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We hypothesized that distinct insulin\u2010derived mechanisms and lipid profiles discriminate sex differences and can be used to identify subjects at higher risk to develop diabetes\u2010related complications.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The PREVADIAB2 study evaluated metabolic alterations after 5\u2009years in individuals initially free of Type 2 Diabetes (PREVADIAB1). In this analysis, 953 participants were stratified into clusters using hierarchical clustering based on insulinogenic index (IGI), fasting insulin secretion rate, HOMA\u2010IR, and fasting insulin clearance. A subset of participants (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009488) had their lipidome assessed using LC\/MS\u2010QTOF.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Four clusters were identified: Liver Sensitive (LS), Pancreas Glucose Sensitive (PGS), Insulin Deficient (ID), and Insulin Resistant (IR), each with distinct dysglycemia risk. While metabolic features were similar across sexes, the parameter thresholds differed, resulting in sex\u2010specific lipidomic profiles. Women exhibited higher levels of circulating dihydroceramides (5.3\u2009\u00b1\u20091.9 vs. 4.7\u2009\u00b1\u20091.8,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.001), associated with de novo ceramide synthesis, and elevated sphingomyelins (SM), suggesting altered lipid metabolism. Conversely, the ceramide\u2010to\u2010SM ratio was higher in men (1.04\u2009\u00b1\u2009.21 vs. .90\u2009\u00b1\u2009.18,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.001). Except for the LS cluster, all other clusters exhibit distinct lipid signatures associated with metabolic dysfunction, further accentuated by specific lipid profile sex differences.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Distinct insulin\u2010related metabolic features and sex identify different phenotypes with distinct lipidome profiles, highlighting the need to place prediabetes in a broader context of metabolism beyond glucose.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/eci.70137","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T09:58:59Z","timestamp":1761299939000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Lipidomic profiling unveils sex differences in diabetes risk: Implications for precision medicine"],"prefix":"10.1111","volume":"56","author":[{"given":"Ana F.","family":"Pina","sequence":"first","affiliation":[{"name":"iNOVA4Health, NOVA Medical School, Faculdade de Ci\u00eancias M\u00e9dicas, NMS, FCM Universidade NOVA de Lisboa  Lisbon Portugal"},{"name":"ProRegeM PhD Program, NOVA Medical School, NMS Universidade Nova de Lisboa  Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8236-5411","authenticated-orcid":false,"given":"Maria Jo\u00e3o","family":"Meneses","sequence":"additional","affiliation":[{"name":"iNOVA4Health, NOVA Medical School, Faculdade de Ci\u00eancias M\u00e9dicas, NMS, FCM Universidade NOVA de Lisboa  Lisbon Portugal"},{"name":"APDP \u2013 Diabetes Portugal Education and Research Center  Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizia","family":"Carli","sequence":"additional","affiliation":[{"name":"National Research Council (CNR) Institute of Clinical Physiology (IFC)  Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rog\u00e9rio T.","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"APDP \u2013 Diabetes Portugal Education and Research Center  Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu\u00eds","family":"Gardete\u2010Correia","sequence":"additional","affiliation":[{"name":"APDP \u2013 Diabetes Portugal Education and Research Center  Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 M.","family":"Boavida","sequence":"additional","affiliation":[{"name":"APDP \u2013 Diabetes Portugal Education and Research Center  Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o F.","family":"Raposo","sequence":"additional","affiliation":[{"name":"iNOVA4Health, NOVA Medical School, Faculdade de Ci\u00eancias M\u00e9dicas, NMS, FCM Universidade NOVA de Lisboa  Lisbon Portugal"},{"name":"APDP \u2013 Diabetes Portugal Education and Research Center  Lisbon Portugal"},{"name":"Portuguese Society of Diabetology  Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amalia","family":"Gastaldelli","sequence":"additional","affiliation":[{"name":"National Research Council (CNR) Institute of Clinical Physiology (IFC)  Pisa Italy"},{"name":"Scuola Superiore Sant'Anna  Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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