Ablation of PDK1 in pancreatic beta cells induces diabetes as a result of loss of beta cell mass

Nature Genetics
Naoko HashimotoMasato Kasuga

Abstract

The total mass of islets of Langerhans is reduced in individuals with type 2 diabetes, possibly contributing to the pathogenesis of this condition. Although the regulation of islet mass is complex, recent studies have suggested the importance of a signaling pathway that includes the insulin or insulin-like growth factor-1 receptors, insulin receptor substrate and phosphatidylinositol (PI) 3-kinase. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) is a serine-threonine kinase that mediates signaling downstream of PI 3-kinase. Here we show that mice that lack PDK1 specifically in pancreatic beta cells (betaPdk1-/- mice) develop progressive hyperglycemia as a result of a loss of islet mass. The mice show reductions in islet density as well as in the number and size of cells. Haploinsufficiency of the gene for the transcription factor Foxo1 resulted in a marked increase in the number, but not the size, of cells and resulted in the restoration of glucose homeostasis in betaPdk1-/- mice. These results suggest that PDK1 is important in maintenance of pancreatic cell mass and glucose homeostasis.

References

Jun 1, 1997·The EMBO Journal·H B JefferiesG Thomas
Mar 12, 1998·Nature·D J WithersM F White
Jan 22, 2000·The Journal of Clinical Investigation·Y KidoD Accili
Sep 12, 2000·Current Opinion in Genetics & Development·H Stocker, E Hafen
Jan 10, 2002·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Sara C Kozma, George Thomas
Jul 12, 2002·The EMBO Journal·Margaret A LawlorDario R Alessi
Dec 28, 2002·Diabetes·Alexandra E ButlerPeter C Butler
Jul 5, 2003·The Journal of Clinical Investigation·Robert S GarofaloKevin G Coleman
Oct 7, 2004·The Journal of Clinical Investigation·Xueying LinMorris F White
Oct 7, 2004·The Journal of Clinical Investigation·Naoto KubotaTetsuo Noda
Jan 5, 2005·The Journal of Clinical Investigation·Naoko HashimotoMasato Kasuga
Feb 17, 2005·Molecular and Cellular Biology·Rachael M EastonMorris J Birnbaum
Apr 4, 2006·Cell Metabolism·Hiroshi InoueMasato Kasuga
Apr 28, 2006·Nature Genetics·Kohjiro UekiRohit N Kulkarni

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Citations

Oct 23, 2008·Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico·Oliver RennerAmancio Carnero
Apr 13, 2011·Cell Research·Xiaolong Yang, Tian Xu
Apr 22, 2009·Proceedings of the National Academy of Sciences of the United States of America·Sharon S ZhangGen-Sheng Feng
May 12, 2009·Proceedings of the National Academy of Sciences of the United States of America·Kaoru ItoIssei Komuro
Nov 10, 2010·Proceedings of the National Academy of Sciences of the United States of America·Jiangying LiuDoris A Stoffers
Nov 17, 2007·The Journal of Biological Chemistry·Emilyn U Alejandro, James D Johnson
Jul 10, 2010·Antioxidants & Redox Signaling·Zhiyong Cheng, Morris F White
Jul 17, 2009·Genes & Development·Nader ChalhoubSuzanne J Baker
Oct 9, 2007·Diabetes, Obesity & Metabolism·L ElghaziE Bernal-Mizrachi
Oct 13, 2009·Diabetes, Obesity & Metabolism·Yanmei LiuMichele Solimena
Oct 13, 2009·Diabetes, Obesity & Metabolism·C TalchaiD Accili
Mar 5, 2008·Molecular and Cellular Biology·Yutaka ShigeyamaTetsuo Noda
Mar 19, 2008·Molecular and Cellular Biology·Jose R BayascasDario R Alessi
May 17, 2008·Annual Review of Nutrition·Ingo B LeibigerPer-Olof Berggren
Sep 14, 2006·Annual Review of Pharmacology and Toxicology·Chung-Han LeeKun-Liang Guan
Aug 20, 2009·American Journal of Physiology. Endocrinology and Metabolism·Hiroyuki MoriKun-Liang Guan
Jul 11, 2006·The Journal of Clinical Investigation·Masato Kasuga
Oct 3, 2007·The Journal of Clinical Investigation·Tomoaki MoriokaRohit N Kulkarni
Dec 30, 2009·The Journal of Clinical Investigation·Marie-Therese RachedStavroula Kousteni
Nov 19, 2013·PLoS Computational Biology·Natalie BerestovskyLuay Nakhleh
Dec 16, 2011·European Journal of Endocrinology·Jaime Guevara-AguirreArlan L Rosenbloom
Oct 13, 2007·Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine·Masato Kasuga
Apr 16, 2014·Journal of Diabetes Research·Valérie PlaisanceAmar Abderrahmani
May 2, 2014·The Journal of Endocrinology·Haiyong ChenWilliam C Cho
Jun 24, 2015·Proceedings of the National Academy of Sciences of the United States of America·Shun-ichiro AsaharaYoshiaki Kido
Mar 25, 2009·Biochemical and Biophysical Research Communications·Shun-ichiro AsaharaMasato Kasuga
May 3, 2008·Molecular and Cellular Endocrinology·Neil A HanleyTimo Otonkoski
Aug 2, 2012·Experimental Diabetes Research·Michael D Williams, Geraldine M Mitchell

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