title: Myotubes derived from human-induced pluripotent stem cells mirror in vivo insulin resistance.
abstract: Induced pluripotent stem cells (iPS cells) represent a unique tool for the study of the pathophysiology of human disease, because these cells can be differentiated into multiple cell types in vitro and used to generate patient- and tissue-specific disease models. Given the critical role for skeletal muscle insulin resistance in whole-body glucose metabolism and type 2 diabetes, we have created a novel cellular model of human muscle insulin resistance by differentiating iPS cells from individuals with mutations in the insulin receptor (IR-Mut) into functional myotubes and characterizing their response to insulin in comparison with controls. Morphologically, IR-Mut cells differentiated normally, but had delayed expression of some muscle differentiation-related genes. Most importantly, whereas control iPS-derived myotubes exhibited in vitro responses similar to primary differentiated human myoblasts, IR-Mut myotubes demonstrated severe impairment in insulin signaling and insulin-stimulated 2-deoxyglucose uptake and glycogen synthesis. Transcriptional regulation was also perturbed in IR-Mut myotubes with reduced insulin-stimulated expression of metabolic and early growth response genes. Thus, iPS-derived myotubes from individuals with genetically determined insulin resistance demonstrate many of the defects observed in vivo in insulin-resistant skeletal muscle and provide a new model to analyze the molecular impact of muscle insulin resistance.
authors.affiliation: Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Iovino
authors.affiliation: Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Burkart
authors.affiliation: Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215.
authors.forename: Laura
authors.initials: L
authors.lastname: Warren
authors.affiliation: Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215.
authors.forename: Mary Elizabeth
authors.initials: ME
authors.lastname: Patti
authors.affiliation: Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215 c.ronald.kahn@joslin.harvard.edu.
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
mesh_terms: D002454:Cell Differentiation; D002675:Child, Preschool; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology; D005260:Female; D006801:Humans; D007223:Infant; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D018485:Muscle Fibers, Skeletal; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007328:Insulin
keywords: genetic disease; iPS cells; insulin resistance; insulin signaling; skeletal muscle
references.citation: J Clin Invest. 2000 Feb;105(3):311-20
references.pmid: 10675357
references.citation: Cell. 2013 Nov 7;155(4):909-21
references.pmid: 24209627
references.citation: Diabetologia. 2000 Jul;43(7):821-35
references.pmid: 10952453
references.citation: Biochem Soc Trans. 2001 Aug;29(Pt 4):552-8
references.pmid: 11498027
references.citation: Science. 1975 Oct 3;190(4209):63-5
references.pmid: 170678
references.citation: N Engl J Med. 1976 Apr 1;294(14):739-45
references.pmid: 176581
references.citation: J Clin Endocrinol Metab. 1982 Dec;55(6):1108-13
references.pmid: 7130338
references.citation: Biochemistry. 1991 Nov 5;30(44):10778-83
references.pmid: 1931997
references.citation: Lancet. 1992 Oct 17;340(8825):925-9
references.pmid: 1357346
references.citation: Science. 1993 Nov 26;262(5138):1441-4
references.pmid: 8248782
references.citation: Diabetes. 1995 Feb;44(2):243-7
references.pmid: 7859947
references.citation: Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):983-7
references.pmid: 7862678
references.citation: Endocr Rev. 1995 Apr;16(2):143-63
references.pmid: 7540132
references.citation: J Biol Chem. 1995 Sep 1;270(35):20801-7
references.pmid: 7657664
references.citation: Diabetes. 1996 Nov;45(11):1644-54
references.pmid: 8866574
references.citation: Cytokine Growth Factor Rev. 1996 Aug;7(2):153-9
references.pmid: 8899293
references.citation: J Biol Chem. 1999 Feb 5;274(6):3253-6
references.pmid: 9920861
references.citation: Hepatology. 1999 Jun;29(6):1743-51
references.pmid: 10347117
references.citation: Diabetes. 2005 Apr;54(4):1157-63
references.pmid: 15793256
references.citation: Endocrinology. 2015 Jun;156(6):2039-48
references.pmid: 25811318
references.citation: Stem Cell Reports. 2015 May 12;4(5):939-52
references.pmid: 25937370
references.citation: Cell. 2007 Nov 30;131(5):861-72
references.pmid: 18035408
references.citation: Science. 2007 Dec 21;318(5858):1917-20
references.pmid: 18029452
references.citation: Mol Cell Biol. 2008 Sep;28(18):5634-45
references.pmid: 18644868
references.citation: Cold Spring Harb Perspect Biol. 2014 Jan;6(1). pii: a009191. doi: 10.1101/cshperspect.a009191
references.pmid: 24384568
references.citation: N Engl J Med. 2014 Sep 18;371(12):1131-41
references.pmid: 25229917
references.citation: Cell. 2014 Oct 9;159(2):428-39
references.pmid: 25303535
references.citation: Biomed Res Int. 2015;2015:592915
references.pmid: 26075247
references.citation: Diabetes. 2014 Dec;63(12):4130-42
references.pmid: 25059784
references.citation: Mol Cell Endocrinol. 2010 Feb 5;315(1-2):153-8
references.pmid: 19505532
references.citation: Endocr Rev. 2011 Aug;32(4):498-514
references.pmid: 21536711
references.citation: Nature. 2012 Jan 19;481(7381):295-305
references.pmid: 22258608
references.citation: Nat Cell Biol. 2012 Feb;14(2):209-19
references.pmid: 22246346
references.citation: Lancet. 2012 Jun 16;379(9833):2279-90
references.pmid: 22683128
references.citation: Diabetes. 2000 Feb;49(2):284-92
references.pmid: 10868945