong Bock Choi, Noseki Iwashita, and Ryuzo Kawamori
Subjects: Male, Vascular Endothelial Growth Factor A, endocrine system, medicine.medical_specialty, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Biology, Endothelial progenitor cell, Diabetes Mellitus, Experimental, Mice, Insulin-Secreting Cells, Internal medicine, Internal Medicine, medicine, Animals, Bone Marrow Transplantation, digestive, oral, and skin physiology, Endothelial Cells, nutritional and metabolic diseases, Glucose Tolerance Test, Streptozotocin, Mice, Inbred C57BL, Endothelial stem cell, Transplantation, Disease Models, Animal, Transplantation, Isogeneic, Vascular endothelial growth factor A, Endocrinology, medicine.anatomical_structure, Hyperglycemia, Bone marrow, Beta cell, Stem cell, Whole-Body Irradiation, medicine.drug
Abstract: Recent studies have shown that bone marrow transplantation reduces hyperglycaemia in a mouse model of diabetes induced by streptozotocin. However, the essential factors for the improvement of hyperglycaemia by bone marrow transplantation have not been fully elucidated. The aim of this study was to search for such factors.We investigated the effect of irradiation to whole body, to abdomen alone or to whole body excluding abdomen, followed by infusion or no infusion of bone marrow cells. We also investigated the effect of bone marrow transplantation on beta cell-specific vascular endothelial growth factor-A gene (Vegfa) knockout mice.Bone marrow transplantation improved streptozotocin-induced hyperglycaemia and partially restored islet mass. This change was associated with increased islet vascularisation. Among the other methods investigated, low-dose irradiation of the whole body without infusion of bone marrow cells also improved blood glucose level. In streptozotocin-treated beta cell-specific Vegfa knockout mice, which exhibit impaired islet vascularisation, bone marrow transplantation neither improved hyperglycaemia, relative beta cell mass nor islet vascularisation.Our results indicate that whole body irradiation is essential and sufficient for restoration of beta cell mass after streptozotocin treatment independent of infusion of bone marrow cells. Vascular endothelial growth factor-A produced in beta cells is also essential for this phenomenon.
Published: 2008
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22. Dose-dependent requirement of patched homologue 1 in mouse pancreatic beta cell mass

Author: Shiho Nakayama, Masayuki Arakawa, K. Azuma, Ryuzo Kawamori, Takahisa Hirose, Rei Kanno, Takeshi Ogihara, Hirotaka Watada, Fuki Ikeda, Toyoyoshi Uchida, and Yoshio Fujitani
Subjects: Patched Receptors, Patched, endocrine system, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Receptors, Cell Surface, Biology, Glucagon, Mice, Insulin-Secreting Cells, Internal medicine, Internal Medicine, medicine, Animals, Beta (finance), Pancreas, Pancreatic hormone, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Cell Differentiation, Immunohistochemistry, Molecular biology, Patched-1 Receptor, medicine.anatomical_structure, Endocrinology, PTCH1, PDX1, Beta cell
Abstract: Ectopic activation of hedgehog (HH) signalling in pancreas induces various abnormal morphogenetic events in the pancreas. This study analysed the dose-dependent requirement of patched homologue 1 (PTCH1), a negative regulator of HH signalling on pancreatic development. We used a recessive spontaneous mutant mouse denoted as mes which carries a mutated Ptch1 resulting in deletion of the most carboxy-terminal cytoplasmic domain of the PTCH1 protein. In this study, we analysed pancreatic morphology in Ptch1 +/+ , Ptch1 +/mes , Ptch1 +/−, Ptch1 mes/me s and Ptch1 −/mes mouse embryos, as well as the islet mass in adult Ptch1 +/+, Ptch1 +/mes and Ptch1 +/− mice. Until embryonic day (E) 12.5, no obvious abnormality of pancreas was observed in any of the Ptch1 mutants. The levels of PDX1 and glucagon were also not evidently different among the mice genotypes studied. Thereafter, morphological abnormalities appeared in the Ptch1 mutant mice. The beta, alpha and exocrine cell masses decreased at E18.5 in parallel with increased HH signalling, with beta cell mass showing the highest sensitivity to HH signalling with a significant decrease even in Ptch1 +/mes mice. Adult Ptch1 +/− mice also showed a significant decrease in beta cell mass compared with wild-type mice. Our findings indicate that the carboxy-terminal domain of Ptch1 is essential for pancreatic development. In addition, the loss of Ptch1 function decreases both the endocrine and exocrine cell mass in a dose-dependent manner, with beta cells particularly sensitive to changes in HH signalling.
Published: 2008
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23. Combined Expression of Transcription Factors Induces AR42J-B13 Cells to Differentiate into Insulin-Producing Cells

Author: Yoshio Fujitani, Hirotaka Watada, Toyoyoshi Uchida, Takeshi Ogihara, Takahisa Hirose, Rei Kanno, Ryuzo Kawamori, and Jong Bock Choi
Subjects: endocrine system, medicine.medical_specialty, PAX6 Transcription Factor, Transcription, Genetic, Endocrinology, Diabetes and Metabolism, Cellular differentiation, Nerve Tissue Proteins, Enteroendocrine cell, Biology, Transfection, digestive system, Adenoviridae, Cell Line, Endocrinology, Insulin-Secreting Cells, Internal medicine, Basic Helix-Loop-Helix Transcription Factors, medicine, Animals, Insulin, Paired Box Transcription Factors, Lectins, C-Type, Progenitor cell, Eye Proteins, Transcription factor, Homeodomain Proteins, Membrane Glycoproteins, Stem Cells, Cell Differentiation, Rats, Cell biology, Repressor Proteins, Homeobox Protein Nkx-2.2, Cell culture, PAX4, PAX6
Abstract: Neurogenin 3 (Ngn3) is a transcription factor that regulates an initial step of differentiation from uncommitted pancreatic progenitors into endocrine cells. Additional transcription factors are required for complete differentiation into mature pancreatic beta cells. In this study, we established an in vitro model system of beta-cell differentiation by adenovirus-mediated expression of several transcription factors in AR42J-B13 cells, a pancreatic progenitor-like cell line derived from exocrine pancreas. Exogenous expression of Ngn3 in AR42J-B13 cells induced expression of Nkx2.2, Pax4, and Pax6, which are all essential for beta-cell differentiation in mouse embryos. However, Ngn3 did not induce more downstream regulators of beta-cell differentiation, Nkx6.1 and Maf A. Coexpression of Nkx6.1 and Ngn3 induced endogenous expression of the insulin 2 gene, while coexpression of Maf A and Ngn3 induced both insulin 1 and 2 genes in AR42J-B13 cells. Our data demonstrated that Ngn3 expressed together with Nkx6.1 or MafA induces AR42J-B13 cells to differentiate into insulin-producing cells, supporting the use of these cells as a model system for studying beta-cell differentiation in vitro.
Published: 2008
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24. Expression mechanism of tryptophan hydroxylase 1 in mouse islets during pregnancy

Author: Hitoshi Iida, Kyoko Fujimaki, Mun-kyeong Min, Akemi Hara, Yoshio Fujitani, Hirotaka Watada, Hail Kim, Takeshi Ogihara, Yeong Gi Kim, and Motoyuki Tamaki
Subjects: endocrine system, medicine.medical_specialty, Serotonin, Transcription, Genetic, MAP Kinase Signaling System, Tryptophan Hydroxylase, Transactivation, Mice, Phosphatidylinositol 3-Kinases, Endocrinology, Pregnancy, Internal medicine, Cell Line, Tumor, Insulin-Secreting Cells, medicine, STAT5 Transcription Factor, Animals, RNA, Messenger, Promoter Regions, Genetic, Molecular Biology, STAT5, Reporter gene, Messenger RNA, TPH1, Tyrosine hydroxylase, biology, Exons, Janus Kinase 2, Molecular biology, Prolactin, biology.protein, Trans-Activators, Female, Transcription Initiation Site, Chromatin immunoprecipitation, hormones, hormone substitutes, and hormone antagonists, Signal Transduction
Abstract: Serotonin signaling plays key roles in augmentation of pancreatic β-cell function during pregnancy. Increased expression of tryptophan hydroxylase 1 (Tph1), a rate-limiting enzyme for serotonin synthesis by lactogenic hormones, is involved in this phenomenon. To investigate its mechanisms, we here performed 5′-RACE and identified β-cell-specific transcription initiation sites for Tph1. Prolactin enhanced the expression of mRNA containing these exons; however, reporter gene plasmids containing the proximal 5′-flanking region of these exons did not show prolactin responsiveness in MIN6 cells. Prolactin-induced Tph1 expression was inhibited by a Jak2 inhibitor and was partially inhibited by an MEK1/2 or PI3K inhibitor. Therefore, we analyzed interferon γ-activated sequences (GAS) and found GAS-A about 9-kbp upstream of the transcription start site. The reporter gene plasmid containing the GAS-A region linked to a heterologous promoter showed increased promoter activity by prolactin, which was inhibited by the forced expression of a dominant-negative mutant form of Stat5A and a Jak2 inhibitor. Chromatin immunoprecipitation analysis showed that prolactin treatment augmented Stat5 binding to the GAS-A region in MIN6 cells, as well as in isolated mouse islets, and that Stat5 recognized the GAS-A region in pregnant mouse islets. In addition, the transactivation activity of Stat5 was enhanced by prolactin through the Erk and PI3K pathways in MIN6 cells. Finally, serotonin expression was attenuated in islets of β-cell-specific Stat5-deficient mice compared with that of control littermates during pregnancy. Our findings suggest that prolactin-induced Tph1 expression is mediated by the activation of Jak2/Stat5, Erk, and PI3K pathways in β cells.
Published: 2015

25. SET7/9 Enzyme Regulates Cytokine-induced Expression of Inducible Nitric-oxide Synthase through Methylation of Lysine 4 at Histone 3 in the Islet β Cell*

Author: Hitoshi Iida, Hirotaka Watada, Carmella Evans-Molina, David L. Morris, Hisanobu Oda, Takeshi Ogihara, Yoshio Fujitani, Kyoko Fujimaki, and Raghavendra G. Mirmira
Subjects: medicine.medical_treatment, Interleukin-1beta, Nitric Oxide Synthase Type II, Apoptosis, Biochemistry, Methylation, Proinflammatory cytokine, Histones, Transactivation, Interferon-gamma, Islets of Langerhans, Mice, Transcription (biology), Insulin-Secreting Cells, Histone methylation, medicine, Animals, Protein Methyltransferases, Molecular Biology, Mice, Knockout, Gene knockdown, biology, Tumor Necrosis Factor-alpha, Lysine, Cell Biology, Histone-Lysine N-Methyltransferase, Molecular biology, Histone, Cytokine, Metabolism, biology.protein, Interleukin-1
Abstract: SET7/9 is an enzyme that methylates histone 3 at lysine 4 (H3K4) to maintain euchromatin architecture. Although SET7/9 is enriched in islets and contributes to the transactivation of β cell-specific genes, including Ins1 and Slc2a, SET7/9 has also been reported to bind the p65 subunit of nuclear factor κB in non-β cells and modify its transcriptional activity. Given that inflammation is a central component of β cell dysfunction in Type 1 and Type 2 diabetes, the aim of this study was to elucidate the role of SET7/9 in proinflammatory cytokine signaling in β cells. To induce inflammation, βTC3 insulinoma cells were treated with IL-1β, TNF-α, and IFN-γ. Cytokine treatment led to increased expression of inducible nitric-oxide synthase, which was attenuated by the diminution of SET7/9 using RNA interference. Consistent with previous reports, SET7/9 was co-immunoprecipitated with p65 and underwent cytosolic to nuclear translocation in response to cytokines. ChIP analysis demonstrated augmented H3K4 mono- and dimethylation of the proximal Nos2 promoter with cytokine exposure. SET7/9 was found to occupy this same region, whereas SET7/9 knockdown attenuated cytokine-induced histone methylation of the Nos2 gene. To test this relationship further, islets were isolated from SET7/9-deficient and wild-type mice and treated with IL-1β, TNF-α, and IFN-γ. Cytokine-induced Nos2 expression was reduced in the islets from SET7/9 knock-out mice. Together, our findings suggest that SET7/9 contributes to Nos2 transcription and proinflammatory cytokine signaling in the pancreatic β cell through activating histone modifications.
Published: 2015

26. Impaired insulin secretion in vivo but enhanced insulin secretion from isolated islets in pancreatic beta cell-specific vascular endothelial growth factor-A knock-out mice

Author: Toyoyoshi Uchida, Jong Bock Choi, Hirotaka Watada, Masahiro Inoue, Takeshi Ogihara, Hans-Peter Gerber, K. Azuma, Napoleone Ferrara, Noseki Iwashita, and Ryuzo Kawamori
Subjects: Blood Glucose, Male, Vascular Endothelial Growth Factor A, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Mice, Transgenic, Biology, Islets of Langerhans, Mice, Insulin-Secreting Cells, Internal medicine, Insulin Secretion, Internal Medicine, medicine, Animals, Insulin, Secretion, Crosses, Genetic, Pancreatic hormone, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Insulin oscillation, Mice, Inbred C57BL, Endothelial stem cell, Vascular endothelial growth factor A, Endocrinology, Knockout mouse, RNA, Female, Endothelium, Vascular, Beta cell
Abstract: Endothelial cells are considered to be essential for normal pancreatic beta cell function. However, there have been no reports showing their importance for beta cell function.Using mice with disrupted vascular endothelial growth factor-A gene specifically in beta cells, we investigated the relation between islet vascular structure and beta cell function.Mice with disrupted vascular endothelial growth factor-A gene specifically in beta cells had reduced islet vascular density with impaired formation of endothelial fenestration. While their fasting glucose and body weight were comparable with control mice, their glucose- and tolbutamide-induced rapid insulin release were impaired, thus resulting in glucose intolerance. On the other hand, glucose and KCl enhanced the levels of insulin secreted from islets isolated from these mice. In addition, the production of soluble N-ethylmaleimide-sensitive factor attachment protein receptors in the islets was increased. Insulin content and expression of insulin I and pancreas duodenum homeobox 1 mRNA in the islets were also increased.Our results indicate that an abnormal quality and quantity of blood vessels due to reduced expression of vascular endothelial growth factor-A in beta cells could be a cause of impaired insulin secretion without impairment of beta cell function.
Published: 2006
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27. The polymorphism of manganese superoxide dismutase is associated with diabetic nephropathy in Japanese type 2 diabetic patients

Author: Takashi Nomiyama, Lianshan Piao, Kunihiro Nakajima, Takeshi Ogihara, Yasushi Tanaka, Keiko Nagasaka, Ken Sakai, Ryuzo Kawamori, and Hirotaka Watada
Subjects: Male, medicine.medical_specialty, Genotype, Type 2 diabetes, Nephropathy, Diabetic nephropathy, Gene Frequency, Risk Factors, Internal medicine, Diabetes mellitus, Genetics, medicine, Humans, Diabetic Nephropathies, Allele frequency, Genetics (clinical), Polymorphism, Genetic, Superoxide Dismutase, business.industry, Odds ratio, Middle Aged, medicine.disease, Endocrinology, Diabetes Mellitus, Type 2, Regression Analysis, Female, Microalbuminuria, business
Abstract: We evaluated the relationship of an alanine or valine polymorphism at amino acid sequence 16 [Val(16)Ala] of manganese superoxide dismutase (Mn-SOD) with diabetes and diabetic nephropathy in Japanese type 2 diabetic patients. Val(16)Ala genotyping of Mn-SOD was done by polymerase chain reaction-restriction fragment length polymorphism with a restriction enzyme ( Bsaw I) in 478 Japanese type 2 diabetic patients and 261 nondiabetic Japanese healthy subjects. The genotype distribution of diabetic and nondiabetic subjects was then compared, and the association of genotype with diabetic nephropathy was evaluated in the diabetic patients. The allele frequency and genotype of the diabetic patients were not different from those of the healthy nondiabetic subjects. The VV type showed a significantly higher frequency in the diabetic patients with nephropathy than did the AA or VA type [VV type: normoalbuminuria 70.8%, microalbuminuria 84.8% (P = 0.0057), macroalbuminuria 84.1% (P = 0.0128)]. Furthermore, logistic regression analysis showed that this polymorphism is associated with diabetic nephropathy independently (odds ratio = 0.461925, P = 0.03). Accordingly, the Val(16)Ala polymorphism of Mn-SOD may be unrelated to the etiology of type 2 diabetes, but it seems to be associated with diabetic nephropathy in Japanese type 2 diabetic patients.
Published: 2003
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28. Combined genotypes of ACE and NADPH oxidase p22phox associated with somatic mutation of mtDNA and carotid intima-media thickness in Japanese patients with type 2 diabetes mellitus

Author: Takeshi Ogihara, Hirotaka Watada, Takashi Nomiyama, Shinnya Miwa, Ryuzo Kawamori, Yasushi Tanaka, Kunihiro Nakajima, Lianshan Piao, and Takao Urabe
Subjects: Pharmacology, Genetics, medicine.medical_specialty, biology, business.industry, Type 2 Diabetes Mellitus, Angiotensin-converting enzyme, Endocrinology, Germline mutation, Intima-media thickness, Polymorphism (computer science), Internal medicine, Genotype, medicine, biology.protein, Pharmacology (medical), P22phox, business, Pharmacogenetics
Abstract: Background: We previously reported that the carotid artery intima-media thickness (IMT) increased with age and that patients with type 2 diabetes mellitus (DM) had a significantly larger IMT than did age-matched nondiabetic subjects with normal glucose tolerance. Although the exact mechanism behind the increase in IMT in diabetic patients has not been determined, data obtained from in vivo and in vitro studies suggest that hyperglycemia-induced oxidative stress may lead to atherogenesis. Objective: The aim of this single-center study was to determine whether long-term oxidative stress and the carotid IMT are influenced by differences of the angiotensin-converting enzyme insertion/deletion ( ACE I/D ) and NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) oxidase p22phox C242T genotypes. Methods: Eligible subjects were Japanese patients with type 2 DM. Polymorphism of the ACE I/D and p22phox gene was investigated using polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism, respectively. The rate of an acquired mutation of mitochondrial DNA—that is, A-to-G substitution at position 3243 (mtDNA A3243G )—was determined by real-time PCR. As a marker of early atherosclerosis, the carotid artery IMT was measured using high-resolution B-mode ultrasonography. Results: A total of 262 Japanese patients (173 men, 89 women; mean [SEM] age, 58 [0.6] years [range, 18–80 years]) were recruited and enrolled for study. An ACE D - positive ( DD or DI ) and p22phox 242T -negative genotype ( CC ) was associated with a significantly higher mtDNA A3243G mutation rate than the other 3 possible genotypes (0.0219% [0.0028%] vs 0.0097% [0.0012%]; P P Conclusion: In this study, the ACE D - positive and p22phox 242T -negative genotype showed higher rates of somatic mtDNA mutation (mtDNA A3243G ) and higher carotid mean and maximum IMT levels.
Published: 2002
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29. One year follow-up after a randomized controlled trial of a 130 g/day low-carbohydrate diet in patients with type 2 diabetes mellitus and poor glycemic control

Author: Takeshi Ogihara, Chie Hatae, Takeshi Miyatsuka, Tomoaki Shimizu, Kiyoe Kobayashi, Yoshiko Miura, Hirotaka Watada, Tomoya Mita, Manami Iwaoka, Yoshifumi Tamura, Hiromasa Goto, Sumiko Makita, Koji Komiya, Akio Kanazawa, Takehito Watanabe, Nao Hirashima, Fuki Ikeda, Junko Sato, Toyoyoshi Uchida, and Chie Ohmura
Subjects: Blood Glucose, Male, lcsh:Medicine, Type 2 diabetes, Biochemistry, law.invention, Endocrinology, 0302 clinical medicine, Randomized controlled trial, law, Diabetes diagnosis and management, Insulin, Medicine, 030212 general & internal medicine, Medical nutrition therapy, lcsh:Science, Multidisciplinary, Organic Compounds, Poor glycemic control, Middle Aged, Type 2 Diabetes, Chemistry, Physical Sciences, Female, Research Article, medicine.medical_specialty, HbA1c, Drug Research and Development, Endocrine Disorders, Diet therapy, Carbohydrates, 030209 endocrinology & metabolism, Research and Analysis Methods, 03 medical and health sciences, Internal medicine, Diabetes mellitus, Dietary Carbohydrates, Diabetes Mellitus, Humans, Clinical Trials, In patient, Hemoglobin, Aged, Nutrition, Medicine and health sciences, Pharmacology, Diabetic Endocrinology, Biology and life sciences, business.industry, Organic Chemistry, lcsh:R, Chemical Compounds, Proteins, nutritional and metabolic diseases, Type 2 Diabetes Mellitus, medicine.disease, Diagnostic medicine, Randomized Controlled Trials, Hormones, Diabetes Mellitus, Type 2, Diet and Type 2 Diabetes, Metabolic Disorders, lcsh:Q, Clinical Medicine, business, Follow-Up Studies
Abstract: Background & aims Recently, we conducted a prospective randomized controlled trial (RCT) showing that a 6-month 130g/day low-carbohydrate diet (LCD) reduced HbA1c and BMI more than a calorie restricted diet (CRD). [1] To assess whether the benefits of the LCD persisted after the intensive intervention, we compared HbA1c and BMI between the LCD and CRD groups at 1 year after the end of the 6-month RCT. Methods Following the end of the 6-month RCT, patients were allowed to manage their own diets with periodic outpatient visits. One year later, we analyzed clinical and nutrition data. Results Of the 66 participants in the original study, 27 in the CRD group and 22 in the LCD group completed this trial. One year after the end of the original RCT, the carbohydrate intake was comparable between the groups (215 [189–243]/day in the CRD group and 214 (176–262) g/day in the LCD group). Compared with the baseline data, HbA1c and BMI were decreased in both groups (CRD: HbA1c -0.4 [-0.9 to 0.3] % and BMI -0.63 [-1.20 to 0.18] kg/m2; LCD: HbA1c -0.35 [-1.0 to 0.35] % and BMI -0.77 [-1.15 to -0.12] kg/m2). There were no significant differences in HbA1c and BMI between the groups. Conclusions One year after the diet therapy intervention, the beneficial effect of the LCD on reduction of HbA1c and BMI did not persist in comparison with CRD. However, combining the data of both groups, significant improvements in HbA1c and BMI from baseline were observed. Although the superiority of the LCD disappeared 1 year after the intensive intervention, these data suggest that well-constructed nutrition therapy programs, both CRD and LCD, were equally effective in improving HbA1c for at least 1 year. Trial registration University Hospital Medical Information Network (UMIN) ID000010663
Published: 2017
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30. Chemokine Receptor Genotype Is Associated With Diabetic Nephropathy in Japanese With Type 2 Diabetes

Author: Takashi Nomiyama, Lianshan Piao, Ryuzo Kawamori, Tomio Onuma, Kunihiro Nakajima, Yasushi Tanaka, Takeshi Ogihara, and Ken Sakai
Subjects: Male, medicine.medical_specialty, CCR2, Genotype, Receptors, CCR5, Receptors, CCR2, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, Peptidyl-Dipeptidase A, Nephropathy, Diabetic nephropathy, chemistry.chemical_compound, Asian People, Japan, Internal medicine, Internal Medicine, Albuminuria, Humans, Medicine, Diabetic Nephropathies, Sequence Deletion, Glycated Hemoglobin, Creatinine, business.industry, Cholesterol, HDL, Smoking, Odds ratio, Middle Aged, medicine.disease, Cholesterol, Endocrinology, Diabetes Mellitus, Type 2, chemistry, DNA Transposable Elements, Female, Receptors, Chemokine, Microalbuminuria, business
Abstract: Glomerular infiltration of monocytes/macrophages occurs in diabetic patients with nephropathy, and chemokine receptor signals are thought to play a key role in the development of nephropathy. Recently, polymorphism of the chemokine receptor (CCR)2 coding region V64I and the CCR5 promoter region 59029 (G/A) have been identified. Accordingly, we evaluated the effects of these genotypes on diabetic nephropathy. CCR2 V64I and CCR5 59029 (G/A) were detected by polymerase chain reaction–restriction fragment–length polymorphism in 401 patients with type 2 diabetes who had a serum creatinine
Published: 2002
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31. Relationships between lifestyle patterns and cardio-renal-metabolic parameters in patients with type 2 diabetes mellitus: A cross-sectional study

Author: Yuki Someya, Shiho Nakayama, Hirotaka Watada, Tomoya Mita, Masahiko Gosho, Akio Kanazawa, Takeshi Osonoi, Atsuko Tamasawa, Hidenori Ishida, Takeshi Ogihara, Yusuke Osonoi, and Miyoko Saito
Subjects: Male, Physiology, Cross-sectional study, lcsh:Medicine, Aminotransferases, Type 2 diabetes, Logistic regression, Biochemistry, Mathematical and Statistical Techniques, Endocrinology, 0302 clinical medicine, Japan, Risk Factors, Surveys and Questionnaires, Medicine and Health Sciences, Public and Occupational Health, 030212 general & internal medicine, lcsh:Science, Pulse wave velocity, Alcohol Consumption, Multidisciplinary, Middle Aged, Type 2 Diabetes, Enzymes, Chemistry, Cardiovascular Diseases, Physical Sciences, Regression Analysis, Female, Kidney Diseases, medicine.symptom, Statistics (Mathematics), Research Article, Adult, Endocrine Disorders, 030209 endocrinology & metabolism, Linear Regression Analysis, Research and Analysis Methods, 03 medical and health sciences, Transferases, Diabetes mellitus, Diabetes Mellitus, medicine, Humans, Statistical Methods, Life Style, Nutrition, Aged, business.industry, lcsh:R, Chemical Compounds, Biology and Life Sciences, Proteins, Type 2 Diabetes Mellitus, Physical Activity, medicine.disease, Diet, Uric Acid, Cross-Sectional Studies, Blood pressure, Diabetes Mellitus, Type 2, Metabolic Disorders, Enzymology, Albuminuria, lcsh:Q, Physiological Processes, Sleep, business, Acids, Mathematics, Biomarkers
Abstract: Introduction While individuals tend to show accumulation of certain lifestyle patterns, the effect of such patterns in real daily life on cardio-renal—metabolic parameters remains largely unknown. This study aimed to assess clustering of lifestyle patterns and investigate the relationships between such patterns and cardio-renal-metabolic parameters. Participants and methods The study participants were 726 Japanese type 2 diabetes mellitus (T2DM) outpatients free of history of cardiovascular diseases. The relationship between lifestyle patterns and cardio-renal-metabolic parameters was investigated by linear and logistic regression analyses. Results Factor analysis identified three lifestyle patterns. Subjects characterized by evening type, poor sleep quality and depressive status (type 1 pattern) had high levels of HbA1c, alanine aminotransferase and albuminuria. Subjects characterized by high consumption of food, alcohol and cigarettes (type 2 pattern) had high levels of γ-glutamyl transpeptidase, triglycerides, HDL-cholesterol, blood pressure, and brachial-ankle pulse wave velocity. Subjects characterized by high physical activity (type 3 pattern) had low uric acid and mild elevation of alanine aminotransferase and aspartate aminotransferase. In multivariate regression analysis adjusted by age, gender and BMI, type 1 pattern was associated with higher HbA1c levels, systolic BP and brachial-ankle pulse wave velocity. Type 2 pattern was associated with higher HDL-cholesterol levels, triglycerides, aspartate aminotransferase, ɤ- glutamyl transpeptidase levels, and diastolic BP. Conclusions The study identified three lifestyle patterns that were associated with distinct cardio-metabolic-renal parameters in T2DM patients. Trial registration UMIN000010932
Published: 2017
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32. Human IAPP–induced pancreatic β cell toxicity and its regulation by autophagy

Author: Henry J. Hiddinga, Hirotaka Watada, Yasuo Uchiyama, Toyoyoshi Uchida, Takeshi Miyatsuka, Yoshio Fujitani, Tamotsu Yoshimori, Koji Komiya, Motoyuki Tamaki, Akemi Hara, Ayako Fukunaka, Hiroko Abe, Norman L. Eberhardt, Nayumi Shigihara, Takeshi Ogihara, Yukiko Toyofuku, Masato Koike, Setsuya Sakagashira, and Akira Honda
Subjects: Programmed cell death, Amyloid, Cell growth, Pancreatic islets, Autophagy, Cell, General Medicine, Cell cycle, Biology, Cell biology, medicine.anatomical_structure, medicine, Autophagy-Related Protein 7, Research Article
Abstract: Pancreatic islets in patients with type 2 diabetes mellitus (T2DM) are characterized by loss of β cells and formation of amyloid deposits derived from islet amyloid polypeptide (IAPP). Here we demonstrated that treatment of INS-1 cells with human IAPP (hIAPP) enhances cell death, inhibits cytoproliferation, and increases autophagosome formation. Furthermore, inhibition of autophagy increased the vulnerability of β cells to the cytotoxic effects of hIAPP. Based on these in vitro findings, we examined the pathogenic role of hIAPP and its relation to autophagy in hIAPP-knockin mice. In animals fed a standard diet, hIAPP had no toxic effects on β cell function; however, hIAPP-knockin mice did not exhibit a high-fat-diet-induced compensatory increase in β cell mass, which was due to limited β cell proliferation and enhanced β cell apoptosis. Importantly, expression of hIAPP in mice with a β cell-specific autophagy defect resulted in substantial deterioration of glucose tolerance and dispersed cytoplasmic expression of p62-associated toxic oligomers, which were otherwise sequestrated within p62-positive inclusions. Together, our results indicate that increased insulin resistance in combination with reduced autophagy may enhance the toxic potential of hIAPP and enhance β cell dysfunction and progression of T2DM.
Published: 2014

33. The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance

Author: Takahiro Watanabe, Motoyuki Tamaki, Shintaro Hojyo, Kageumi Takeno, Toshiyuki Fukada, Minako Kawaguchi, Ayako Fukunaka, Akemi Hara, Ryuzo Kawamori, Mica Ohara Imaizumi, Yoshio Fujitani, Yoshifumi Tamura, Takaya Abe, Takeshi Kawauchi, Tomoaki Shimizu, Akio Kanazawa, Takeshi Ogihara, Tomoya Mita, Shinya Nagamatsu, Hirotaka Watada, Hiroshi Kiyonari, Toyoyoshi Uchida, and Toshio Hirano
Subjects: Male, medicine.medical_specialty, medicine.medical_treatment, Type 2 diabetes, Zinc Transporter 8, Biology, Internal medicine, Diabetes mellitus, medicine, Animals, Humans, Insulin, Cation Transport Proteins, SLC30A8, General Medicine, medicine.disease, Solute carrier family, Insulin oscillation, Insulin receptor, Endocrinology, Diabetes Mellitus, Type 2, Liver, biology.protein, Research Article
Abstract: 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.
Published: 2013

34. Compression method using LZW coding and a sliding window

Author: Koji Torii, H. Iida, Takeshi Ogihara, and Katsuro Inoue
Subjects: Lossless compression, Phrase, LZ77 and LZ78, Computer science, business.industry, Pattern recognition, Data_CODINGANDINFORMATIONTHEORY, Compression method, Execution time, Sliding window protocol, Artificial intelligence, Electrical and Electronic Engineering, business, Coding (social sciences), Data compression
Abstract: This paper proposes a new compression method which uses a sliding window with an Lempel-Ziv-Welch (LZW) dictionary. When an LZW phrase is constructed, the location of the phrase on the window is also recorded in the dictionary. Using this information, there are cases where we can find that a new LZW phrase is already included in the sliding window. If the current input matches the string on the window longer than the LZW phrase constructed, the length of the string is encoded instead of the phrase itself. For most kinds of inputs, the compression performance of this method is better than the original LZW method and is equal or superior to various improved LZW methods. In addition, compared with that of the LZW method, the execution time of this method increases only about 25 percent.
Published: 1994
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35. MANAGEMENT OF COMPUTER SYSTEMS FOR EDUCATION AND MOTIVATION SURVEY OF STUDENTS

Author: Akinori Saitoh, Seigo Yasutome, Takeshi Ogihara, Ken-ichi Baba, Mitsuo Yoshida, Akira Harada, Toshio Matuura, and Takenao Ohkawa
Subjects: Coping (psychology), Workstation, Computer science, law, Computer literacy, ComputingMilieux_COMPUTERSANDEDUCATION, Information processing, Mathematics education, Computer education, Safeguarding, Curriculum, law.invention, Primary research
Abstract: Personal computers or workstations are used widely in Japan. Many students need to be educated now to use computers. The importance of computer literacy is emphasized these days. To obtain computer literacy, students must not only depend on school lessons but make an effort to practice using a computer outside the curriculum. It is necessary to furnish the students with many computers so they can use them freely. In this paper, we discussed four points of computer education:(1)coping with the questions and or troubles of the users, (2)safeguarding the system, (3)improving the educational technique of teachers, and(4)motivating the students. This paper contains our primary research of these four points from our studies in site at Educational Center for Information Processing, Osaka University.
Published: 1994
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36. An islet in distress: β cell failure in type 2 diabetes

Author: Raghavendra G. Mirmira and Takeshi Ogihara
Subjects: Islet, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, 030209 endocrinology & metabolism, Inflammation, Review Article, Type 2 diabetes, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Glucose homeostasis, 030304 developmental biology, 0303 health sciences, geography, geography.geographical_feature_category, business.industry, Insulin, Diabetes, General Medicine, medicine.disease, 3. Good health, Endocrinology, Lipotoxicity, medicine.symptom, business
Abstract: Over 200 million people worldwide suffer from diabetes, a disorder of glucose homeostasis. The majority of these individuals are diagnosed with type 2 diabetes. It has traditionally been thought that tissue resistance to the action of insulin is the primary defect in type 2 diabetes. However, recent longitudinal and genome‐wide association studies have shown that insulin resistance is more likely to be a precondition, and that the failure of the pancreatic β cell to meet the increased insulin requirements is the triggering factor in the development of type 2 diabetes. A major emphasis in diabetes research has therefore shifted to understanding the causes of β cell failure. Collectively, these studies have implicated a complex network of triggers, which activate intersecting execution pathways leading to β cell dysfunction and death. In the present review, we discuss these triggers (glucotoxicity, lipotoxicity, amyloid and cytokines) with respect to the pathways they activate (oxidative stress, inflammation and endoplasmic reticulum stress) and propose a model for understanding β cell failure in type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00021.x, 2010)
Published: 2010
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37. The unique hypusine modification of eIF5A promotes islet beta cell inflammation and dysfunction in mice

Author: John E. Thompson, Anthony P. Trace, Craig S. Nunemaker, Bernhard Maier, Jerry L. Nadler, Natalie D. Stull, Eli C. Lewis, Raghavendra G. Mirmira, Swarup K. Chakrabarti, Takeshi Ogihara, Charles A. Dinarello, Sarah A. Tersey, Richard Dondero, Catherine A. Taylor, and Reiesha D. Robbins
Subjects: Mice, SCID, Proinflammatory cytokine, chemistry.chemical_compound, Islets of Langerhans, Mice, Mice, Inbred NOD, Peptide Initiation Factors, medicine, Deoxyhypusine synthase, Animals, Hypusine, geography, Gene knockdown, geography.geographical_feature_category, biology, Lysine, RNA-Binding Proteins, General Medicine, Streptozotocin, Islet, Cell biology, Mice, Inbred C57BL, chemistry, Immunology, biology.protein, Commentary, Beta cell, EIF5A, medicine.drug
Abstract: In both type 1 and type 2 diabetes, pancreatic islet dysfunction results in part from cytokine-mediated inflammation. The ubiquitous eukaryotic translation initiation factor 5A (eIF5A), which is the only protein to contain the amino acid hypusine, contributes to the production of proinflammatory cytokines. We therefore investigated whether eIF5A participates in the inflammatory cascade leading to islet dysfunction during the development of diabetes. As described herein, we found that eIF5A regulates iNOS levels and that eIF5A depletion as well as the inhibition of hypusination protects against glucose intolerance in inflammatory mouse models of diabetes. We observed that following knockdown of eIF5A expression, mice were resistant to beta cell loss and the development of hyperglycemia in the low-dose streptozotocin model of diabetes. The depletion of eIF5A led to impaired translation of iNOS-encoding mRNA within the islet. A role for the hypusine residue of eIF5A in islet inflammatory responses was suggested by the observation that inhibition of hypusine synthesis reduced translation of iNOS-encoding mRNA in rodent beta cells and human islets and protected mice against the development of glucose intolerance the low-dose streptozotocin model of diabetes. Further analysis revealed that hypusine is required in part for nuclear export of iNOS-encoding mRNA, a process that involved the export protein exportin1. These observations identify the hypusine modification of eIF5A as a potential therapeutic target for preserving islet function under inflammatory conditions.
Published: 2009

38. Impact of oxidative stress and peroxisome proliferator-activated receptor gamma coactivator-1alpha in hepatic insulin resistance

Author: Yoshio Fujitani, Hideki Mochizuki, Takeshi Ogihara, Toyoyoshi Uchida, Yoshifumi Tamura, Takahisa Hirose, Naoki Kumashiro, Hirotaka Watada, and Ryuzo Kawamori
Subjects: medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Blotting, Western, Genetic Vectors, Peroxisome proliferator-activated receptor, Biology, CREB, Adenoviridae, Mice, Insulin resistance, Superoxide Dismutase-1, Internal medicine, Cell Line, Tumor, Glucose Intolerance, Internal Medicine, medicine, Animals, Humans, Immunoprecipitation, Insulin, Phosphorylation, chemistry.chemical_classification, Reactive oxygen species, Kinase, Forkhead Box Protein O1, Reverse Transcriptase Polymerase Chain Reaction, Superoxide Dismutase, Forkhead Transcription Factors, medicine.disease, Oxidative Stress, Endocrinology, medicine.anatomical_structure, chemistry, Liver, Hepatocyte, biology.protein, Female, Insulin Resistance, Reactive Oxygen Species, Transcription Factors, Signal Transduction
Abstract: OBJECTIVE—Recent studies identified accumulation of reactive oxygen species (ROS) as a common pathway causing insulin resistance. However, whether and how the reduction of ROS levels improves insulin resistance remains to be elucidated. The present study was designed to define this mechanism. RESEARCH DESIGN AND METHODS—We investigated the effect of overexpression of superoxide dismutase (SOD)1 in liver of obese diabetic model (db/db) mice by adenoviral injection. RESULTS— db/db mice had high ROS levels in liver. Overexpression of SOD1 in liver of db/db mice reduced hepatic ROS and blood glucose level. These changes were accompanied by improvement in insulin resistance and reduction of hepatic gene expression of phosphoenol-pyruvate carboxykinase and peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α), which is the main regulator of gluconeogenic genes. The inhibition of hepatic insulin resistance was accompanied by attenuation of phosphorylation of cAMP-responsive element-binding protein (CREB), which is a main regulator of PGC-1α expression, and attenuation of Jun NH2-terminal kinase (JNK) phosphorylation. Simultaneously, overexpression of SOD1 in db/db mice enhanced the inactivation of forkhead box class O1, another regulator of PGC-1α expression, without the changes of insulin-induced Akt phosphorylation in liver. In hepatocyte cell lines, ROS induced phosphorylation of JNK and CREB, and the latter, together with PGC-1α expression, was inhibited by a JNK inhibitor. CONCLUSIONS—Our results indicate that the reduction of ROS is a potential therapeutic target of liver insulin resistance, at least partly by the reduced expression of PGC-1α.
Published: 2008

39. Preferable effect of pravastatin compared to atorvastatin on beta cell function in Japanese early-state type 2 diabetes with hypercholesterolemia

Author: Hirotaka Watada, Shiho Nakayama, Michiko Abe, Tomoaki Shimizu, Takahisa Hirose, Tomoya Mita, Ryuzo Kawamori, Takeshi Ogihara, and Hiroshi Uchino
Subjects: medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Atorvastatin, Hypercholesterolemia, Beta-cell Function, Type 2 diabetes, Pharmacology, Gastroenterology, Endocrinology, Japan, Internal medicine, Insulin-Secreting Cells, Hyperlipidemia, Glucose Intolerance, Medicine, Humans, Pyrroles, Pravastatin, Cross-Over Studies, business.industry, nutritional and metabolic diseases, Type 2 Diabetes Mellitus, Insulin sensitivity, Glucose Tolerance Test, medicine.disease, Clinical trial, Diabetes Mellitus, Type 2, Heptanoic Acids, Patient Compliance, lipids (amino acids, peptides, and proteins), business, medicine.drug
Abstract: While a large numbers of clinical trials using various kinds of statins has been reported, a possible preventive effect on new onset of type 2 diabetes mellitus was shown only by the subanalysis of The West of Scotland Coronary Prevention Study (WOSCOPS) using pravastatin. The aim of this study was to investigate whether pravastatin has a preferable effect on glucose tolerance among statins. An open-label prospective cross-over trial was performed to compare the effect of pravastatin (10 mg/day) or atorvastatin (10 mg/day) in Japanese early-state type 2 diabetes mellitus with hypercholesterolemia. The analyzed study subjects were treated with pravastatin (10 mg/day, n = 12) or atorvastatin (10 mg/day, n = 12) for 12 weeks. After a 4-week-washout period, the drugs were switched and treatment was continued for another 12 weeks. Oral glucose tolerance test (OGTT) was performed to evaluate several parameters including the appropriateness of beta cell function for the individual insulin sensitivity (disposition index: product of a validated secretion parameter and sensitivity) at the end of each therapy. HbA(1c) and 2 h-glucose levels during OGTT in the pravastatin treatment were significantly lower than atorvastatin treatment. Disposition index after pravastatin treatment was significantly higher than after atorvastatin treatment. In conclusion, our study suggests that pravastatin has a favorable effect on pancreatic beta cell function compared with atorvastatin.
Published: 2007

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

Author: Norihiro Tada, Shinya Nagamatsu, Ryuzo Kawamori, Toyoyoshi Uchida, Yoshifumi Tamura, Noseki Iwashita, Shintaro Nagai, Takeshi Ogihara, Jong Bock Choi, Keiichi I. Nakayama, Hirotaka Watada, and Mica Ohara-Imaizumi
Subjects: Male, medicine.medical_specialty, medicine.medical_treatment, Carbohydrate metabolism, In Vitro Techniques, Biochemistry, Exocytosis, Mice, Munc18 Proteins, Internal medicine, Insulin receptor substrate, Insulin-Secreting Cells, Insulin Secretion, medicine, Animals, Insulin, Phosphorylation, Protein kinase A, Molecular Biology, Protein kinase C, biology, Insulin tolerance test, Cell Biology, Perfusion, Insulin receptor, Protein Kinase C-delta, Endocrinology, Glucose, biology.protein, Calcium, Signal transduction, Signal Transduction
Abstract: 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.
Published: 2006

41. Amelioration of glucose tolerance by hepatic inhibition of nuclear factor kappaB in db/db mice

Author: Fumihiko Sato, Hirotaka Watada, Toyoyoshi Uchida, Ryuzo Kawamori, Naoki Kumashiro, Takashi Nomiyama, Yasutaka Tanaka, Takahisa Hirose, Takeshi Ogihara, Hideki Mochizuki, Fuki Ikeda, and Yoshifumi Tamura
Subjects: STAT3 Transcription Factor, medicine.medical_specialty, cells, Endocrinology, Diabetes and Metabolism, Inflammation, IκB kinase, Biology, Carbohydrate metabolism, AMP-Activated Protein Kinases, Protein Serine-Threonine Kinases, environment and public health, Adenoviridae, Pathogenesis, chemistry.chemical_compound, Mice, Insulin resistance, AMP-activated protein kinase, Multienzyme Complexes, Internal medicine, Internal Medicine, medicine, Diabetes Mellitus, Animals, skin and connective tissue diseases, Cyclic AMP Response Element-Binding Protein, Transcription factor, Triglycerides, NF-kappa B, NF-κB, medicine.disease, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Mice, Inbred C57BL, enzymes and coenzymes (carbohydrates), Disease Models, Animal, Endocrinology, Glucose, chemistry, Liver, biology.protein, Trans-Activators, Female, I-kappa B Proteins, biological phenomena, cell phenomena, and immunity, medicine.symptom, Insulin Resistance, Glycogen, Transcription Factors
Abstract: Recent studies have identified the involvement of inhibitor IkappaB kinase (IKK) in the pathogenesis of insulin resistance. To investigate the mechanism involved, we examined the role of nuclear factor kappaB (NF-kappaB), the distal target of IKK, in hepatic glucose metabolism.To inhibit NF-kappaB activity, db/db mice were infected with adenovirus expressing the IkappaBalpha super-repressor.The IkappaBalpha super-repressor adenovirus infection caused a moderate reduction of NF-kappaB activity in liver. The treatment was associated with improved glucose tolerance, reduction in the serum insulin level, and increased hepatic triacylglycerol and glycogen contents, but had no effect on insulin-stimulated phosphorylation of Akt. On the other hand, quantification of mRNA in the liver revealed marked reduction of expression of gluconeogenic genes, such as those encoding phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, concurrent with reduced expression of gene encoding peroxisome proliferator-activated receptor gamma coactivator-1alpha (PPARGC1A, also known as PGC-1alpha). Furthermore, the production of super-repressor IkappaBalpha suppressed the increase in blood glucose level after pyruvate injection.Our results indicate that moderate inhibition of NF-kappaB improved glucose tolerance through decreased gluconeogenesis associated with reduced PGC-1alpha gene expression in db/db mice, and suggest that inhibition of NF-kappaB activity in liver is a potentially suitable strategy for the normalisation of blood glucose concentration in type 2 diabetes.
Published: 2006

42. Normal pancreatic β-cell function in mice with RIP-Cre-mediated inactivation of p62/SQSTM1.

Author: Akira Honda, Koji Komiya, Akemi Hara, Ayako Fukunaka, Luka Suzuki, Takeshi Miyatsuka, Takeshi Ogihara, Yoshio Fujitani, and Hirotaka Watada
Published: 2018
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43. p38 MAPK is involved in activin A- and hepatocyte growth factor-mediated expression of pro-endocrine gene neurogenin 3 in AR42J-B13 cells

Author: Atsuhito Nakao, Rei Kanno, Hirotaka Watada, Itaru Kojima, Michael S. German, Takashi Nomiyama, Fuki Ikeda, Ryuzo Kawamori, Yasushi Tanaka, and Takeshi Ogihara
Subjects: Transcriptional Activation, endocrine system, Time Factors, Transcription, Genetic, Cellular differentiation, Repressor, Nerve Tissue Proteins, SMAD, Transfection, Biochemistry, p38 Mitogen-Activated Protein Kinases, Cell Line, Islets of Langerhans, Genes, Reporter, Endocrine Glands, TGF beta signaling pathway, medicine, Basic Helix-Loop-Helix Transcription Factors, Humans, Enzyme Inhibitors, Luciferases, Molecular Biology, Transcription factor, Activin type 2 receptors, Genes, Dominant, Inhibin-beta Subunits, Chemistry, Hepatocyte Growth Factor, Cell Differentiation, Cell Biology, DNA, Molecular biology, Activins, Mutation, Hepatocyte growth factor, Mitogen-Activated Protein Kinases, ACVR2B, medicine.drug, Signal Transduction
Abstract: Neurogenin3 (ngn3) is a transcription factor that is essential for the differentiation of pancreatic endocrine cells. To investigate the signaling pathway that regulates ngn3 expression, we used AR42J-B13 cells as a model of the differentiation of pancreatic islets. In these cells, treatment with activin A and hepatocyte growth factor (HGF) induced the expression of ngn3. Reporter gene analysis using human ngn3 gene (NEUROG3) promoter fragments of various lengths identified the region between -402 and -327 bp of NEUROG3 as an activin A- and HGF-responsive DNA sequence. This DNA sequence normally functions as a repressor in AR42J-B13 cells, but treatment with activin A and HGF negates the repressor activity. Interestingly, function of the activin A- and HGF-responsive sequence was not influenced by the overexpression of the Smad inhibitory factor, Smad7. Instead, activin A and HGF activation was inhibited by overexpression of a dominant-negative mutant of transforming growth factor-beta-activated kinase 1 (TAK1), or mitogen-activated protein kinase kinase 3 (MKK3), or by treatment with a p38 MAPK-specific inhibitor, SB203580. Activin A and HGF function through the TAK1-MKK3-p38 MAPK pathway to relieve transcription repressors located between -402 and -326 bp on the NEUROG3 promoter, and consequently activate ngn3 expression and endocrine differentiation of AR42J-B13 cells.
Published: 2003

44. RANTES promoter genotype is associated with diabetic nephropathy in type 2 diabetic subjects

Author: Yasushi Tanaka, Hirotaka Watada, Tomio Onuma, Kunihiro Nakajima, Takashi Nomiyama, Fuki Ikeda, Rei Kanno, Takeshi Ogihara, Ken Sakai, Noseki Iwashita, and Ryuzo Kawamori
Subjects: Male, medicine.medical_specialty, Genotype, Receptors, CCR5, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, Nephropathy, Diabetic nephropathy, chemistry.chemical_compound, Japan, Polymorphism (computer science), Risk Factors, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Albuminuria, Humans, Diabetic Nephropathies, Genetic Predisposition to Disease, Promoter Regions, Genetic, Chemokine CCL5, Advanced and Specialized Nursing, Creatinine, Polymorphism, Genetic, business.industry, Middle Aged, medicine.disease, Endocrinology, chemistry, Diabetes Mellitus, Type 2, Female, business, Kidney disease
Abstract: OBJECTIVE—To evaluate the effect of RANTES gene promoter polymorphism and RANTES receptor (CCR5 gene) promoter polymorphism on diabetic nephropathy in Japanese type 2 diabetic subjects.RESEARCH DESIGN AND METHODS—A total 616 Japanese subjects with type 2 diabetes were recruited. Polymorphisms of −28 C/G and −403 G/A in the RANTES gene promoter region, and of 59029 G/A in the CCR5 gene promoter region were detected by PCR-RFLP (restriction fragment length polymorphism). The association of these genotypes with nephropathy was analyzed.RESULTS—While the RANTES −403 genotype showed no association with nephropathy, the frequency of the −28G allele was significantly higher in the DN2 group (urinary albuminuria-to-creatinine ratio [ACR] ≧300 mg/g creatinine, serum creatinine CONCLUSIONS—The RANTES promoter −28G genotype and CCR5 promoter 59029A genotype may be independent risk factors for diabetic nephropathy in patients with type 2 diabetes and may have an additive effect on nephropathy.
Published: 2003

45. Antiatherogenic mitochondrial genotype in patients with type 2 diabetes

Author: Masashi Tanaka, Takashi Nomiyama, Kunio Yagi, Jian-Sheng Gong, Hajime Matsunaga, Osamu Ogawa, Jin Zhang, Takeshi Ogihara, Yasushi Tanaka, Ryuzo Kawamori, and Yoshiji Yamada
Subjects: Adult, Male, medicine.medical_specialty, Genotype, Arteriosclerosis, Endocrinology, Diabetes and Metabolism, Longevity, Mutation, Missense, Type 2 diabetes, DNA, Mitochondrial, Polymerase Chain Reaction, Genomic Imprinting, Methionine, Japan, Polymorphism (computer science), Leucine, Reference Values, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Missense mutation, Humans, Carotid Stenosis, Aged, Advanced and Specialized Nursing, Aged, 80 and over, Vascular disease, business.industry, NADH Dehydrogenase, Middle Aged, medicine.disease, Endocrinology, Amino Acid Substitution, Diabetes Mellitus, Type 2, Etiology, Regression Analysis, Female, Restriction fragment length polymorphism, business, Polymorphism, Restriction Fragment Length
Abstract: OBJECTIVE—To evaluate the significance of a longevity-associated mitochondrial genotype (Mt5178A) derived from a C → A transversion at nucleotide position 5178 of mitochondrial DNA, which causes a Leu-to-Met substitution within the NADH dehydrogenase subunit 2 gene, in type 2 diabetic subjects. RESEARCH DESIGN AND METHODS—Mt5178 typing was done by polymerase chain reaction–restriction fragment-length polymorphism with the restriction enzyme AluI in 1,148 type 2 diabetic Japanese subjects, and the results were compared with the clinical characteristics. Then, the association of Mt5178 type with early atherosclerotic changes of the bilateral carotid arteries on ultrasonography was assessed in 412 diabetic subjects randomly selected from the original 1,148 type 2 diabetic subjects, while maintaining the same frequency of Mt5178A and Mt5178C. RESULTS—The frequency of Mt5178A in the type 2 diabetic subjects (454 of 1,148; 40%) was not different from that previously found in healthy blood donors (114 of 252; 45%). Clinical characteristics regarding diabetes were not significantly different between the Mt5178A group (n = 454) and the Mt5178C group (n = 694). However, the mean intima-media thickness (IMT) at six sites in the bilateral carotid arteries was significantly smaller in the Mt5178A group than in the Mt5178C group (0.906 ± 0.018 vs. 0.995 ± 0.021 mm, mean ± SEM, P = 0.022), and the Mt5178 type was significantly correlated with both the mean IMT and the presence of plaque on multiple regression analysis and discriminant analysis. CONCLUSIONS—The Mt5178A genotype may be unrelated to the etiology of type 2 diabetes. However, Mt5178A seems to have an antiatherogenic effect, at least in type 2 diabetic individuals.
Published: 2001

46. SET7/9 Enzyme Regulates Cytokine-induced Expression of Inducible Nitric-oxide Synthase through Methylation of Lysine 4 at Histone 3 in the Islet β Cell.

Author: Kyoko Fujimaki, Takeshi Ogihara, Morris, David L., Hisanobu Oda, Hitoshi Iida, Yoshio Fujitani, Mirmira, Raghavendra G., Evans-Molina, Carmella, and Hirotaka Watada
Subjects: *ENZYME regulation, *CYTOKINES, *GENE expression, *NITRIC-oxide synthases, *METHYLATION, *LYSINE, *HISTONES, *ISLANDS of Langerhans
Abstract: Set7/9 is an enzyme that methylates lysine 4 on histone 3 (H3K4) to maintain euchromatin architecture. While Set7/9 is enriched in islets and contributes to the transactivation of β cell specific genes including Ins1 and Slc2a, Set7/9 has also been reported to bind the p65 subunit of nuclear factor κB in non β cells and modify its transcriptional activity. Given that inflammation is a central component of β cell dysfunction in Type 1 and Type 2 diabetes, the aim of this study was to elucidate the role of Set7/9 in proinflammatory cytokine signaling in β cells. To induce inflammation, βTC3 insulinoma cells were treated with IL-1β, TNF-α, and IFN-γ. Cytokine treatment led to increased expression of inducible nitric oxide synthase (iNOS), which was attenuated by the diminution of Set7/9 using RNA interference. Consistent with previous reports, Set7/9 was co-immunoprecipitated with p65 and underwent cytosolic to nuclear translocation in response to cytokines. ChIP analysis demonstrated augmented H3K4 mono- and di-methylation of the proximal Nos2 promoter with cytokine exposure. Set7/9 was found to occupy this same region, while Set7/9 knockdown attenuated cytokine-induced histone methylation of the Nos2 gene. To test this relationship further, islets were isolated from Set7/9-deficient and wild-type mice and treated with IL-1β, TNF-α, IFN-γ. Cytokine-induced Nos2 expression was reduced in the islets from Set7/9 knockout mice. Together, our findings suggest that Set7/9 contributes to Nos2 transcription and pro-inflammatory cytokine signaling in the pancreatic β cell through activating histone modifications. [ABSTRACT FROM AUTHOR]
Published: 2015
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47. Gut Dysbiosis and Detection of "Live Gut Bacteria" in Blood of Japanese Patients With Type 2 Diabetes.

Author: Junko Sato, Akio Kanazawa, Fuki Ikeda, Tomoaki Yoshihara, Hiromasa Goto, Hiroko Abe, Koji Komiya, Minako Kawaguchi, Tomoaki Shimizu, Takeshi Ogihara, Yoshifumi Tamura, Yuko Sakurai, Risako Yamamoto, Tomoya Mita, Yoshio Fujitani, Hiroshi Fukuda, Koji Nomoto, Takuya Takahashi, Takashi Asahara, and Takahisa Hirose
Subjects: GUT microbiome, BLOOD microbiology, TYPE 2 diabetes, CLOSTRIDIUM, JAPANESE people
Abstract: OBJECTIVE Mounting evidence indicates that the gut microbiota are an important modifier of obesity and diabetes. However, so far there is no information on gut microbiota and "live gut bacteria" in the systemic circulation of Japanese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Using a sensitive reverse transcription-quantitative PCR (RT-qPCR) method, we determined the composition of fecal gut microbiota in 50 Japanese patients with type 2 diabetes and 50 control subjects, and its association with various clinical parameters, including inflammatory markers. We also analyzed the presence of gut bacteria in blood samples. RESULTS The counts of the Clostridium coccoides group, Atopobium cluster, and Prevotella (obligate anaerobes) were significantly lower (P < 0.05), while the counts of total Lactobacillus (facultative anaerobes) were significantly higher (P < 0.05) in fecal samples of diabetic patients than in those of control subjects. Especially, the counts of Lactobacillus reuteri and Lactobacillus plantarum subgroups were significantly higher (P < 0.05). Gut bacteria were detected in blood at a significantly higher rate in diabetic patients than in control subjects (28% vs. 4%, P < 0.01), and most of these bacteria were Gram-positive. CONCLUSIONS This is the first report of gut dysbiosis in Japanese patients with type 2 diabetes as assessed by RT-qPCR. The high rate of gut bacteria in the circulation suggests translocation of bacteria from the gut to the bloodstream. [ABSTRACT FROM AUTHOR]
Published: 2014
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48. Human IAPP-induced pancreatic β cell toxicity and its regulation by autophagy.

Author: Nayumi Shigihara, Ayako Fukunaka, Akemi Hara, Koji Komiya, Akira Honda, Toyoyoshi Uchida, Hiroko Abe, Yukiko Toyofuku, Motoyuki Tamaki, Takeshi Ogihara, Takeshi Miyatsuka, Hiddinga, Henry J., Setsuya Sakagashira, Masato Koike, Yasuo Uchiyama, Tamotsu Yoshimori, Eberhardt, Norman L., Yoshio Fujitani, and Hirotaka Watada
Subjects: *PANCREATIC beta cells, *CELLULAR control mechanisms, *ISLANDS of Langerhans, *AUTOPHAGY, *LABORATORY mice
Abstract: Pancreatic islets in patients with type 2 diabetes mellitus (T2DM) are characterized by loss of β cells and formation of amyloid deposits derived from islet amyloid polypeptide (IAPP). Here we demonstrated that treatment of INS-1 cells with human IAPP (hIAPP) enhances cell death, inhibits cytoproliferation, and increases autophagosome formation. Furthermore, inhibition of autophagy increased the vulnerability of β cells to the cytotoxic effects of hIAPP. Based on these in vitro findings, we examined the pathogenic role of hIAPP and its relation to autophagy in hIAPP-knockin mice. In animals fed a standard diet, hIAPP had no toxic effects on β cell function; however, hIAPP-knockin mice did not exhibit a high-fat-diet-induced compensatory increase in β cell mass, which was due to limited β cell proliferation and enhanced β cell apoptosis. Importantly, expression of hIAPP in mice with a β cell-specific autophagy defect resulted in substantial deterioration of glucose tolerance and dispersed cytoplasmic expression of p62-associated toxic oligomers, which were otherwise sequestrated within p62-positive inclusions. Together, our results indicate that increased insulin resistance in combination with reduced autophagy may enhance the toxic potential of hIAPP and enhance β cell dysfunction and progression of T2DM. [ABSTRACT FROM AUTHOR]
Published: 2014
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49. The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance.

Author: 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 O. Imaizumi, Takaya Abe, Hiroshi Kiyonari, Shintaro Hojyo, Toshiyuki Fukada, Takeshi Kawauchi, and Shinya Nagamatsu
Subjects: *TYPE 2 diabetes, *ZINC transporters, *PEPTIDES, *INSULIN research, *ENDOCYTOSIS
Abstract: 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-depen-dent 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 [ABSTRACT FROM AUTHOR]
Published: 2013
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