Modeling physiological insulin sensitivity and pre-diabetic insulin resistance in multiple hPSC-derived cell types

Abstract Recently, we demonstrated the development of a human pluripotent stem cell (hPSC)-derived adipocyte (fat cell) model with physiological insulin signaling. For the first time, a human in vitro adipocyte cell model has an insulin response similar to in vivo human adipocytes. We next leveraged this protocol to study the early stages of insulin resistance preceding Type 2 Diabetes, by exposing these cells to diabetic patient levels of hyperinsulinemia. This resulted in mild insulin resistance on all of the aforementioned phenotypes, reminiscent of early T2D development in humans. This is a powerful model to study the mechanisms of T2D development and the underlying molecular pathology. However, while adipocytes are an important metabolic cell type, insulin resistance and T2D are a whole-body affliction, involving many other cell types. To broaden the impact of our work and increase the excitement of the field for the study of insulin signaling and resistance, we expanded our protocol to a panel of 8 other hPSC-derived cell types. We demonstrate physiologically relevant insulin response for each cell type, and we highlight that our insulin-resistance inducing conditions blunt the insulin response in every cell type. Additionally, we validate that key cell identity markers are not lost during this adaptation. By adapting a simple, defined protocol to a wide panel of human in vitro cell types, we can now investigate the cell-autonomous origins of insulin resistance under physiologically relevant conditions.