Changes in metabolomics profiles over ten years and subsequent risk of developing type 2 diabetes: Results from the Nurses' Health Study
Clemens Wittenbecher,
Marta Guasch-Ferré,
Danielle E. Haslam,
Courtney Dennis,
Jun Li,
Shilpa N. Bhupathiraju,
Chih-Hao Lee,
Qibin Qi,
Liming Liang,
A. Heather Eliassen,
Clary Clish,
Qi Sun,
Frank B Hu
Affiliations
Clemens Wittenbecher
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA; Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Corresponding authors at: Department of Nutrition, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA.
Marta Guasch-Ferré
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, MA, USA
Danielle E. Haslam
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, MA, USA
Courtney Dennis
Broad Institute of MIT and Harvard, Cambridge, MA, USA
Jun Li
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
Shilpa N. Bhupathiraju
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, MA, USA
Chih-Hao Lee
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA; Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA
Qibin Qi
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA; Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Liming Liang
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
A. Heather Eliassen
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
Clary Clish
Broad Institute of MIT and Harvard, Cambridge, MA, USA
Qi Sun
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
Frank B Hu
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA; Corresponding authors at: Department of Nutrition, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA.
Summary: Background: Metabolomics profiles were consistently associated with type 2 diabetes (T2D) risk, but evidence on long-term metabolite changes and T2D incidence is lacking. We examined the associations of 10-year plasma metabolite changes with subsequent T2D risk. Methods: We conducted a nested T2D case-control study (n=244 cases, n=244 matched controls) within the Nurses' Health Study. Repeated metabolomics profiling (170 targeted metabolites) was conducted in participant blood specimens from 1989/1990 and 2000/2001, and T2D occurred between 2002 and 2008. We related 10-year metabolite changes (Δ-values) to subsequent T2D risk using conditional logistic models, adjusting for baseline metabolite levels and baseline levels and concurrent changes of BMI, diet quality, physical activity, and smoking status. Findings: The 10-year changes of thirty-one metabolites were associated with subsequent T2D risk (false discovery rate-adjusted p-values [FDR]<0.05). The top three high T2D risk-associated 10-year changes were (odds ratio [OR] per standard deviation [SD], 95%CI): Δisoleucine (2.72, 1.97-3.79), Δleucine (2.53, 1.86-3.47), and Δvaline (1.93, 1.52-2.44); other high-risk-associated metabolite changes included alanine, tri-/diacylglycerol-fragments, short-chain acylcarnitines, phosphatidylethanolamines, some vitamins, and bile acids (ORs per SD between 1.31and 1.82). The top three low T2D risk-associated 10-year metabolite changes were (OR per SD, 95% CI): ΔN-acetylaspartic acid (0.54, 0.42-0.70), ΔC20:0 lysophosphatidylethanolamine (0.68, 0.56-0.82), and ΔC16:1 sphingomyelin (0.68, 0.56-0.83); 10-year changes of other sphingomyelins, plasmalogens, glutamine, and glycine were also associated with lower subsequent T2D risk (ORs per SD between 0.66 and 0.78). Interpretation: Repeated metabolomics profiles reflecting the long-term deterioration of amino acid and lipid metabolism are associated with subsequent risk of T2D.
