title: Genetic insulin resistance is a potent regulator of gene expression and proliferation in human iPS cells.
abstract: Insulin resistance is central to diabetes and metabolic syndrome. To define the consequences of genetic insulin resistance distinct from those secondary to cellular differentiation or in vivo regulation, we generated induced pluripotent stem cells (iPSCs) from individuals with insulin receptor mutations and age-appropriate control subjects and studied insulin signaling and gene expression compared with the fibroblasts from which they were derived. iPSCs from patients with genetic insulin resistance exhibited altered insulin signaling, paralleling that seen in the original fibroblasts. Insulin-stimulated expression of immediate early genes and proliferation were also potently reduced in insulin resistant iPSCs. Global gene expression analysis revealed marked differences in both insulin-resistant iPSCs and corresponding fibroblasts compared with control iPSCs and fibroblasts. Patterns of gene expression in patients with genetic insulin resistance were particularly distinct in the two cell types, indicating dependence on not only receptor activity but also the cellular context of the mutant insulin receptor. Thus, iPSCs provide a novel approach to define effects of genetically determined insulin resistance. This study demonstrates that effects of insulin resistance on gene expression are modified by cellular context and differentiation state. Moreover, altered insulin receptor signaling and insulin resistance can modify proliferation and function of pluripotent stem cell populations.
authors: Integrative Physiology and Metabolism Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA.
authors: Salvatore
authors: S
authors: Iovino
authors: Integrative Physiology and Metabolism Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA.
authors: Alison M
authors: AM
authors: Burkart
authors: Integrative Physiology and Metabolism Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA.
authors: Kristina
authors: K
authors: Kriauciunas
authors: Integrative Physiology and Metabolism Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA.
authors: Laura
authors: L
authors: Warren
authors: Integrative Physiology and Metabolism Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA.
authors: Katelyn J
authors: KJ
authors: Hughes
authors: Integrative Physiology and Metabolism Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA.
authors: Michael
authors: M
authors: Molla
authors: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA.
authors: Youn-Kyoung
authors: YK
authors: Lee
authors: Integrative Physiology and Metabolism Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA c.ronald.kahn@joslin.harvard.edu mary.elizabeth.patti@joslin.harvard.edu.
authors: Mary-Elizabeth
authors: ME
authors: Patti
authors: Integrative Physiology and Metabolism Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA c.ronald.kahn@joslin.harvard.edu mary.elizabeth.patti@joslin.harvard.edu.
authors: C Ronald
authors: CR
authors: Kahn
mesh_terms: D000293:Adolescent; D015703:Antigens, CD / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics*; D002478:Cells, Cultured; D002648:Child; D005347:Fibroblasts / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D007223:Infant; D007231:Infant, Newborn; D007333:Insulin Resistance / Q000235:genetics*; D011972:Receptor, Insulin / Q000235:genetics*
chemical_list: D015703:Antigens, CD; C435941:INSR protein, human; D011972:Receptor, Insulin