Abstract
Alterations in the human metabolome occur years before clinical manifestation of type 2 diabetes (T2DM). By contrast, there is little knowledge of how metabolite alterations in individuals with diabetes relate to risk of diabetes complications and premature mortality. Metabolite profiling was performed using liquid chromatography-mass spectrometry in 743 participants with T2DM from the population-based prospective cohorts The Malmö Diet and Cancer-Cardiovascular Cohort (MDC-CC) and The Malmö Preventive Project (MPP). During follow-up, a total of 175 new-onset cases of cardiovascular disease (CVD) and 298 deaths occurred. Cox regressions were used to relate baseline levels of plasma metabolites to incident CVD and all-cause mortality. A total of 11 metabolites were significantly (false discovery rate (fdr) <0.05) associated with all-cause mortality. Acisoga, acylcarnitine C10:3, dimethylguanidino valerate, homocitrulline, N2,N2-dimethylguanosine, 1-methyladenosine and urobilin were associated with an increased risk, while hippurate, lysine, threonine and tryptophan were associated with a decreased risk. Ten out of 11 metabolites remained significantly associated after adjustments for cardiometabolic risk factors. The associations between metabolite levels and incident CVD were not as strong as for all-cause mortality, although 11 metabolites were nominally significant (p < 0.05). Further examination of the mortality-related metabolites may shed more light on the pathophysiology linking diabetes to premature mortality.
Highlights
The global epidemic of type 2 diabetes (T2DM) and its complications causes an enormous burden on society
Acylcarnitine C10:3, dimethylguanidino valerate (DMGV), homocitrulline, N2,N2-dimethylguanosine, 1-methyladenosine and urobilin were associated with an increased risk for all-cause mortality, while hippurate, lysine, threonine and tryptophan were associated with a decreased risk
We extend these findings by showing that levels of N2,N2-dimethylguanosine and DMGV are associated with increased risk of all-cause mortality in individuals with diabetes
Summary
The global epidemic of type 2 diabetes (T2DM) and its complications causes an enormous burden on society. Diabetes is a major contributor to mortality, as it causes 5 million deaths yearly [4]. With this in mind, T2DM and its complications will remain a major contributor to morbidity and mortality in the coming decades. T2DM and its complications will remain a major contributor to morbidity and mortality in the coming decades Despite these alarming numbers, the pathogenesis of diabetes complications, other than poor control of blood glucose, remain largely unknown [5]
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