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
Department of Medical Sciences and Science for Life Laboratory, Molecular Epidemiology Unit, Uppsala University, Uppsala, Sweden.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, United States of America.
PLoS Genet. 2016 Oct 21;12(10):e1006379. doi: 10.1371/journal.pgen.1006379. eCollection 2016 Oct.
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.
胰岛素抵抗（IR）和胰岛素分泌受损会导致2型糖尿病和心血管疾病。两者都与循环代谢组的变化有关，但因果关系一直难以厘清。我们将液相色谱/质谱非靶向血浆代谢组学与孟德尔随机化（MR）分析相结合，应用于三个非糖尿病队列，以深入了解IR和胰岛素分泌受损早期的代谢改变。在多达910名老年男性中，我们发现52种代谢物与口服葡萄糖耐量试验期间用高胰岛素-正常血糖钳夹法测量的IR和/或β细胞反应性（处置指数）相关。这些结果表明，胆汁酸、甘油磷脂和咖啡因代谢与IR有关，脂肪酸生物合成与胰岛素分泌受损有关。在两个独立队列（n = 2,613）中进行MR分析，随后在三个不同代谢组学平台上进行分析的独立研究中进行重复验证（n = 7,824 / 8,961 / 8,330），我们发现并重复验证了IR对棕榈油酸和油酸水平降低的因果效应。IR对酪氨酸水平升高的因果效应趋势仅在荟萃分析中达到显著水平。在一项将胰岛素反应性的“金标准”测量与非靶向代谢组学相结合的最大规模研究中，我们发现了与IR或胰岛素分泌受损相关的不同代谢谱。我们推测，对单不饱和脂肪酸水平的因果效应可能解释了IR中与糖尿病发展无关的心血管疾病风险升高的部分原因。
