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In three independent cohorts, in total 15,940 individuals were clustered based on five clinical characteristics. In a subset, genetic (N = 12,828), metabolomic (N = 2,945), lipidomic (N = 2,593), and proteomic (N = 1,170) data were obtained in plasma. For each data type, each cluster was compared with the other four clusters as the reference. The insulin-resistant cluster showed the most distinct molecular signature, with higher branched-chain amino acid, diacylglycerol, and triacylglycerol levels and aberrant protein levels in plasma were enriched for proteins in the intracellular PI3K\/Akt pathway. The obese cluster showed higher levels of cytokines. The mild diabetes cluster with high HDL showed the most beneficial molecular profile with effects opposite of those seen in the insulin-resistant cluster. This study shows that clustering people with type 2 diabetes can identify underlying molecular mechanisms related to pancreatic islets, liver, and adipose tissue metabolism. This provides novel biological insights into the diverse aetiological processes that would not be evident when type 2 diabetes is viewed as a homogeneous disease.<\/jats:p>","DOI":"10.2337\/db20-1281","type":"journal-article","created":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T18:05:12Z","timestamp":1628618712000},"page":"2683-2693","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":60,"title":["Distinct Molecular Signatures of Clinical Clusters in People With Type 2 Diabetes: An IMI-RHAPSODY Study"],"prefix":"10.2337","volume":"70","author":[{"given":"Roderick C.","family":"Slieker","sequence":"first","affiliation":[{"name":"Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands"},{"name":"Department of Epidemiology and Data Science, Amsterdam Public Health Institute, Amsterdam UMC, location VUmc, Amsterdam, the 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