Purine Metabolites and Carnitine Biosynthesis Intermediates Are Biomarkers for Incident Type 2 Diabetes

• Published in: The journal of clinical endocrinology and metabolism Vol. 104; no. 10; pp. 4921 - 4930
• Main Authors: Ottosson, Filip, Smith, Einar, Gallo, Widet, Fernandez, Céline, Melander, Olle
• Format: Journal Article
• Language: English
• Published: Washington, DC Endocrine Society 01.10.2019; Oxford University Press
• Subjects: Aged; Aged, 80 and over; Biomarkers; Biomarkers - analysis; Biomarkers - metabolism; Carnitine; Carnitine - biosynthesis; Carnitine - metabolism; Case-Control Studies; Chromatography, Liquid; Clinical Medicine; Clinical s; Cohort Studies; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - diagnosis; Diabetes Mellitus, Type 2 - epidemiology; Diabetes Mellitus, Type 2 - metabolism; Endocrinology and Diabetes; Endokrinologi och diabetes; Female; Humans; Incidence; Intermediates; Klinisk medicin; Liquid chromatography; Male; Mass Spectrometry; Mass spectroscopy; Medical and Health Sciences; Medicin och hälsovetenskap; Metabolites; Metabolome - physiology; Metabolomics; Metabolomics - methods; Methylguanine; Purines - biosynthesis; Purines - metabolism; Risk Factors; Sweden - epidemiology; β-Carotene; Sweden
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2019-00822

Abstract Context Metabolomics has the potential to generate biomarkers that can facilitate understanding relevant pathways in the pathophysiology of type 2 diabetes (T2DM). Methods Nontargeted metabolomics was performed, via liquid chromatography–mass spectrometry, in a discovery case-cohort study from the Malmö Preventive Project (MPP), which consisted of 698 metabolically healthy participants, of whom 202 developed T2DM within a follow-up time of 6.3 years. Metabolites that were significantly associated with T2DM were replicated in the population-based Malmö Diet and Cancer–Cardiovascular Cohort (MDC-CC) (N = 3423), of whom 402 participants developed T2DM within a follow-up time of 18.2 years. Results Using nontargeted metabolomics, we observed alterations in nine metabolite classes to be related to incident T2DM, including 11 identified metabolites. N2,N2-dimethylguanosine (DMGU) (OR = 1.94; P = 4.9e-10; 95% CI, 1.57 to 2.39) was the metabolite most strongly associated with an increased risk, and beta-carotene (OR = 0.60; P = 1.8e-4; 95% CI, 0.45 to 0.78) was the metabolite most strongly associated with a decreased risk. Identified T2DM-associated metabolites were replicated in MDC-CC. Four metabolites were significantly associated with incident T2DM in both the MPP and the replication cohort MDC-CC, after adjustments for traditional diabetes risk factors. These included associations between three metabolites, DMGU, 7-methylguanine (7MG), and 3-hydroxytrimethyllysine (HTML), and incident T2DM. Conclusions We used nontargeted metabolomics in two Swedish prospective cohorts comprising >4000 study participants and identified independent, replicable associations between three metabolites, DMGU, 7MG, and HTML, and future risk of T2DM. These findings warrant additional studies to investigate a potential functional connection between these metabolites and the onset of T2DM. Plasma levels of metabolites DMGU, 7MG, and HTML are associated with incident T2DM in two prospective cohorts comprising >4000 patients.