Insulin Resistance in Human iPS Cells Reduces Mitochondrial Size and Function

Insulin resistance is a key component of type 2 diabetes (T2D) pathophysiology and an early marker and predictor of diabetes risk1, occurring several decades before hyperglycaemia develops. Due to the difficulty in accessing important tissues for study in humans, the specific molecular mechanisms responsible for common forms of insulin resistance remain unknown but likely include genetic, developmental, and environmental contributions. Insights into human insulin resistance have been provided by rare syndromes due to insulin receptor (INSR) mutations, such as Donohue syndrome and type A insulin resistance2,3,4,5,6,7. Clinically, these syndromes share several features, including acanthosis nigricans, hyperandrogenism, and severe insulin resistance. In addition, patients with Donohue syndrome display reduced body weight and postnatal growth. Recent data have also demonstrated that humans with INSR mutations may have abnormalities in mitochondrial function, as indicated by decreased phosphocreatine recovery in muscle after exercise8. While skin fibroblasts derived from these individuals have elucidated key information about the structure and function of the insulin receptor and its downstream signalling pathways9, these cells are already terminally differentiated and are poorly responsive to insulin. To address these limitations, we have utilised induced pluripotent stem cells (iPSC) derived from these patients as a new model system to identify differentiation-independent and cell autonomous molecular drivers of insulin resistance. These cells also allow us to identify mechanisms by which insulin resistance modulates stem cell function and metabolism. Both human and animal studies highlight key links between insulin resistance and energetic defects10,11. For example, in vivo magnetic resonance spectroscopy studies in patients with T2D demonstrate reduced ATP synthesis12,13,14,15 and tricarboxylic acid (TCA) cycle flux16. Moreover, muscle biopsies from individuals with T2D and obesity-linked insulin resistance show reductions in nuclear-encoded mitochondrial gene expression17,18, mitochondrial DNA (mtDNA) levels19, and oxidative phosphorylation (OXPHOS) complex activity20. Conversely, interventions such as exercise, caloric restriction, and weight loss typically improve mitochondrial activity and insulin sensitivity in parallel21,22,23,24. We have previously shown that insulin resistance affects stem cell function through decreased cell proliferation; however, it remains unknown whether insulin resistance can also affect metabolism in these cells. To test the hypothesis that insulin resistance can modulate stem cell metabolism, we utilised our unique collection of iPSC from patients with severe insulin resistance (IR-Mut) and observed several metabolic defects including decreased mitochondrial size and functional capacity.