Quantitative modeling of insulin signaling reveals mechanisms of insulin resistance in obese mice.

Insulin resistance is a deficiency in insulin-mediated regulation of glucose metabolism and is considered a cause of multiple diseases such as diabetes and hypertension. Because the insulin signaling pathway plays a central role in insulin action, it has been extensively studied in the context of insulin resistance. However, the insulin signaling pathway's contribution to insulin resistance remains incompletely understood. Insulin receptor (IR) mutations can cause insulin resistance; however, reduced IR expression in obesity may still permit sufficient signaling due to the characteristics of IR, known as the spare receptor hypothesis. Selective insulin resistance, in which glucose metabolism is impaired while other pathways remain intact, further complicates insulin resistance. Nevertheless, our understanding of how the insulin signaling pathway contributes to these unresolved issues remains limited. To elucidate these mechanisms, we developed mathematical models of the hepatic insulin signaling pathway in mice with diet-induced obesity and found that changes in protein expression levels can largely account for signal attenuation. Insulin resistance was characterized using two indices: sensitivity shift and responsiveness shift. We found a trade-off between the two, whereby loss of responsiveness from upstream decreases was compensated for by decreases in downstream sensitivity. The excess of receptors conferred robustness to receptor decreases via the signaling pathway. Incoherent-feedforward-loop regulation maintained some signaling despite attenuation, potentially explaining selective insulin resistance. These findings provide deeper insights into insulin resistance and quantitative mechanisms underlying signaling pathway regulation.