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Background: Roux-en-Y gastric bypass (RYGB) is an effective surgical treatment for obesity that results insubstantial and sustained weight loss. In addition to its weight-reducing effects, RYGB rapidly improvesglucose homeostasis, often leading to the remission of type 2 diabetes. However, the underlyingneuroendocrine adaptations responsible for these metabolic improvements remain incompletelyunderstood.

Aim: The aim of this study was to characterize changes in the regulation of glucagon, adrenocorticotropichormone (ACTH), and cortisol in response to variable glucose concentrations before and after RYGBsurgery.

Methods: Population modeling was applied to data from individuals who underwent clinical glucoseclamp studies, some of whom were studied both before and after RYGB. A joint nonlinear mixed-effects(NLME) model was first developed using pre-RYGB clamp data to describe hormone dynamics. The modelwas then applied to post-RYGB data, and parameter differences were assessed sequentially: first by fixingeach parameter individually to its pre-RYGB value, and then by testing whether it could be modeled as ashared estimate across pre- and post-RYGB states. In both cases, the likelihood ratio test was used toidentify significant differences in the model fit. Covariate analysis was conducted to investigate whetherchanges in the insulin sensitivity explained the observed parameter differences post-RYGB.

Results: Post-RYGB, ACTH dynamics showed the most pronounced alterations, including reduced baselineconcentrations, slower elimination, slower secretion, and decreased sensitivity to glucose deficit.Glucagon exhibited enhanced insulin-mediated suppression, slower elimination, slower secretion andlower baseline levels; the latter was explained by the increased insulin sensitivity. Cortisol regulationremained largely unchanged.

Conclusion: These findings highlight the adaptive changes in both the central (ACTH) and peripheral(glucagon) counterregulatory hormone systems post-RYGB. The results provide insight into how RYGBreprograms hormonal responses to hypoglycemia and may support the development ofpharmacotherapies that mimic these beneficial neuroendocrine adaptations.