Competitive catabolism in systemic mammalian metabolic homeostasis

Systemic metabolic homeostasis maintains circulating nutrient concentrations within physiological ranges. Insulin is central to this process, lowering circulating levels of glucose, free fatty acids, and ketones. Yet, how simultaneous homeostasis of these nutrients is achieved remains unclear. Here we develop a differential equation model of fasting metabolic homeostasis. Grounded in mass action kinetics, this multi-nutrient model reveals how a fixed energy demand naturally leads to competition between major circulating nutrients for oxidation ( competitive catabolism). Perturbative nutrient infusions confirm this emergent behavior. The multi-nutrient model predicts that insulin promotes fasting glucose homeostasis primarily indirectly by slowing lipolysis. It further identifies a physiological circuit by which obesity causes diabetes: Increased fat mass promotes lipolysis, releasing fatty acids into circulation that compete with glucose for oxidation, elevating glucose. Resulting hyperinsulinemia restores proper lipid catabolic flux but not euglycemia. Thus, quantitative modeling reveals a physiological homeostatic circuit through which obesity causes type 2 diabetes.