{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T16:58:22Z","timestamp":1781801902823,"version":"3.54.5"},"reference-count":36,"publisher":"American Diabetes Association","issue":"5","license":[{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"name":"NIH","award":["R01AG061378"],"award-info":[{"award-number":["R01AG061378"]}]},{"name":"NIH","award":["R33AG070455"],"award-info":[{"award-number":["R33AG070455"]}]},{"name":"CIFAR CBD Network"},{"name":"KNAW Ter Meulen Grant"},{"DOI":"10.13039\/501100023281","name":"Australian Youth and Health Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100023281","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Atheros Foundation"},{"name":"Royal Netherlands Academy of Arts & Sciences"},{"name":"Australian NHMRC","award":["APP1177797"],"award-info":[{"award-number":["APP1177797"]}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,5,1]]},"abstract":"<jats:sec>\n                    <jats:title>OBJECTIVE<\/jats:title>\n                    <jats:p>To investigate the long-term metabolic and hormonal consequences of sustained weight loss versus weight regain after 1 year of caloric restriction (CR), with attention to insulin resistance and type 2 diabetes risk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                    <jats:p>In the 2-year Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy 2 (CALERIE-2) trial (n = 220), participants were randomized to 25% CR or control diet. The intervention targeted weight loss over the first 6\u201312 months, followed by a 12-month maintenance phase. To assess weight-regain consequences, participants were stratified by weight trajectory regardless of randomization, and group differences were balanced by propensity score weighting. Cardiometabolic and hormonal markers of available participants (n = 190), as well as a biomarker-based estimate of biological age, were compared across weight trajectory groups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>At 12 months, weight loss ranged from 5.0 to 5.8 kg between groups. Between months 12 and 24, most participants either maintained weight (n = 112) or continued to lose weight (n = 58), whereas a smaller group regained &amp;gt;5% of baseline weight (n = 20). This group had the largest initial caloric reductions. Weight regain reversed improvements in insulin area under the curve and the ratio of insulin-like growth factor 1 (IGF-1) to insulin-like growth factor-binding protein 1, and sustained weight loss maintained metabolic benefits and was associated with greater reductions in biological age.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>Substantial weight loss followed by weight regain can attenuate or reverse CR-induced benefits on key regulators of the insulin\u2013IGF-1 nutrient-sensing pathway and markers of biological aging. Sustained, moderate weight loss more effectively improves insulin resistance and maintains favorable hormonal profiles linked to type 2 diabetes risk and aging biology.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/dc25-1911","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T15:48:17Z","timestamp":1773676097000},"page":"783-791","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":0,"title":["Weight Regain Reverses Caloric Restriction\u2013Induced Benefits on the Insulin\u2013IGF-1 Nutrient-Sensing Pathway: Post Hoc Analysis From the CALERIE-2 Randomized Controlled Trial"],"prefix":"10.2337","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3548-6728","authenticated-orcid":false,"given":"Moritz V.","family":"Warmbrunn","sequence":"first","affiliation":[{"name":"Charles Perkins Center, Faculty of Medicine and Health, University of Sydney 1 , Sydney, New South Wales, Australia"},{"name":"Department of Internal and Vascular Medicine, Amsterdam University Medical Centers 2 , Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cancer Epidemiology and Prevention Research, Cancer Care Alberta, Alberta Health Services 3 , Calgary, Alberta, Canada"},{"name":"Departments of Oncology and Community Health Sciences, University of Calgary, Calgary 4 , Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raaj","family":"Kishore Biswas","sequence":"additional","affiliation":[{"name":"Charles Perkins Center, Faculty of Medicine and Health, University of Sydney 1 , Sydney, New South Wales, Australia"},{"name":"Sydney Local Health District Clinical Research Centre, Royal Prince Alfred Hospital 5 , Camperdown, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Calen P.","family":"Ryan","sequence":"additional","affiliation":[{"name":"Robert N. Butler Columbia Aging Center, Mailman School of Public Health, Columbia University 6 , New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Harper","sequence":"additional","affiliation":[{"name":"Departments of Oncology and Community Health Sciences, University of Calgary, Calgary 4 , Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel W.","family":"Belsky","sequence":"additional","affiliation":[{"name":"Robert N. Butler Columbia Aging Center, Mailman School of Public Health, Columbia University 6 , New York, NY"},{"name":"Department of Epidemiology, Mailman School of Public Health, Columbia University 7 , New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Fiorito","sequence":"additional","affiliation":[{"name":"Clinical Bioinformatics Unit, IRCCS Istituto Giannina Gaslini 8 , Genoa, Italy"},{"name":"MRC-PHE Centre for Environment and Health, Imperial College London 9 , London, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8500-5537","authenticated-orcid":false,"given":"Luigi","family":"Fontana","sequence":"additional","affiliation":[{"name":"Charles Perkins Center, Faculty of Medicine and Health, University of Sydney 1 , Sydney, New South Wales, Australia"},{"name":"Department of Endocrinology, Royal Prince Alfred Hospital 10 , Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"2026061812472044300_B1","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s41580-021-00411-4","article-title":"Molecular mechanisms of dietary restriction promoting health and longevity","volume":"23","author":"Green","year":"2022","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2026061812472044300_B2","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1038\/s42255-019-0121-0","article-title":"A nutritional memory effect counteracts benefits of dietary restriction in old mice","volume":"1","author":"Hahn","year":"2019","journal-title":"Nat Metab"},{"key":"2026061812472044300_B3","doi-asserted-by":"crossref","first-page":"e676","DOI":"10.3399\/bjgp17X692309","article-title":"Epidemiology of adult overweight recording and management by UK GPs: a systematic review","volume":"67","author":"McLaughlin","year":"2017","journal-title":"Br J Gen Pract"},{"key":"2026061812472044300_B4","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1001\/jama.2017.7092","article-title":"Associations of weight gain from early to middle adulthood with major health outcomes later in life","volume":"318","author":"Zheng","year":"2017","journal-title":"JAMA"},{"key":"2026061812472044300_B5","doi-asserted-by":"crossref","first-page":"2392","DOI":"10.1056\/NEJMoa1014296","article-title":"Changes in diet and lifestyle and long-term weight gain in women and men","volume":"364","author":"Mozaffarian","year":"2011","journal-title":"N Engl J Med"},{"key":"2026061812472044300_B6","doi-asserted-by":"crossref","first-page":"e000415","DOI":"10.1136\/bmjdrc-2017-000415","article-title":"Insulin-sensitive and insulin-resistant obese and non-obese phenotypes: role in prediction of incident pre-diabetes in a longitudinal biracial cohort","volume":"5","author":"Owei","year":"2017","journal-title":"BMJ Open Diabetes Res Care"},{"key":"2026061812472044300_B7","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1016\/S0140-6736(09)60619-X","article-title":"Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study","volume":"373","author":"Tab\u00e1k","year":"2009","journal-title":"Lancet"},{"key":"2026061812472044300_B8","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1016\/S0140-6736(09)61457-4","article-title":"10-Year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study","volume":"374","author":"Knowler","year":"2009","journal-title":"Lancet"},{"key":"2026061812472044300_B9","doi-asserted-by":"crossref","first-page":"S167","DOI":"10.2337\/dc25-S008","article-title":"8. 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