Weight loss and metabolic changes in response to diet restriction and bariatric surgery

Objective: The objective of this study was to investigate how different weight-loss interventions result in metabolic changes, at different time scales. Methods: Mathematical models (differential equations) of energy metabolism were used to study weight loss trajectories and changes in postprandial dynamics in response to diet restriction, Roux-en-Y gastric bypass (RYGB) surgery and semaglutide (Ozempic, Wegovy) interventions. Personalized models and Virtual Patients were created and analyzed. Results and Conclusions: Model for long-term obesity-driven development and progression of diabetes based on the 'twin cycle hypothesis' (liver cycle, pancreas cycle) expanded with inflammation contributing to glucolipotoxicity. The model identifies a window of opportunity for remission through weight loss. RYGB surgery increases glucagon-like peptide 1 (GLP-1) and improves glucose levels, but also increases (postprandial) insulin. Strikingly, postprandial hypoglycemia is a common problem after RYGB. Model trajectory simulations suggest that interplay between changed anatomy, GLP-1 kinetics and changes in insulin sensitivity may explain the emergence of post-bariatric hypoglycemia months or years after surgery. Both RYGB surgery and GLP-1 receptor agonism interventions weaken the appetite feedback control circuit that regulates body weight. Treatment with semaglutide not only lowers body weight, but also glucose levels, an effect that warrants further investigation for non-diabetic individuals.