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One in six people has BMI &amp;lt;27 kg\/m2 at diagnosis, and their T2D is assumed to have different aetiology. The Personal Fat Threshold hypothesis postulated differing individual thresholds for lipid overspill and adverse effects on \u03b2-cell function. To test this hypothesis, people with Type 2 diabetes and body mass index &amp;lt;27kg\/m2 (n = 20) underwent repeated 5% weight loss cycles. Metabolic assessments were carried out at stable weight after each cycle and after 12 months. To determine how closely metabolic features returned to normal, 20 matched normoglycemic controls were studied once. Between baseline and 12 months: BMI fell (mean \u00b1 SD), 24.8 \u00b1 0.4 to 22.5 \u00b1 0.4 kg\/m2 (P&amp;lt;0.0001) (controls: 21.5 \u00b1 0.5); total body fat, 32.1 \u00b1 1.5 to 27.6 \u00b1 1.8% (P&amp;lt;0.0001) (24.6 \u00b1 1.5). Liver fat content and fat export fell to normal as did fasting plasma insulin. Post-meal insulin secretion increased but remained subnormal. Sustained diabetes remission (HbA1c &amp;lt; 48 mmol\/mol off all glucose-lowering agents) was achieved by 70% (14\/20) by initial weight loss of 6.5 (5.5\u201310.2)%. Correction of concealed excess intra-hepatic fat reduced hepatic fat export, with recovery of \u03b2-cell function, glycaemic improvement in all and return to a non-diabetic metabolic state in the majority of this group with BMI &amp;lt;27 kg\/m2 as previously demonstrated for overweight or obese groups. The data confirm the Personal Fat Threshold hypothesis: aetiology of Type 2 diabetes does not depend on BMI. This pathophysiological insight has major implications for management.<\/jats:p>","DOI":"10.1042\/cs20230586","type":"journal-article","created":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T09:01:04Z","timestamp":1692349264000},"page":"1333-1346","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Aetiology of Type 2 diabetes in people with a \u2018normal\u2019 body mass index: testing the personal fat threshold hypothesis"],"prefix":"10.1042","volume":"137","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6273-0170","authenticated-orcid":false,"given":"Roy","family":"Taylor","sequence":"first","affiliation":[{"name":"1Magnetic Resonance Centre, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison\u00a0C.","family":"Barnes","sequence":"additional","affiliation":[{"name":"1Magnetic Resonance Centre, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kieren\u00a0G.","family":"Hollingsworth","sequence":"additional","affiliation":[{"name":"1Magnetic Resonance Centre, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keaton\u00a0M.","family":"Irvine","sequence":"additional","affiliation":[{"name":"1Magnetic Resonance Centre, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra\u00a0S.","family":"Solovyova","sequence":"additional","affiliation":[{"name":"2Faculty of Medical Sciences Professional Services, Newcastle University, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy","family":"Clark","sequence":"additional","affiliation":[{"name":"1Magnetic Resonance Centre, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tara","family":"Kelly","sequence":"additional","affiliation":[{"name":"1Magnetic Resonance Centre, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Martin-Ruiz","sequence":"additional","affiliation":[{"name":"3BioScreening Core Facility, Campus for Ageing and Vitality, Faculty of Medical Sciences, Newcastle University, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Romeres","sequence":"additional","affiliation":[{"name":"4Department of Endocrinology, University of Virginia, Charlottesville, VA, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Koulman","sequence":"additional","affiliation":[{"name":"5Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Box 289, Cambridge Biomedical Campus, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire\u00a0M.","family":"Meek","sequence":"additional","affiliation":[{"name":"5Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Box 289, Cambridge Biomedical Campus, Cambridge, U.K."},{"name":"6Wolfson Diabetes and Endocrine Centre, Cambridge Universities NHS Foundation Trust, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Jenkins","sequence":"additional","affiliation":[{"name":"5Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Box 289, Cambridge Biomedical Campus, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Cobelli","sequence":"additional","affiliation":[{"name":"7Department of Woman and Child's Health, University of Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rury\u00a0R.","family":"Holman","sequence":"additional","affiliation":[{"name":"8Diabetes Trials Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2023,8,31]]},"reference":[{"key":"2023083111003832200_B1","article-title":"IDF Diabetes Atlas","author":"Federation ID","year":"2021"},{"key":"2023083111003832200_B2","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1038\/s41575-021-00448-y","article-title":"The complex link between NAFLD and type 2 diabetes mellitus - mechanisms and treatments","volume":"18","author":"Targher","year":"2021","journal-title":"Nat. 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