Glucose-dependent dynamics of glucagon, cortisol and adrenocorticotropic hormone before and after gastric bypass

Context: Roux-en-Y gastric bypass (RYGB) improves glucose homeostasis beyond weight loss, but the underlying mechanisms remain incompletely understood. Counter-regulatory hormones such as glucagon, ACTH, and cortisol are key components of glucose regulation. Objective: The aim of this study was to characterize alterations in glucagon, ACTH, and cortisol regulation before and after RYGB using nonlinear mixed-effects (NLME) population modeling, and to explore potential mediators of these changes. Design: Post-hoc analysis of one cross-sectional and two prospective cohort studies. Setting: Clinical research unit. Patients or Other Participants: In total, 62 individuals without diabetes from three previous clamp studies were included: 39 from a cross-sectional cohort covering a wide range of BMI and insulin sensitivity (cohort 1, utilized for model development only), and 23 participants examined both before and approximately four months after RYGB (cohort 2). Interventions: Hyperinsulinemic-euglycemic-hypoglycemic (both cohorts) and hyperglycemic (cohort 1 only) clamps. Main Outcome Measures: Glucose-dependent secretion dynamics of glucagon, ACTH, and cortisol quantified through NLME modeling and the impact of RYGB and metabolic characteristics on corresponding model parameters. Results: According to models developed using presurgical data from both cohorts, glucagon and ACTH turnover rates and baseline concentrations decreased post-RYGB in cohort 2. Insulin-mediated glucagon suppression and the glucose deficit required for ACTH stimulation increased, while cortisol dynamics remained stable. Higher insulin sensitivity was associated with lower baseline glucagon levels. Conclusion: RYGB induces reductions in glucagon and ACTH responsiveness to hypoglycemia, partially indicative of central nervous system-mediated resetting of glucose regulation. These adaptations may contribute to improved metabolic control following bariatric surgery.