364-OR: Unsupervised Approach Systematically Analyzes the Multiomics Profiles Associated with T2D Insulin Insensitivity—An IMI-RHAPSODY Study

Abstract

Considerable heterogeneity exists in Type 2 diabetes disease onset and subsequent outcomes. Multi-omics analysis may provide a means to better assess inter-patient variations and design personalised approaches. Previous T2D biomarker discovery mainly focused on associating biomarkers with clinical pre-assigned patients. Here, we attempt to group T2D patients with similar multi-omics profiles using a multi-omics integrating clustering approach, Similarity Network Fusion (SNF). Each T2D subgroup’s unique omics profiles were then associated with T2D progression. In both cohorts, 180 and 1195 circulating lipids and proteins from a total of 1,134 subjects in DCS and GoDARTS cohorts group patients into two subgroups. Two subgroups are likely to represent the different stages of T2D insulin insensitivity with differences at HOMA2 (p=0.0008;4.2e-11;1.1e-09, -B, -IR and -S, DCS), C-peptide (p=3.7e-11;2.5e-06) and overall disease progression (HR=0.6;0.7). This is the first study solely relying on integrated lipidomics and proteomics to capture the stages of T2D insulin insensitivity, allowing potential novel biomarker discovery which may be masked by traditional approaches. In both cohorts, a number of discriminative omics features can be observed. Immune proteins, such as IL-18R, CLP, IL-1R and COD antigen showed strong but differing associations with insulin insensitivity, which may be related to the inflammation associated with T2D. Moreover, growth factors such as GHR and IGFs also exhibit strong associations with the present study. For lipids, patients with less severe insulin insensitivity exhibit elevated levels of sphingomyelins. In conclusion, we systematically analysed the multi-omics profiles associated with T2D insulin insensitivity. The molecular signatures may be used to investigate molecular mechanisms underpinning progression and provide insights for precision medicine. Disclosure S.Li: None. I.J.Dragan: None. K.Simons: Other Relationship; Lipotype, I have no there compoanz. L.A.Donnelly: None. V.T.Tran: None. F.Mehl: None. L.M.'t hart: Research Support; European Union. M.Ibberson: Consultant; Novo Nordisk Foundation. G.A.Rutter: Consultant; Sun Pharmaceutical Industries Ltd. E.Pearson: Speaker's Bureau; Novo Nordisk, Lilly, Illumina. R.Slieker: None. J.Beulens: None. M.K.Hansen: None. D.Kuznetsov: None. M.J.Gerl: Employee; Lipotype GmbH.