Abstract
Aims/hypothesisThe tryptophan metabolite kynurenine has potent immune modulatory and vasoactive properties. Experimental data implicate kynurenine in obesity-related morbidities. Epidemiological studies are, however, sparse. We evaluated associations of the plasma and urine kynurenine:tryptophan ratio (KTR) to incident type 2 diabetes.MethodsWe followed 2519 individuals with coronary artery disease (CAD; 73.1% men) without diabetes at baseline for a median of 7.6 years, during which 173 (6.9%) new incidences of type 2 diabetes were identified. Multivariate Cox regression analyses were applied to investigate the prospective relationships of plasma and urine KTR with new onset type 2 diabetes.ResultsAt inclusion, mean (SD) age was 61.3 (10.4) years, BMI was 25.9 (3.71) kg/m2 and median (interquartile range) HbA1c was 5.6% (5.0%–6.0%) (38 [31–42] mmol/mol). Plasma KTR was not significantly related to type 2 diabetes risk. By contrast, urine KTR showed a strong positive association. Comparing quartile 4 with quartile 1, the HRs (95% CIs) were 2.59 (1.56, 4.30) and 2.35 (1.39, 3.96) in the age- and sex-adjusted and multivariate models, respectively.Conclusions/interpretationUrine KTR is a strong predictor of incident type 2 diabetes in individuals with CAD. Potential clinical implications and possible pathogenic roles of renal kynurenine excretion in type 2 diabetes development should be further elucidated.
Highlights
Type 2 diabetes mellitus is a chronic and slowly evolving disease characterised by impaired insulin-mediated glucose uptake in peripheral tissues and a failure of the insulin secreting capacity of the pancreas [1]
While traditionally considered primarily a disorder of glucose homeostasis, it is recognised that type 2 diabetes is associated with profound metabolic dysfunction including amino acid metabolism [1]
1107 (26.6%) had single measurements of plasma glucose and/or HbA1c suggestive of undiagnosed diabetes. Both plasma and urine kynurenine:tryptophan ratio (KTR) levels were elevated among participants with self-reported diabetes at study
Summary
Type 2 diabetes mellitus is a chronic and slowly evolving disease characterised by impaired insulin-mediated glucose uptake in peripheral tissues and a failure of the insulin secreting capacity of the pancreas [1]. In addition to reflecting the activity of the IDO1 enzyme, plasma KTR is, along with the pteridine derivative neopterin [5], a reliable indicator of IFN-γ mediated immune activation [3, 4]. IFN-γ has been implicated in the pathogenesis of insulin resistance [5,6,7] and IDO1 induction has well-characterised immunomodulatory effects [8]. Kynurenine has been identified as an endothelium-derived vasodilator [9, 10] In experimental models, this metabolite [11, 12] and its downstream intermediates kynurenic acid [11, 13, 14] and xanthurenic acid [14] have been implicated in the pathogenesis of type 2 diabetes. We explored plasma and urine KTR as predictors of new onset type 2 diabetes in a cohort of individuals with suspected or verified stable coronary artery disease (CAD)
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