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Whether similar adaptations are observed after the ingestion of a mixed-macronutrient meal is unclear.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>In a secondary analysis of data derived from two randomised, controlled trials, we studied the temporal responses of insulin clearance after the ingestion of a standardised breakfast meal consisting of cereal and milk in lean normoglycaemic individuals (<jats:italic>n<\/jats:italic>=12; Lean-NGT), normoglycaemic individuals with central obesity (<jats:italic>n<\/jats:italic>=11; Obese-NGT) and in people with type 2 diabetes (<jats:italic>n<\/jats:italic>=19). Pre-hepatic insulin secretion rates were determined by the deconvolution of C-peptide, and insulin clearance was calculated using a single-pool model. Insulin sensitivity was measured by an oral minimal model.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>There were divergent time course changes in insulin clearance between groups. In the Lean-NGT group, there was an immediate post-meal increase in insulin clearance compared with pre-meal values (<jats:italic>p<\/jats:italic>&lt;0.05), whereas insulin clearance remained stable at baseline values in Obese-NGT or declined slightly in the type 2 diabetes group (<jats:italic>p<\/jats:italic>&lt;0.05). The mean AUC for insulin clearance during the test was ~40% lower in the Obese-NGT (1.3 \u00b1 0.4 l min<jats:sup>\u22121<\/jats:sup> m<jats:sup>\u22122<\/jats:sup>) and type 2 diabetes (1.4 \u00b1 0.7 l min<jats:sup>\u22121<\/jats:sup> m<jats:sup>\u22122<\/jats:sup>) groups compared with Lean-NGT (1.9 \u00b1 0.5 l min<jats:sup>\u22121<\/jats:sup> m<jats:sup>\u22122<\/jats:sup>; <jats:italic>p<\/jats:italic>&lt;0.01), with no difference between the Obese-NGT and type 2 diabetes groups. HOMA-IR and glucagon AUC emerged as predictors of insulin clearance AUC, independent of BMI, age or insulin sensitivity (adjusted <jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>=0.670). Individuals with increased glucagon AUC had a 40% reduction in insulin clearance AUC (~ \u22120.75 l min<jats:sup>\u22121<\/jats:sup> m<jats:sup>\u22122<\/jats:sup>; <jats:italic>p<\/jats:italic>&lt;0.001).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions\/interpretation<\/jats:title>\n                <jats:p>The ingestion of a mixed-macronutrient meal augments differing temporal profiles in insulin clearance among individuals without type 2 diabetes, which is associated with HOMA-IR and the secretion of glucagon. Further research investigating the role of hepatic glucagon signalling in postprandial insulin kinetics is warranted.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>ISRCTN17563146 and ISRCTN95281775<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Graphical Abstract<\/jats:title>\n                \n              <\/jats:sec>","DOI":"10.1007\/s00125-024-06249-7","type":"journal-article","created":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T19:02:21Z","timestamp":1723575741000},"page":"2555-2567","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Elevations in plasma glucagon are associated with reduced insulin clearance after ingestion of a mixed-macronutrient meal in people with and without type 2 diabetes"],"prefix":"10.1007","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7275-4379","authenticated-orcid":false,"given":"Kieran","family":"Smith","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy S.","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wouter","family":"Peeters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Walker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Perazzolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naeimeh","family":"Atabaki-Pasdar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly A.","family":"Bowden Davies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fredrik","family":"Karpe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2648-6526","authenticated-orcid":false,"given":"Leanne","family":"Hodson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma J.","family":"Stevenson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2246-4925","authenticated-orcid":false,"given":"Daniel J.","family":"West","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,8,13]]},"reference":[{"issue":"6","key":"6249_CR1","doi-asserted-by":"publisher","first-page":"1649","DOI":"10.2337\/diabetes.54.6.1649","volume":"54","author":"JJ Meier","year":"2005","unstructured":"Meier JJ, Veldhuis JD, Butler PC (2005) Pulsatile insulin secretion dictates systemic insulin delivery by regulating hepatic insulin extraction in humans. 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Arla Foods Ingredients group P\/S had no role in the collection, analysis, or interpretation of data. Funding was supported by a Philanthropic Award to DJW from the Francis James Bell Endowment Fund, County Durham Community Foundation, UK.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"The authors declare 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":"KS designed and conducted the research, analysed the data and wrote the manuscript. SP performed oral minimal modelling. GST, WP, MW, SP, NA-P, KABD, FK, LH, EJS and DJW reviewed and edited the manuscript and contributed to interpretation of the data. All authors provided final approval of the final manuscript. KS, EJS and DJW acquired funding. DJW is the guarantor of this work and takes responsibility for the integrity of the data and the accuracy of the data analysis.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}