Total insulin and IGF-I resistance in pancreatic beta cells causes overt diabetes

Nature Genetics
Kohjiro UekiRohit N Kulkarni

Abstract

An appropriate beta cell mass is pivotal for the maintenance of glucose homeostasis. Both insulin and IGF-1 are important in regulation of beta cell growth and function (reviewed in ref. 2). To define the roles of these hormones directly, we created a mouse model lacking functional receptors for both insulin and IGF-1 only in beta cells (betaDKO), as the hormones have overlapping mechanisms of action and activate common downstream proteins. Notably, betaDKO mice were born with a normal complement of islet cells, but 3 weeks after birth, they developed diabetes, in contrast to mild phenotypes observed in single mutants. Normoglycemic 2-week-old betaDKO mice manifest reduced beta cell mass, reduced expression of phosphorylated Akt and the transcription factor MafA, increased apoptosis in islets and severely compromised beta cell function. Analyses of compound knockouts showed a dominant role for insulin signaling in regulating beta cell mass. Together, these data provide compelling genetic evidence that insulin and IGF-I-dependent pathways are not critical for development of beta cells but that a loss of action of these hormones in beta cells leads to diabetes. We propose that therapeutic improvement of insulin and IGF-I signalin...Continue Reading

References

Mar 12, 1998·Nature·D J WithersM F White
Dec 22, 1999·The Journal of Clinical Investigation·R N KulkarniC R Kahn
Dec 12, 2001·Endocrine Reviews·J NakaeD Accili
Dec 14, 2001·Nature·D MathisC Benoist
Jan 30, 2002·Diabetes·Robert T KennedySung-Kwon Jung
May 16, 2002·Proceedings of the National Academy of Sciences of the United States of America·Martin OlbrotArun Sharma
Jun 25, 2002·Trends in Neurosciences·David P WolferHans Peter Lipp
Feb 18, 2003·The Journal of Clinical Investigation·Simon J Fisher, C Ronald Kahn
Oct 2, 2003·American Journal of Physiology. Endocrinology and Metabolism·Kenichi OtaniKenneth S Polonsky
Jan 28, 2004·Cell·Nika N Danial, Stanley J Korsmeyer
Jun 1, 2005·Molecular and Cellular Biology·Chuan ZhangSatoru Takahashi
Sep 10, 2005·Reviews in Endocrine & Metabolic Disorders·Rohit N Kulkarni
Sep 13, 2005·Cell Metabolism·Yukari Ido KitamuraDomenico Accili
Dec 6, 2005·The Journal of Biological Chemistry·Ji-Yeon LeeLothar Hennighausen
Dec 27, 2005·The Journal of Biological Chemistry·Atsuko MiuraIichiro Shimomura

❮ Previous
Next ❯

Citations

Sep 12, 2007·Diabetologia·E FerranniniUNKNOWN Relationship between Insulin Sensitivity and Cardiovascular Disease Risk (RISC) Project Investigators
Jun 11, 2008·Apoptosis : an International Journal on Programmed Cell Death·Ru-Jiang LiYong-Wei Huo
Aug 10, 2007·Current Diabetes Reports·Shay Porat, Yuval Dor
Aug 22, 2007·Cell Biochemistry and Biophysics·Jun-Li Liu
Mar 7, 2007·Biochemistry·Melissa Villanueva, R Mark Wightman
Apr 22, 2009·Proceedings of the National Academy of Sciences of the United States of America·Sharon S ZhangGen-Sheng Feng
Sep 26, 2013·Proceedings of the National Academy of Sciences of the United States of America·Yu Hsuan Carol YangJames D Johnson
Oct 17, 2009·The Journal of Biological Chemistry·Rohan K HumphreyUlupi S Jhala
Dec 5, 2006·The Journal of Biological Chemistry·Nathan L VanderfordSabire Ozcan
Nov 19, 2008·Antioxidants & Redox Signaling·George VardatsikosAshok K Srivastava
Aug 6, 2011·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Emilyn U AlejandroJames D Johnson
Aug 5, 2008·Genes & Development·Jennifer M Oliver-Krasinski, Doris A Stoffers
Oct 18, 2008·Diabetes, Obesity & Metabolism·A KhalailehY Dor
Sep 7, 2012·Diabetes, Obesity & Metabolism·A B Goldfine, R N Kulkarni
Jun 30, 2010·Molecular and Cellular Biology·Jeffrey C RaumRoland Stein
Jun 10, 2009·Molecular and Cellular Biology·Tadahiro KitamuraDomenico Accili
Mar 5, 2008·Molecular and Cellular Biology·Yutaka ShigeyamaTetsuo Noda
May 17, 2008·Annual Review of Nutrition·Ingo B LeibigerPer-Olof Berggren
Nov 9, 2012·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Jinny R LavezziPaul J Rozance
May 6, 2008·Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology·Jiawei ZhaoRenming Hu
May 6, 2008·Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology·Diana AvramSusanne Ullrich
Jul 11, 2006·The Journal of Clinical Investigation·Masato Kasuga
Jan 4, 2007·The Journal of Clinical Investigation·Gordon C Weir, Susan Bonner-Weir
Oct 3, 2007·The Journal of Clinical Investigation·Tomoaki MoriokaRohit N Kulkarni
Oct 11, 2008·The Journal of Clinical Investigation·Samira AlliouacheneMario Pende
May 11, 2011·The Journal of Clinical Investigation·Yingjie WuDerek LeRoith
Oct 19, 2010·Journal of Biomedical Science·Gerard HonigLaurence H Tecott
Jan 19, 2008·Endocrinology·Jennifer L BeithJames D Johnson
Jul 11, 2009·Endocrine Reviews·Claes OhlssonJohan Svensson
Nov 10, 2009·Molecular Endocrinology·Catherine E GleasonMorris J Birnbaum

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis