Quantitative study on insulin response threshold and how it determines body composition
ABSTRACT
To balance the safety and rapidity of glycemic control, the muscle’s insulin response is bistable (ALL-or-NONE with hysteresis; that is, the same insulin concentration may elicit either ALL response or NONE response, depending on the cell’s original state), as predicted by previous theoretical studies. However, the bistability has not been verified by experiment. Here, we tested the insulin response of single C2C12 myotube by FRET analysis of Akt activation and demonstrated that C2C12 myotubes respond to insulin in a bistable manner, with typical switch-on and switch-off thresholds of approximately 300 pM and 100 pM, respectively. The switch-on threshold can be used to quantify peripheral insulin resistance (IR), which allows us to extend Forbes’ formula to the LM-IR-FM equation (LIFE), which reveals how IR determines our body composition (LM: lean mass; FM: fat mass). LIFE provides an easy way to obtain IR because the body composition can be easily measured. Moreover, LIFE reveals the positive correlation between IR and fatness, which, together with the fact that IR can be easily measured, makes IR a promising biomarker for obesity. In future, we would like to investigate aging effects on insulin response curve of single cells by isolating and analyzing primary muscle cells from young, middle-aged and old mice. Additionally, to estimate the accuracy and feasibility of the body composition-based method, we would like to use rat model to establish a much better way to monitor peripheral insulin resistance and obesity.
