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Article History

Received: 25 March 2025

Accepted: 9 June 2025

First Online: 9 September 2025

Data availability

: Data will be made available by the corresponding authors upon reasonable request.

: Computer code used for the simulations will be posted in the Johns Hopkins Research Data Repository: .

: Open access funding provided by Copenhagen University. Research performed by VS and reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases under award number K25DK131328. The work by ASS was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. Original work by Bagger et al previously published in the Journal of Clinical Endocrinology and Metabolism was funded by an unrestricted research grant number 34851 from the Investigator Initiated Studies Program of Merck&Co. The content of this manuscript is solely the responsibility of the authors, and does not necessarily represent the official views of the National Institutes of Health.

: ASS has a collaboration with Eli Lilly Inc. to use mathematical modelling. JIB has served on scientific advisory panels and/or received research support from Novo Nordisk and Zealand Pharma. JJH is a consultant with Novo Nordisk, and is also on advisory boards for Novo Nordisk. He is the founder and an advisory board member for Antag Therapeutics. FKK has served on scientific advisory panels and/or been part of speakers’ bureaus for, served as a consultant to, holds stocks in, and/or has received research support from 89bio, Amgen, Altimmune, AstraZeneca, Bayer, Boehringer Ingelheim, Carmot Therapeutics, Chr. Hansen, Cytoki Pharma, Eli Lilly, Gubra, MedImmune, MSD/Merck, Mundipharma, Norgine, Novo Nordisk, MedImmune, Pharmacosmos, Sanofi, Structure Therapeutics, Zealand Pharma and Zucara, is a co-founder of and minority shareholder in Antag Therapeutics, and is currently employed full-time by Novo Nordisk. TV has served on scientific advisory panels, been part of speakers’ bureaus, served as a consultant to and/or received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Gilead, GSK, MSD/Merck, Novo Nordisk, Roche, Sanofi, Sun Pharmaceuticals and Zealand Pharma. VS declares that there are no relationships or activities that might bias, or be perceived to bias, their work.

: VS contributed to model development, implementation, analysis and manuscript preparation. ASS contributed to model development and analysis, and reviewed/edited the manuscript. JIB was responsible for experimental procedures and collection of samples and delivery of raw data, and contributed to interpretation of results and manuscript review. JJH was responsible for the biochemical analysis of glucagon and contributed to interpretation of results and manuscript review. FKK performed the experimental protocol, and contributed to interpretation of results, and manuscript review. TV was the principal investigator, performed the experimental protocol, and contributed to interpretation of results and manuscript review. All authors have reviewed and approved the final version of the manuscript. VS and JIB are guarantors of this work.