{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T19:47:08Z","timestamp":1791229628454,"version":"4.1.0"},"reference-count":79,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T00:00:00Z","timestamp":1746144000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T00:00:00Z","timestamp":1746144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Diabetologia"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>This review describes a prolonged research endeavour to test the twin cycle hypothesis\u00a0that type 2 diabetes is caused by fat-induced dysfunction of the liver and pancreas, guided by the happenstance of clinical practice. Testing of the personal fat threshold hypothesis, that individuals exhibit different levels of tolerance to intra-organ fat accumulation, is also described. Both hypotheses predict that type 2 diabetes is potentially reversible by weight loss. The results of the Counterpoint study supported the twin cycle hypothesis, leading to a second study which determined that short-duration diabetes was more likely to remit following the 10\u201315 kg weight loss. It also confirmed that remission was durable over 6 months on an isoenergetic, normal diet. Subsequently, it was shown that weight loss caused an immediate decrease of pancreas fat only in people with type 2 diabetes and also that postprandial incretin spikes after bariatric surgery had no role in normalising fasting plasma glucose. DiRECT, a 2 year randomised controlled study, demonstrated clinical utility, observing functional beta cell capacity to return almost to normal over 12 months. A small group of participants regained weight and redeveloped type 2 diabetes, allowing observation that the underlying pathophysiological mechanisms during onset of diabetes were as postulated by the twin cycle hypothesis. Major clinical benefit was demonstrated after a further 3 year follow-up in routine care, halving the incidence of serious adverse effect compared with the standard treatment control group. In answer to the question of whether individuals have a personal fat threshold for tolerance of fat, stepwise weight loss in people with type 2 diabetes and BMI in the range 21\u201327 kg\/m<jats:sup>2<\/jats:sup> resulted in remission in 70%, with a wide range of fat thresholds. Type 2 diabetes can be regarded as a condition of homogenous aetiology in genetically heterogenous individuals.<\/jats:p>\n          <jats:p>\n            <jats:bold>Graphical Abstract<\/jats:bold>\n          <\/jats:p>","DOI":"10.1007\/s00125-025-06428-0","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T15:14:13Z","timestamp":1746198853000},"page":"1375-1389","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Aetiology of type 2 diabetes: an experimental medicine odyssey"],"prefix":"10.1007","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6273-0170","authenticated-orcid":false,"given":"Roy","family":"Taylor","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,2]]},"reference":[{"key":"6428_CR1","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1093\/oxfordjournals.bmb.a072322","volume":"45","author":"R Taylor","year":"1989","unstructured":"Taylor R (1989) Aetiology of non-insulin dependent diabetes. Br Med Bull 45:73\u201391","journal-title":"Br Med Bull"},{"key":"6428_CR2","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1111\/j.1464-5491.1990.tb01417.x","volume":"7","author":"AB Johnson","year":"1990","unstructured":"Johnson AB, Argyraki M, Thow JC et al (1990) Effects of intensive dietary treatment on insulin-stimulated skeletal muscle glycogen synthase activation and insulin secretion in newly presenting type 2 diabetic patients. Diabetic Med 7:420\u2013428","journal-title":"Diabetic Med"},{"key":"6428_CR3","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1042\/cs0820219","volume":"82","author":"AB Johnson","year":"1992","unstructured":"Johnson AB, Argyraki M, Thow JC et al (1992) Effect of increased free fatty acid supply on glucose metabolism and skeletal muscle glycogen synthase activity in normal man. Clin Sci 82:219\u2013226","journal-title":"Clin Sci"},{"key":"6428_CR4","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/0026-0495(91)90106-7","volume":"40","author":"AB Johnson","year":"1991","unstructured":"Johnson AB, Argyraki M, Thow JC et al (1991) Impaired activation of muscle glycogen synthase in non-insulin dependent diabetes mellitus is unrelated to the degree of obesity. Metab Clin Exp 40:252\u2013260","journal-title":"Metab Clin Exp"},{"key":"6428_CR5","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1056\/NEJM199001253220403","volume":"322","author":"GI Shulman","year":"1990","unstructured":"Shulman GI, Rothman DL, Jue T et al (1990) Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin dependent diabetes by {+13}C nuclear magnetic resonance spectroscopy. N Engl J Med 322:223\u2013228","journal-title":"N Engl J Med"},{"key":"6428_CR6","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1002\/mrm.1910270103","volume":"27","author":"R Taylor","year":"1992","unstructured":"Taylor R, Price TB, Rothman DL et al (1992) Validation of 13C NMR measurement of human skeletal muscle glycogen by direct biochemical assay of needle biopsy samples. Magn Reson Med 27:13\u201320","journal-title":"Magn Reson Med"},{"key":"6428_CR7","doi-asserted-by":"crossref","first-page":"E224","DOI":"10.1152\/ajpcell.1993.265.3.C801","volume":"265","author":"R Taylor","year":"1993","unstructured":"Taylor R, Price TB, Katz LD et al (1993) Direct measurement of change in muscle glycogen concentration after a mixed meal in normal subjects. Am J Physiol 265:E224\u2013E229","journal-title":"Am J Physiol"},{"key":"6428_CR8","first-page":"E286","volume":"284","author":"PE Carey","year":"2003","unstructured":"Carey PE, Halliday J, Snaar JEM et al (2003) Direct assessment of muscle glycogen storage after mixed meals in normal and type 2 diabetic subjects. Am J Physiol 284:E286-294","journal-title":"Am J Physiol"},{"key":"6428_CR9","doi-asserted-by":"publisher","first-page":"12587","DOI":"10.1073\/pnas.0705408104","volume":"104","author":"KF Petersen","year":"2007","unstructured":"Petersen KF, Dufour S, Savage DB et al (2007) The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc Natl Acad Sci U S A 104:12587\u201312594","journal-title":"Proc Natl Acad Sci U S A"},{"key":"6428_CR10","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1042\/CS20140681","volume":"128","author":"M Macauley","year":"2015","unstructured":"Macauley M, Smith FE, Thelwall PE et al (2015) Diurnal variation in skeletal muscle and liver glycogen in humans with normal health and Type 2 diabetes. Clin Sci (Lond) 128:707\u2013713","journal-title":"Clin Sci (Lond)"},{"key":"6428_CR11","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1093\/qjmed\/90.4.271","volume":"90","author":"AJ Turnbull","year":"1997","unstructured":"Turnbull AJ, Mitchison HC, Peaston RTP et al (1997) The prevalence of hereditary haemochromatosis in a diabetic population in North-East England. Q J Med 90:271\u2013275","journal-title":"Q J Med"},{"key":"6428_CR12","doi-asserted-by":"publisher","first-page":"2288","DOI":"10.2337\/db07-1828","volume":"57","author":"B Ravikumar","year":"2008","unstructured":"Ravikumar B, Gerrard J, Dalla Man C et al (2008) Pioglitazone decreases fasting and postprandial endogenous glucose production in proportion to decrease in hepatic triglyceride content. Diabetes 57:2288\u20132295","journal-title":"Diabetes"},{"key":"6428_CR13","doi-asserted-by":"publisher","first-page":"E275","DOI":"10.1152\/ajpendo.00424.2001","volume":"283","author":"P Singhal","year":"2002","unstructured":"Singhal P, Caumo A, Carey PE et al (2002) Regulation of endogenous glucose production after a mixed meal in type 2 diabetes. Am J Physiol Endocrinol Metab 283:E275\u2013E283","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"6428_CR14","doi-asserted-by":"publisher","first-page":"603","DOI":"10.2337\/diabetes.54.3.603","volume":"54","author":"KF Petersen","year":"2005","unstructured":"Petersen KF, Dufour S, Befroy D et al (2005) Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 54:603\u2013608","journal-title":"Diabetes"},{"key":"6428_CR15","doi-asserted-by":"publisher","first-page":"2042","DOI":"10.2337\/diabetes.53.8.2042","volume":"53","author":"R Basu","year":"2004","unstructured":"Basu R, Basu A, Johnson CM et al (2004) Insulin dose-response curves for stimulation of splanchnic glucose uptake and suppression of endogenous glucose production differ in nondiabetic humans and are abnormal in people with type 2 diabetes. Diabetes 53:2042\u20132050","journal-title":"Diabetes"},{"key":"6428_CR16","first-page":"E732","volume":"256","author":"H Yki-Jarvinen","year":"1989","unstructured":"Yki-Jarvinen H, Helve E, Sane T et al (1989) Insulin inhibition of overnight glucose production and gluconeogenesis from lactate in NIDDM. Am J Physiol 256:E732\u2013E739","journal-title":"Am J Physiol"},{"key":"6428_CR17","doi-asserted-by":"publisher","first-page":"850","DOI":"10.2337\/diab.41.7.850","volume":"41","author":"BC Martin","year":"1992","unstructured":"Martin BC, Warram JH, Rosner B et al (1992) Familial clustering of insulin sensitivity. Diabetes 41:850\u2013854","journal-title":"Diabetes"},{"key":"6428_CR18","doi-asserted-by":"publisher","first-page":"909","DOI":"10.7326\/0003-4819-113-12-909","volume":"113","author":"JH Warram","year":"1990","unstructured":"Warram JH, Martin BC, Krolewski AS et al (1990) Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Int Med 113:909\u2013915","journal-title":"Ann Int Med"},{"key":"6428_CR19","doi-asserted-by":"publisher","first-page":"10878","DOI":"10.1073\/pnas.91.23.10878","volume":"91","author":"Y Lee","year":"1994","unstructured":"Lee Y, Hirose H, Ohneda M et al (1994) Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships. Proc Natl Acad Sci U S A 91:10878\u201310882","journal-title":"Proc Natl Acad Sci U S A"},{"key":"6428_CR20","doi-asserted-by":"publisher","first-page":"2461","DOI":"10.2337\/diabetes.52.10.2461","volume":"52","author":"S Kashyap","year":"2003","unstructured":"Kashyap S, Belfort R, Gastaldelli A et al (2003) A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes 52:2461\u20132474","journal-title":"Diabetes"},{"key":"6428_CR21","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1016\/S0026-0495(03)00102-1","volume":"52","author":"H Storgaard","year":"2003","unstructured":"Storgaard H, Jensen CB, Vaag AA et al (2003) Insulin secretion after short- and long-term low-grade free fatty acid infusion in men with increased risk of developing type 2 diabetes. Metab Clin Exp 52:885\u2013894","journal-title":"Metab Clin Exp"},{"key":"6428_CR22","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1038\/ijo.2009.245","volume":"34","author":"Y Lee","year":"2010","unstructured":"Lee Y, Lingvay I, Szczepaniak LS et al (2010) Pancreatic steatosis: harbinger of type 2 diabetes in obese rodents. Int J Obes (Lond) 34:396\u2013400","journal-title":"Int J Obes (Lond)"},{"key":"6428_CR23","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1111\/ajt.15698","volume":"20","author":"DM Tremmel","year":"2020","unstructured":"Tremmel DM, Feeney AK, Mitchell SA et al (2020) Hypertension, but not body mass index, is predictive of increased pancreatic lipid content and islet dysfunction. Am J Transplant 20:1105\u20131115","journal-title":"Am J Transplant"},{"key":"6428_CR24","first-page":"410","volume-title":"Clinics in endocringology and metabolism","author":"GF Cahill","year":"1976","unstructured":"Cahill GF (1976) Starvation in man. In: Albrink MJ (ed) Clinics in endocringology and metabolism. W B. Saunders, London, p 410"},{"key":"6428_CR25","doi-asserted-by":"publisher","first-page":"2506","DOI":"10.1007\/s00125-011-2204-7","volume":"54","author":"EL Lim","year":"2011","unstructured":"Lim EL, Hollingsworth KG, Aribisala BS et al (2011) Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 54:2506\u20132514","journal-title":"Diabetologia"},{"key":"6428_CR26","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1038\/nature13478","volume":"510","author":"RJ Perry","year":"2014","unstructured":"Perry RJ, Samuel VT, Petersen KF et al (2014) The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 510:84\u201391","journal-title":"Nature"},{"key":"6428_CR27","doi-asserted-by":"publisher","first-page":"114746","DOI":"10.1016\/j.celrep.2024.114746","volume":"43","author":"W Xu","year":"2024","unstructured":"Xu W, Zhang D, Ma Y et al (2024) Ceramide synthesis inhibitors prevent lipid-induced insulin resistance through the DAG-PKCepsilon-insulin receptor(T1150) phosphorylation pathway. Cell Rep 43:114746","journal-title":"Cell Rep"},{"key":"6428_CR28","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1016\/j.cmet.2017.10.004","volume":"27","author":"RJ Perry","year":"2018","unstructured":"Perry RJ, Peng L, Cline GW et al (2018) Mechanisms by which a very-low-calorie diet reverses hyperglycemia in a rat model of type 2 diabetes. Cell Metab 27:210-217 e213","journal-title":"Cell Metab"},{"key":"6428_CR29","doi-asserted-by":"publisher","first-page":"808","DOI":"10.2337\/dc15-1942","volume":"39","author":"S Steven","year":"2016","unstructured":"Steven S, Hollingsworth KG, Al-Mrabeh A et al (2016) Very low-calorie diet and 6 months of weight stability in type 2 diabetes: pathophysiological changes in responders and nonresponders. Diabetes Care 39:808\u2013815","journal-title":"Diabetes Care"},{"key":"6428_CR30","doi-asserted-by":"publisher","first-page":"1554","DOI":"10.1111\/dme.13426","volume":"34","author":"L Rehackova","year":"2017","unstructured":"Rehackova L, Ara\u00fajo-Soares V, Adamson AJ et al (2017) Acceptability of a very low energy diet in type 2 diabetes: patient experiences and behaviour regulation. Diabetic Med 34:1554\u20131567","journal-title":"Diabetic Med"},{"key":"6428_CR31","doi-asserted-by":"publisher","first-page":"1465","DOI":"10.3390\/nu13051465","volume":"13","author":"S Melhem","year":"2021","unstructured":"Melhem S, Steven S, Taylor R et al (2021) Effect of weight loss by low-calorie diet on cardiovascular health in type 2 diabetes: an interventional cohort study. Nutrients 13:1465","journal-title":"Nutrients"},{"key":"6428_CR32","doi-asserted-by":"publisher","first-page":"2025","DOI":"10.2337\/db06-0068","volume":"55","author":"C Guidone","year":"2006","unstructured":"Guidone C, Manco M, Valera-Mora E et al (2006) Mechanisms of recovery from type 2 diabetes after malabsorptive bariatric surgery. Diabetes 55:2025\u20132031","journal-title":"Diabetes"},{"key":"6428_CR33","doi-asserted-by":"publisher","first-page":"2741","DOI":"10.2337\/dc12-2316","volume":"36","author":"I Lingvay","year":"2013","unstructured":"Lingvay I, Guth E, Islam A et al (2013) Rapid improvement in diabetes after gastric bypass surgery: is it the diet or surgery? Diabetes Care 36:2741\u20132747","journal-title":"Diabetes Care"},{"key":"6428_CR34","doi-asserted-by":"publisher","first-page":"1723","DOI":"10.1111\/dme.13257","volume":"33","author":"S Steven","year":"2016","unstructured":"Steven S, Hollingsworth KG, Small PK et al (2016) Calorie restriction and not glucagon-like peptide-1 explains the acute improvement in glucose control after gastric bypass in type 2 diabetes. Diabetic Med J 33:1723\u20131731","journal-title":"Diabetic Med J"},{"key":"6428_CR35","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1056\/NEJMoa2003697","volume":"383","author":"M Yoshino","year":"2020","unstructured":"Yoshino M, Kayser BD, Yoshino J et al (2020) Effects of diet versus gastric bypass on metabolic function in diabetes. N Engl J Med 383:721\u2013732","journal-title":"N Engl J Med"},{"key":"6428_CR36","doi-asserted-by":"publisher","first-page":"158","DOI":"10.2337\/dc15-0750","volume":"39","author":"S Steven","year":"2016","unstructured":"Steven S, Hollingsworth KG, Small P et al (2016) Weight loss decreases excess pancreatic triacylglycerol specifically in type 2 diabetes. Diabetes Care 39:158\u2013165","journal-title":"Diabetes Care"},{"key":"6428_CR37","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.2337\/dc12-1805","volume":"36","author":"R Taylor","year":"2013","unstructured":"Taylor R (2013) Type 2 diabetes: etiology and reversibility. Diabetes Care 36:1047\u20131055","journal-title":"Diabetes Care"},{"key":"6428_CR38","doi-asserted-by":"crossref","first-page":"e135","DOI":"10.1111\/dme.12081","volume":"30","author":"S Steven","year":"2013","unstructured":"Steven S, Lim EL, Taylor R (2013) Population response to information on reversibility of type 2 diabetes. Diabetic Med J 30:e135-138","journal-title":"Diabetic Med J"},{"key":"6428_CR39","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/s12875-016-0406-2","volume":"17","author":"WS Leslie","year":"2016","unstructured":"Leslie WS, Ford I, Sattar N et al (2016) The Diabetes Remission Clinical Trial (DiRECT): protocol for a cluster randomised trial. BMC Fam Pract 17:20","journal-title":"BMC Fam Pract"},{"key":"6428_CR40","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1007\/s00125-017-4503-0","volume":"61","author":"R Taylor","year":"2017","unstructured":"Taylor R, Leslie WS, Barnes AC et al (2017) Clinical and metabolic features of the randomised controlled Diabetes Remission Clinical Trial (DiRECT) cohort. Diabetologia 61:589\u2013598","journal-title":"Diabetologia"},{"key":"6428_CR41","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1111\/dme.14282","volume":"37","author":"N Oliver","year":"2020","unstructured":"Oliver N, Holt RIG (2020) The James Lind Alliance Research Priorities for Diabetes revisited. Diabetic Med J 37:511\u2013512","journal-title":"Diabetic Med J"},{"key":"6428_CR42","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1111\/dme.13851","volume":"36","author":"R Taylor","year":"2019","unstructured":"Taylor R, Barnes AC (2019) Can type 2 diabetes be reversed and how can this best be achieved? James Lind Alliance research priority number one. Diabetic Med 36:308\u2013315","journal-title":"Diabetic Med"},{"key":"6428_CR43","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1016\/S0140-6736(17)33102-1","volume":"391","author":"ME Lean","year":"2018","unstructured":"Lean ME, Leslie WS, Barnes AC et al (2018) Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet 391:541\u2013551","journal-title":"Lancet"},{"key":"6428_CR44","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1038\/s41574-019-0186-6","volume":"15","author":"MEJ Lean","year":"2019","unstructured":"Lean MEJ (2019) Low-calorie diets in the management of type 2 diabetes mellitus. Nat Rev Endocrinol 15:251\u2013252","journal-title":"Nat Rev Endocrinol"},{"key":"6428_CR45","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/j.cmet.2019.11.018","volume":"31","author":"A Al-Mrabeh","year":"2020","unstructured":"Al-Mrabeh A, Zhyzhneuskaya SV, Peters C et al (2020) Hepatic lipoprotein export and remission of human type 2 diabetes after weight loss. Cell Metab 31:233-249 e234","journal-title":"Cell Metab"},{"key":"6428_CR46","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1016\/j.cmet.2018.07.003","volume":"28","author":"R Taylor","year":"2018","unstructured":"Taylor R, Al-Mrabeh A, Zhyzhneuskaya S et al (2018) Remission of human type 2 diabetes requires decrease in liver and pancreas fat content but is dependent upon capacity for beta cell recovery. Cell Metab 28:547-556 e543","journal-title":"Cell Metab"},{"key":"6428_CR47","doi-asserted-by":"publisher","first-page":"813","DOI":"10.2337\/dc19-0371","volume":"43","author":"SV Zhyzhneuskaya","year":"2020","unstructured":"Zhyzhneuskaya SV, Al-Mrabeh A, Peters C et al (2020) Time course of normalization of functional beta-cell capacity in the diabetes remission clinical trial after weight loss in type 2 diabetes. Diabetes Care 43:813\u2013820","journal-title":"Diabetes Care"},{"key":"6428_CR48","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/S2213-8587(23)00385-6","volume":"12","author":"MEJ Lean","year":"2024","unstructured":"Lean MEJ, Leslie WS, Barnes AC et al (2024) Five-year follow-up of the randomised Diabetes Remission Clinical Trial (DiRECT): extension study of continued support for weight loss maintenance. Lancet Diabetes Endocrinol 12:233\u2013246","journal-title":"Lancet Diabetes Endocrinol"},{"key":"6428_CR49","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1111\/jhn.12839","volume":"34","author":"N Brosnahan","year":"2021","unstructured":"Brosnahan N, Leslie W, Mccombie L et al (2021) Brief formula low-energy-diet for relapse management during weight loss maintenance in the Diabetes Remission Clinical Trial (DiRECT). J Hum Nutr Diet 34:472\u2013479","journal-title":"J Hum Nutr Diet"},{"key":"6428_CR50","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1002\/oby.24024","volume":"32","author":"K Taylor","year":"2024","unstructured":"Taylor K, Indulkar T, Thompson B et al (2024) Early outcomes of referrals to the English National Health Service Digital Weight Management Programme. Obesity 32:1083\u20131092","journal-title":"Obesity"},{"key":"6428_CR51","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1038\/s41591-023-02278-8","volume":"29","author":"M O'hearn","year":"2023","unstructured":"O\u2019hearn M, Lara-Castor L, Cudhea F et al (2023) Incident type 2 diabetes attributable to suboptimal diet in 184 countries. Nat Med 29:982\u2013995","journal-title":"Nat Med"},{"key":"6428_CR52","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1007\/s00125-023-06048-6","volume":"67","author":"EW Gregg","year":"2024","unstructured":"Gregg EW, Chen H, Bancks MP et al (2024) Impact of remission from type 2 diabetes on long-term health outcomes: findings from the Look AHEAD study. Diabetologia 67:459\u2013469","journal-title":"Diabetologia"},{"key":"6428_CR53","doi-asserted-by":"publisher","first-page":"73","DOI":"10.15277\/bjd.2019.221","volume":"19","author":"D Nagi","year":"2019","unstructured":"Nagi D, Hambling C, Taylor R (2019) Remission of type 2 diabetes: a position statement from the Association of British Clinical Diabetologists (ABCD) and the Primary Care Diabetes Society (PCDS). Br J Diabetes 19:73\u201376","journal-title":"Br J Diabetes"},{"key":"6428_CR54","doi-asserted-by":"publisher","first-page":"2438","DOI":"10.2337\/dci21-0034","volume":"44","author":"MC Riddle","year":"2021","unstructured":"Riddle MC, Cefalu WT, Evans PH et al (2021) Consensus report: definition and interpretation of remission in type 2 diabetes. Diabetes Care 44:2438\u20132444","journal-title":"Diabetes Care"},{"key":"6428_CR55","unstructured":"World Health Organization (1980) WHO Expert Committee on Diabetes Mellitus: Second Report. World Health Organization Technical Report Series 646. WHO, Geneva"},{"key":"6428_CR56","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1016\/S2213-8587(24)00194-3","volume":"12","author":"J Valabhji","year":"2024","unstructured":"Valabhji J, Gorton T, Barron E et al (2024) Early findings from the NHS Type 2 Diabetes Path to Remission Programme: a prospective evaluation of real-world implementation. Lancet Diabetes Endo 12:653\u2013663","journal-title":"Lancet Diabetes Endo"},{"key":"6428_CR57","doi-asserted-by":"publisher","first-page":"1927","DOI":"10.1007\/s00125-021-05471-x","volume":"64","author":"WS Leslie","year":"2021","unstructured":"Leslie WS, Ali E, Harris L et al (2021) Antihypertensive medication needs and blood pressure control with weight loss in the Diabetes Remission Clinical Trial (DiRECT). Diabetologia 64:1927\u20131938","journal-title":"Diabetologia"},{"key":"6428_CR58","doi-asserted-by":"publisher","first-page":"958","DOI":"10.1056\/NEJMoa2410819","volume":"392","author":"AM Jastreboff","year":"2025","unstructured":"Jastreboff AM, Le Roux CW, Stefanski A et al (2025) Tirzepatide for obesity treatment and diabetes prevention. N Engl J Med 392:958\u2013971","journal-title":"N Engl J Med"},{"key":"6428_CR59","doi-asserted-by":"publisher","first-page":"1553","DOI":"10.1111\/dom.14725","volume":"24","author":"JPH Wilding","year":"2022","unstructured":"Wilding JPH, Batterham RL, Davies M et al (2022) Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension. Diabetes Obes Metab 24:1553\u20131564","journal-title":"Diabetes Obes Metab"},{"key":"6428_CR60","doi-asserted-by":"publisher","first-page":"1652","DOI":"10.1038\/s12276-023-01043-8","volume":"55","author":"J Son","year":"2023","unstructured":"Son J, Accili D (2023) Reversing pancreatic beta-cell dedifferentiation in the treatment of type 2 diabetes. Exp Mol Med 55:1652\u20131658","journal-title":"Exp Mol Med"},{"key":"6428_CR61","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1007\/BF00400195","volume":"34","author":"Ukpds","year":"1991","unstructured":"Ukpds (1991) UK Prospective Diabetes Study (UKPDS). VIII. Study design, progress and performance. Diabetologia 34:877\u2013890","journal-title":"Diabetologia"},{"key":"6428_CR62","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1080\/03014468500007621","volume":"12","author":"S Rosenbaum","year":"1985","unstructured":"Rosenbaum S, Skinner RK, Knight IB et al (1985) A survey of heights and weights of adults in Great Britain, 1980. Ann Hum Biol 12:115\u2013127","journal-title":"Ann Hum Biol"},{"key":"6428_CR63","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1007\/BF00423146","volume":"16","author":"RJ Jarrett","year":"1979","unstructured":"Jarrett RJ, Keen H, Fuller JH et al (1979) Worsening to diabetes in men with impaired glucose tolerance (\u201cborderline diabetes\u201d). Diabetologia 16:25\u201330","journal-title":"Diabetologia"},{"key":"6428_CR64","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1056\/NEJMoa010492","volume":"345","author":"FB Hu","year":"2001","unstructured":"Hu FB, Manson JE, Stampfer MJ et al (2001) Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. N Engl J Med 345:790\u2013797","journal-title":"N Engl J Med"},{"key":"6428_CR65","doi-asserted-by":"publisher","first-page":"S51","DOI":"10.1111\/j.1753-4887.1999.tb01788.x","volume":"57","author":"PH Bennett","year":"1999","unstructured":"Bennett PH (1999) Type 2 diabetes among the Pima Indians of Arizona: an epidemic attributable to environmental change? Nutr Rev 57:S51-54","journal-title":"Nutr Rev"},{"key":"6428_CR66","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1042\/CS20140553","volume":"128","author":"R Taylor","year":"2015","unstructured":"Taylor R, Holman R (2015) Normal weight individuals who develop type 2 diabetes: the personal fat threshold. Clin Sci 128:405\u2013410. https:\/\/doi.org\/10.1042\/CS20140553","journal-title":"Clin Sci"},{"key":"6428_CR67","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1042\/CS20230586","volume":"137","author":"R Taylor","year":"2023","unstructured":"Taylor R, Barnes AC, Hollingsworth KG et al (2023) Aetiology of type 2 diabetes in people with a \u201cnormal\u201d body mass index: testing the personal fat threshold hypothesis. Clin Sci (Lond) 137:1333\u20131346. https:\/\/doi.org\/10.1042\/CS20230586","journal-title":"Clin Sci (Lond)"},{"key":"6428_CR68","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1001\/jama.1914.02570110041011","volume":"63","author":"FM Allen","year":"1914","unstructured":"Allen FM (1914) Studies concerning diabetes. JAMA 63:939\u2013943. https:\/\/doi.org\/10.1001\/jama.1914.02570110041011","journal-title":"JAMA"},{"key":"6428_CR69","doi-asserted-by":"publisher","first-page":"E462","DOI":"10.1152\/ajpendo.00064.2004","volume":"288","author":"LS Szczepaniak","year":"2005","unstructured":"Szczepaniak LS, Nurenberg P, Leonard D et al (2005) Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 288:E462-468","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"6428_CR70","doi-asserted-by":"publisher","first-page":"e157906","DOI":"10.1172\/jci.insight.157906","volume":"7","author":"KF Petersen","year":"2022","unstructured":"Petersen KF, Dufour S, Li F et al (2022) Ethnic and sex differences in hepatic lipid content and related cardiometabolic parameters in lean individuals. JCI Insight 7:e157906","journal-title":"JCI Insight"},{"key":"6428_CR71","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.1016\/j.metabol.2016.01.001","volume":"65","author":"JM Hazelhurst","year":"2016","unstructured":"Hazelhurst JM (2016) Non-alcoholic fatty liver disease and diabetes. Metab Clin Exp 65:1096\u20131108","journal-title":"Metab Clin Exp"},{"key":"6428_CR72","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1038\/s41575-021-00448-y","volume":"18","author":"G Targher","year":"2021","unstructured":"Targher G, Corey KE, Byrne CD et al (2021) The complex link between NAFLD and type 2 diabetes mellitus - mechanisms and treatments. Nat Rev Gastroenterol Hepatol 18:599\u2013612","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"6428_CR73","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1016\/S2213-8587(19)30068-3","volume":"7","author":"MEJ Lean","year":"2019","unstructured":"Lean MEJ, Leslie WS, Barnes AC et al (2019) Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomised trial. Lancet Diabetes Endocrinol 7:344\u2013355","journal-title":"Lancet Diabetes Endocrinol"},{"key":"6428_CR74","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1016\/S2213-8587(24)00157-8","volume":"12","author":"R Taylor","year":"2024","unstructured":"Taylor R (2024) Understanding the cause of type 2 diabetes. Lancet Diabetes Endocrinol 12:664\u2013673","journal-title":"Lancet Diabetes Endocrinol"},{"key":"6428_CR75","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1038\/ng.3714","volume":"49","author":"LA Lotta","year":"2016","unstructured":"Lotta LA, Gulati P, Day FR et al (2016) Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance. Nat Genet 49:17\u201326","journal-title":"Nat Genet"},{"key":"6428_CR76","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1016\/j.ypmed.2007.07.020","volume":"45","author":"EW Gregg","year":"2007","unstructured":"Gregg EW, Cheng YJ, Narayan KM et al (2007) The relative contributions of different levels of overweight and obesity to the increased prevalence of diabetes in the United States: 1976\u20132004. Prev Med 45:348\u2013352","journal-title":"Prev Med"},{"key":"6428_CR77","first-page":"1","volume":"34","author":"A Hrdlicka","year":"1908","unstructured":"Hrdlicka A (1908) Physiological and medical observations amongs the Indians of southwestern United States and north Mexico. Bureau Am Ethnol Bull 34:1\u2013460","journal-title":"Bureau Am Ethnol Bull"},{"key":"6428_CR78","doi-asserted-by":"publisher","first-page":"2033","DOI":"10.1001\/jama.1940.02810500001001","volume":"115","author":"EP Joslin","year":"1940","unstructured":"Joslin EP (1940) The universality of diabetes: a survey of diabetes mortality in Arizona. JAMA 115:2033\u20132038","journal-title":"JAMA"},{"key":"6428_CR79","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1111\/dme.12039","volume":"30","author":"R Taylor","year":"2012","unstructured":"Taylor R (2012) Banting memorial lecture 2012 - reversing the twin cycles of type 2 diabetes. Diabetic Med 30:267\u2013275","journal-title":"Diabetic Med"}],"container-title":["Diabetologia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-025-06428-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00125-025-06428-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-025-06428-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T15:02:33Z","timestamp":1750258953000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00125-025-06428-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,2]]},"references-count":79,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2025,7]]}},"alternative-id":["6428"],"URL":"https:\/\/doi.org\/10.1007\/s00125-025-06428-0","relation":{},"ISSN":["0012-186X","1432-0428"],"issn-type":[{"value":"0012-186X","type":"print"},{"value":"1432-0428","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,2]]},"assertion":[{"value":"20 December 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 February 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 May 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"I was very fortunate to be introduced the thinking of Claude Bernard as a medical student by Reginald Passmore, Professor of Physiology at Edinburgh University. The described studies were brilliantly executed by Clinical Research fellows P. Singhal, B. Ravikumar, P. Carey, E. Lin Lim, S. Steven, M. Macauley, C. Peters and S. Zhyzyneuskaya. G. I. Shulman pioneered in vivo magnetic resonance studies of metabolism and has been a long-term friend and collaborator. The research depended upon development of new magnetic resonance methodology by the physicists K.G. Hollingsworth, A. Blamire, P. Thelwall and P. Morris. I am grateful to A. Al-Mrabeh for scientific input. M. E. J. Lean deserves special mention as collaborator on DiRECT, as do the wider DiRECT research team and especially A. C. Barnes and K. M. Irvine, research dietitians. K. F. Petersen and R. Holman have been excellent senior colleagues on the journey. K. G. M. M. Alberti created an excellent research environment in Newcastle and I am most grateful to him for support and advice. Finally, the research participants selflessly gave time, effort and blood, without which the research would not have been possible. No AI was used in writing this article.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"The research depended upon grants from Diabetes UK for Counterpoint, DiRECT, DiRECT follow-up and ReTUNE. Counterbalance was funded by the National Institute for Health Research Newcastle Biomedical Research Center and a NovoNordisk Research Foundation fellowship. The European Foundation for the Study of Diabetes funded the Pancreas study. The Medical Research Council funded the sabbatical at Yale and the physiological studies of muscle and liver were funded by The Wellcome Trust.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"RT has received academic lecture fees from Eli Lilly, Novartis, NovoNordisk and Abbott Laboratories and is an advisor to Fast800. He is a member of the Advisory Group for NHS England Type 2 Diabetes Path to Remission Programme.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Author\u2019s relationships and activities"}},{"value":"The author was the sole contributor to this review.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}