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Alpha cell dysregulation occurs in tandem with the development of insulin resistance and changes in beta cell function. Our aim was to investigate, using mathematical modelling, the role of alpha cell dysregulation in beta cell compensatory insulin secretion and subsequent failure in the progression from normoglycaemia to type 2 diabetes defined by ADA criteria.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We developed a physiological model of glucose homeostasis, whereby the fast dynamics of glucose, insulin and glucagon are coupled to the dynamics of beta cell functional mass (a product of individual beta cell functional capacity and mass). Beta cell functional mass exhibits an initial compensatory increase in response to hyperglycaemia, followed by an eventual decline due to glucotoxicity. Alpha cell dysregulation, defined as increased glucagon secretion and lowered glucagon suppression resulting in hyperglycaemia, was introduced to varying extents, and simulations were carried out to assess the effects on beta cell functional mass over a 20\u00a0year period.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The simulations were carried out under conditions of moderate, mild or no alpha cell dysregulation. The parameters representing insulin resistance, glucagon secretion and suppression for an individual with normoglycaemia obtained from previously published work were evolved over a period of 20 years to the mean values observed in type 2 diabetes. The model was validated by visually matching the beta cell functional mass obtained from the simulations of the disease progression model to previously published parameters. Those parameters were obtained from fits of a model of OGTTs to data from a cross-sectional cohort that spanned the spectrum from normoglycaemia to type 2 diabetes. We found that mild alpha cell dysregulation elicited robust beta cell compensation, resulting in controlled postprandial glucose excursions despite the development of insulin resistance. Moderate alpha cell dysregulation initially enhanced compensation but eventually accelerated the progression to type 2 diabetes. Alpha cell dysregulation impacted the time course of the standard markers of diabetes (fasting glucose, 2\u00a0h plasma glucose and HbA\n                      <jats:sub>1c<\/jats:sub>\n                      ) during disease progression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>\n                      The early stages of alpha cell dysregulation led to robust beta cell functional mass compensation driven by elevated fasting glucose. When the dysregulation progressed further, glucose levels rose to levels of glucotoxicity, exacerbating beta cell functional mass loss and accelerating the onset of type 2 diabetes. The various markers of diabetes (fasting glucose, 2\u00a0h plasma glucose and HbA\n                      <jats:sub>1c<\/jats:sub>\n                      ) differed in terms of the prediction of timing of onset of disease, depending on the extent of alpha cell dysregulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-025-06524-1","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T05:35:44Z","timestamp":1757396144000},"page":"2595-2608","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Evaluating the role of alpha cell dysregulation in the progression to type 2 diabetes using mathematical simulations"],"prefix":"10.1007","volume":"68","author":[{"given":"Vijaya","family":"Subramanian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur S.","family":"Sherman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens J.","family":"Holst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filip K.","family":"Knop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Vilsb\u00f8ll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonatan I.","family":"Bagger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,9]]},"reference":[{"key":"6524_CR1","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1007\/s11892-022-01486-9","volume":"22","author":"AH Owora","year":"2022","unstructured":"Owora AH, Allison DB, Zhang X et al (2022) Risk of type 2 diabetes among individuals with excess weight: weight trajectory effects. 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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\u00a0al previously published in the\n                      Journal of Clinical Endocrinology and Metabolism\n                      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.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"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\u2019 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\u2019 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.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"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.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}