{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T02:01:46Z","timestamp":1780970506950,"version":"3.54.1"},"reference-count":50,"publisher":"American Diabetes Association","issue":"6","license":[{"start":{"date-parts":[[2024,3,26]],"date-time":"2024-03-26T00:00:00Z","timestamp":1711411200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["RE\/18\/6\/34217"],"award-info":[{"award-number":["RE\/18\/6\/34217"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000361","name":"Diabetes UK","doi-asserted-by":"publisher","award":["17\/0005594"],"award-info":[{"award-number":["17\/0005594"]}],"id":[{"id":"10.13039\/501100000361","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,6,1]]},"abstract":"<jats:sec>\n                  <jats:title\/>\n                  <jats:p>We aimed to unravel the mechanisms connecting adiposity to type 2 diabetes. We used MR-Clust to cluster independent genetic variants associated with body fat percentage (388 variants) and BMI (540 variants) based on their impact on type 2 diabetes. We identified five clusters of adiposity-increasing alleles associated with higher type 2 diabetes risk (unfavorable adiposity) and three clusters associated with lower risk (favorable adiposity). We then characterized each cluster based on various biomarkers, metabolites, and MRI-based measures of fat distribution and muscle quality. Analyzing the metabolic signatures of these clusters revealed two primary mechanisms connecting higher adiposity to reduced type 2 diabetes risk. The first involves higher adiposity in subcutaneous tissues (abdomen and thigh), lower liver fat, improved insulin sensitivity, and decreased risk of cardiometabolic diseases and diabetes complications. The second mechanism is characterized by increased body size and enhanced muscle quality, with no impact on cardiometabolic outcomes. Furthermore, our findings unveil diverse mechanisms linking higher adiposity to higher disease risk, such as cholesterol pathways or inflammation. These results reinforce the existence of adiposity-related mechanisms that may act as protective factors against type 2 diabetes and its complications, especially when accompanied by reduced ectopic liver fat.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Article Highlights<\/jats:title>\n               <\/jats:sec>","DOI":"10.2337\/db23-1005","type":"journal-article","created":{"date-parts":[[2024,3,26]],"date-time":"2024-03-26T18:46:43Z","timestamp":1711478803000},"page":"1012-1025","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":15,"title":["Genetic Evidence for Distinct Biological Mechanisms That Link Adiposity to Type 2 Diabetes: Toward Precision Medicine"],"prefix":"10.2337","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9010-8909","authenticated-orcid":false,"given":"Angela","family":"Abraham","sequence":"first","affiliation":[{"name":"1Joseph Banks Laboratories, College of Health and Science, University of Lincoln, Lincoln, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeleine","family":"Cule","sequence":"additional","affiliation":[{"name":"2Calico Life Sciences LLC, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjola","family":"Thanaj","sequence":"additional","affiliation":[{"name":"3Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Basty","sequence":"additional","affiliation":[{"name":"3Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Amin","family":"Hashemloo","sequence":"additional","affiliation":[{"name":"4Department of Life Sciences, Brunel University London, Uxbridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena P.","family":"Sorokin","sequence":"additional","affiliation":[{"name":"2Calico Life Sciences LLC, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Whitcher","sequence":"additional","affiliation":[{"name":"3Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, U.K."},{"name":"5MRI Unit, Department of Radiology, The Royal Marsden National Health Service Foundation Trust, London, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Burgess","sequence":"additional","affiliation":[{"name":"6Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimmy D.","family":"Bell","sequence":"additional","affiliation":[{"name":"3Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1604-2593","authenticated-orcid":false,"given":"Naveed","family":"Sattar","sequence":"additional","affiliation":[{"name":"7School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. Louise","family":"Thomas","sequence":"additional","affiliation":[{"name":"3Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9672-9477","authenticated-orcid":false,"given":"Hanieh","family":"Yaghootkar","sequence":"additional","affiliation":[{"name":"1Joseph Banks Laboratories, College of Health and Science, University of Lincoln, Lincoln, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2024,3,26]]},"reference":[{"key":"2024052018520557300_B1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.cmet.2021.12.012","article-title":"Why does obesity cause diabetes","volume":"34","author":"Klein","year":"2022","journal-title":"Cell Metab"},{"key":"2024052018520557300_B2","doi-asserted-by":"crossref","first-page":"1161521","DOI":"10.3389\/fendo.2023.1161521","article-title":"Obesity and type 2 diabetes mellitus: connections in epidemiology, pathogenesis, and treatments","volume":"14","author":"Ruze","year":"2023","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2024052018520557300_B3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11892-020-1285-4","article-title":"Heterogeneity in obesity: genetic basis and metabolic consequences","volume":"20","author":"Sulc","year":"2020","journal-title":"Curr Diab Rep"},{"key":"2024052018520557300_B4","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1038\/s41591-022-01790-7","article-title":"Heterogeneity in phenotype, disease progression and drug response in type 2 diabetes","volume":"28","author":"Nair","year":"2022","journal-title":"Nat Med"},{"key":"2024052018520557300_B5","doi-asserted-by":"crossref","first-page":"424","DOI":"10.3390\/jpm12030424","article-title":"Clinical and genetic predictors of glycemic control and weight loss response to liraglutide in patients with type 2 diabetes","volume":"12","author":"Kyriakidou","year":"2022","journal-title":"J Pers Med"},{"key":"2024052018520557300_B6","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1007\/s00125-021-05628-8","article-title":"Dietary carbohydrate restriction augments weight loss-induced improvements in glycaemic control and liver fat in individuals with type 2 diabetes: a randomised controlled trial","volume":"65","author":"Thomsen","year":"2022","journal-title":"Diabetologia"},{"key":"2024052018520557300_B7","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1093\/ajcn\/nqz133","article-title":"Metabolically healthy obesity: what\u2019s in a name","volume":"110","author":"Magkos","year":"2019","journal-title":"Am J Clin Nutr"},{"key":"2024052018520557300_B8","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.1007\/s00125-021-05484-6","article-title":"Are people with metabolically healthy obesity really healthy? 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