Metabolite signature of albuminuria involves amino acid pathways in 8,661 Finnish men without diabetes.

OBJECTIVE To investigate metabolite signature of albuminuria in individuals without diabetes or chronic kidney disease to identify possible mechanisms resulting in increased albuminuria and elevated risk of T2D. RESEARCH DESIGN AND METHODS The study cohort was a population based METSIM study including 8,861 middle-aged and elderly Finnish men without diabetes or chronic kidney disease at baseline. A total of 5,504 men participated in a 7.5-year follow-up study, and 5,181 of them had metabolomics data measured by Metabolon's ultra-high performance liquid chromatography-tandem mass spectroscopy. RESULTS We found 32 metabolites significantly (P<5.8x10 -5) and positively associated with urinary albumin excretion rate (UAE). These metabolites were especially downstream metabolites in the amino acid metabolism pathways (threonine, phenylalanine, leucine, arginine). In our 7.5-year follow-up study UAE was significantly associated with a 19% increase (Hazard ratio 1.19, 95% confidence intervals 1.13-1.25) in the risk of type 2 diabetes after the adjustment for confounding factors. Conversion to diabetes was more strongly associated with a decrease in insulin secretion than a decrease in insulin sensitivity. CONCLUSIONS Metabolic signature of UAE included multiple metabolites especially from the amino acid metabolism pathways known to be associated with low grade inflammation, and accumulation of reactive oxygen species that play an important role in the pathogenesis of UAE. These metabolites were primarily associated with an increase in UAE and secondarily a decrease in insulin secretion and insulin sensitivity resulting in an increased risk of incident type 2 diabetes.