Glucose-dependent Dynamics of Glucagon, Cortisol and Adrenocorticotropic Hormone Before and After Gastric Bypass

Abstract 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 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. Conclusions 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 surgery.