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 (iPSC) from individuals with insulin receptor mutations and age-appropriate controls, and studied insulin signaling and gene expression in comparison to fibroblasts from which they were derived. iPSC 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 iPSC. Global gene expression analysis revealed marked differences in both insulin-resistant iPSC and corresponding fibroblasts as compared to control iPSC 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, iPSC provide a novel approach to define effects of genetically-determined insulin resistance. Our 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.
3 Contributed equally to this manuscript.
- Received January 30, 2014.
- Accepted July 7, 2014.
- © 2014 by the American Diabetes Association.
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