A differential equation model of fasting metabolic homeostasis was developed to explain how simultaneous homeostasis of multiple circulating nutrients (glucose, lactate, free fatty acids, ketones) is achieved, and how obesity leads to hyperglycemia and hyperinsulinemia.
The model reveals that a fixed energy demand causes circulating nutrients to compete for oxidation ('competitive catabolism'); in obesity, increased fat mass drives excess lipolysis, fatty acids outcompete glucose for oxidation, raising circulating glucose and insulin — providing a quantitative circuit linking obesity to type 2 diabetes. Perturbative nutrient infusions confirmed this emergent behavior.
The model is grounded in mass action kinetics and mathematical assumptions that may not fully capture in vivo complexity; it focuses on fasting homeostasis and may not generalize to postprandial states; experimental validation appears limited to perturbative infusions without direct in vivo genetic or pharmacologic testing of the proposed circuit.
This work suggests that in obese patients, reducing lipolysis (e.g., targeting fat mass or lipolytic pathways) may be a more direct strategy to restore glucose homeostasis than targeting glucose metabolism directly. Clinicians should consider lipid catabolic flux — not just insulin signaling — as a central driver of fasting hyperglycemia in obesity.
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