Myotubes derived from human-induced pluripotent stem cells mirror in vivo insulin resistance

Iovino Salvatore; Burkart Alison M.; Warren LauraPatti Mary ElizabethKahn C. Ronald

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Myotubes derived from human-induced pluripotent stem cells mirror in vivo insulin resistance

机译：Myotubes derived from human-induced pluripotent stem cells mirror in vivo insulin resistance

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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.

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《Proceedings of the National Academy of Sciences of the United States of America.》 |2016年第7期|1889-1894|共6页
作者
Iovino Salvatore; Burkart Alison M.; Warren LauraPatti Mary ElizabethKahn C. Ronald;
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作者单位

Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab,Res Div, Boston, MA 02215 USA;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
iPS cells; insulin resistance; insulin signaling; skeletal muscle; genetic disease;

Myotubes derived from human-induced pluripotent stem cells mirror in vivo insulin resistance

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