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Metabolic signatures elucidate the effect of body mass index on type 2 diabetes.
Metabolites 13:227 (2023)
Obesity plays an important role in the development of insulin resistance and diabetes, but the molecular mechanism that links obesity and diabetes is still not completely understood. Here, we used 146 targeted metabolomic profiles from the German KORA FF4 cohort consisting of 1715 participants and associated them with obesity and type 2 diabetes. In the basic model, 83 and 51 metabolites were significantly associated with body mass index (BMI) and T2D, respectively. Those metabolites are branched-chain amino acids, acylcarnitines, lysophospholipids, or phosphatidylcholines. In the full model, 42 and 3 metabolites were significantly associated with BMI and T2D, respectively, and replicate findings in the previous studies. Sobel mediation testing suggests that the effect of BMI on T2D might be mediated via lipids such as sphingomyelin (SM) C16:1, SM C18:1 and diacylphosphatidylcholine (PC aa) C38:3. Moreover, mendelian randomization suggests a causal relationship that BMI causes the change of SM C16:1 and PC aa C38:3, and the change of SM C16:1, SM C18:1, and PC aa C38:3 contribute to T2D incident. Biological pathway analysis in combination with genetics and mice experiments indicate that downregulation of sphingolipid or upregulation of phosphatidylcholine metabolism is a causal factor in early-stage T2D pathophysiology. Our findings indicate that metabolites like SM C16:1, SM C18:1, and PC aa C38:3 mediate the effect of BMI on T2D and elucidate their role in obesity related T2D pathologies.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Mediation ; Mendelian Randomization ; Metabolomics ; Obesity ; Type 2 Diabetes ; Type 2 Diabetes Pathology; Novo Sphingolipid Biosynthesis; Polyunsaturated Fatty-acids; Chain Amino-acids; Insulin-resistance; Wide Association; Obesity; Expression; Inflammation; Sensitivity; Desaturase
ISSN (print) / ISBN
2218-1989
e-ISSN
2218-1989
Journal
Metabolites
Quellenangaben
Volume: 13,
Issue: 2,
Article Number: 227
Publisher
MDPI
Publishing Place
St Alban-anlage 66, Ch-4052 Basel, Switzerland
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Epidemiology II (EPI2)
Institute of Translational Genomics (ITG)
CF Metabolomics & Proteomics (CF-MPC)
Institute of Experimental Genetics (IEG)
Institute of Translational Genomics (ITG)
CF Metabolomics & Proteomics (CF-MPC)
Institute of Experimental Genetics (IEG)
Grants
China Scholarship Council (CSC)