Dynamic modulation of glucose utilisation by glucocorticoid rhythms in health and disease

A systems level coordination of physiological rhythms is essential to sustain healthy states, especially in the face of stimuli that may disrupt such rhythms. The timing of meals, medication and chronic stress can profoundly influence metabolism, which depends on the dynamic interactions between glucose, insulin and cortisol. Although the metabolic and stress endocrine axes are simultaneously disrupted in many diseases, a theoretical framework to understand how chronodisruption leads to disease is lacking. By developing a mathematical model of glucose utilisation that accounts for the antagonism between insulin and cortisol, we investigate the dynamic effects of glucose boluses under normal and disrupted cortisol rhythms, including the effects of cortisol agonists and antagonists. We also predict how cortisol rhythms modulate circadian responses to oral glucose diagnostic tests, and analyse the disruptions caused by hypercortisolism. Finally, we predict the mechanisms leading to type 2 diabetes in patients with normal and excess cortisol.