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

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T1 - Purine Metabolites and Carnitine Biosynthesis Intermediates Are Biomarkers for Incident Type 2 Diabetes

AU - Ottosson, Filip

AU - Smith, Einar

AU - Gallo, Widet

AU - Fernandez, Céline

AU - Melander, Olle

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

U2 - 10.1210/jc.2019-00822

DO - 10.1210/jc.2019-00822

M3 - Article

C2 - 31502646

AN - SCOPUS:85071986631

VL - 104

SP - 4921

EP - 4930

JO - The Journal of clinical endocrinology and metabolism

JF - The Journal of clinical endocrinology and metabolism

SN - 1945-7197

IS - 10

ER -