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.