Effect of insulin resistance on monounsaturated fatty acid levels: A multi-cohort non-targeted metabolomics and mendelian randomization study

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.
Author Summary Impaired glucose homeostasis leads to diabetes and cardiovascular disease and has two main components: failure to secrete enough insulin from pancreatic β-cells and reduced insulin-stimulated cellular uptake of glucose and other nutrients in target tissues (insulin resistance, IR). We used metabolomics analysis in non-diabetic persons to measure a non-selective range of small molecules including amino acids, lipids, and sugars. Pathway analysis highlighted distinct metabolic pathways linked to IR (e.g. bile acid production) and impaired insulin secretion (fatty acid biosynthesis), but causal directions remained unclear. Mendelian Randomization (MR) analysis can test for causal effects in observational studies in the absence of randomized controlled trials. Using MR analysis in up to four large independent studies, we found evidence that IR causes a decrease in levels of the main endogenous monounsaturated fatty acids palmitoleic acid and oleic acid, as well as suggestive evidence for higher levels of the amino acid tyrosine. We provide a possible explanation for parts of the diabetes-independent risk of cardiovascular disease in persons with IR.