Requirements for multi-level systems pharmacology models to reach end-usage: the case of type 2 diabetes.
Insulin resistance, characterized by a reduced cellular response to insulin, is a major factor in type 2 diabetes pathogenesis, with a complex etiology consisting of a combination of environmental and genetic factors. Oxidative stress, which develops through an accumulation of toxic reactive oxygen species generated by mitochondria, is believed to contribute to insulin resistance in certain tissues. We develop mathematical models of feedback between reactive oxygen species production and dysfunction in mitochondria to provide insight into the role of oxidative stress in insulin resistance. Our models indicate that oxidative stress generated by glucose overload accelerates irreversible mitochondrial dysfunction. These models provide a foundation for understanding the long-term progression of insulin resistance and type 2 diabetes.