Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study

• Published in: PLoS genetics Vol. 12; no. 10; p. e1006379
• Main Authors: Nowak, Christoph, Salihovic, Samira, Ganna, Andrea, Brandmaier, Stefan, Tukiainen, Taru, Broeckling, Corey D, Magnusson, Patrik K, Prenni, Jessica E, Wang-Sattler, Rui, Peters, Annette, Strauch, Konstantin, Meitinger, Thomas, Giedraitis, Vilmantas, Ärnlöv, Johan, Berne, Christian, Gieger, Christian, Ripatti, Samuli, Lind, Lars, Pedersen, Nancy L, Sundström, Johan, Ingelsson, Erik, Fall, Tove
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.10.2016; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Aged, 80 and over; Bile Acids and Salts - metabolism; Biology and Life Sciences; Caffeine - metabolism; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - pathology; Fatty Acids, Monounsaturated - metabolism; Glucose; Glucose - metabolism; Glucose Tolerance Test; Glycerophospholipids - metabolism; Health and Welfare; Health aspects; Health risk assessment; Humans; Hälsa och välfärd; Insulin - blood; Insulin - genetics; Insulin - metabolism; Insulin resistance; Insulin Resistance - genetics; Insulin Secretion; Male; Medicin och hälsovetenskap; Medicine and Health Sciences; Metabolic Networks and Pathways - genetics; Metabolites; Metabolomics; Middle Aged; Monounsaturated fatty acids; Observations; Physical Sciences; Science; Tyrosine - blood; Sweden; United States > US; Colorado; Massachusetts; Germany; Finland
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006379

Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 elderly men we found associations of 52 metabolites with hyperinsulinemic-euglycemic clamp-measured IR and/or β-cell responsiveness (disposition index) during an oral glucose tolerance test. These implicated bile acid, glycerophospholipid and caffeine metabolism for IR and fatty acid biosynthesis for impaired insulin secretion. In MR analysis in two separate cohorts (n = 2,613) followed by replication in three independent studies profiled on different metabolomics platforms (n = 7,824 / 8,961 / 8,330), we discovered and replicated causal effects of IR on lower levels of palmitoleic acid and oleic acid. A trend for a causal effect of IR on higher levels of tyrosine reached significance only in meta-analysis. In one of the largest studies combining "gold standard" measures for insulin responsiveness with non-targeted metabolomics, we found distinct metabolic profiles related to IR or impaired insulin secretion. We speculate that the causal effects on monounsaturated fatty acid levels could explain parts of the raised cardiovascular disease risk in IR that is independent of diabetes development.