The kynurenine:tryptophan ratio as a predictor of incident type 2 diabetes mellitus in individuals with coronary artery disease

Rebnord, Eirik Wilberg; Strand, Elin; Midttun, Øivind; Svingen, G.F.T.; Christensen, Monika H. E.; Ueland, Per Magne; Mellgren, Gunnar; Njølstad, Pål R.; Tell, Grethe S.; Nygård, Ottar; Pedersen, Eva Ringdal

doi:10.1007/s00125-017-4329-9

Cited by 69 publications

(56 citation statements)

References 47 publications

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“…Enzyme expression was greatest in activated macrophages, consistent with the finding that pathway activation could be induced in adipocytes by pro-inflammatory cytokines. There is strong evidence implicating the kynurenine pathway in the ‘metabolic syndrome’ and insulin resistance which is one of its major features in many obese individuals ( Filho et al, 2018 ; Oh et al, 2017 ; Oxenkrug et al, 2017 ; Rebnord et al, 2017 ). There is a clear correlation between plasma levels of tryptophan and its metabolites, leptin and BMI ( Samad et al, 2017 ).…”

Section: New Conceptsmentioning

confidence: 99%

Obesity and Cancer: Existing and New Hypotheses for a Causal Connection

2018

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Existing explanations of obesity-associated cancer emphasise direct mutagenic effects of dietary components or hormonal imbalance. Some of these hypotheses are reviewed briefly, but recent evidence suggests a major role for chronic inflammation in cancer risk, possibly involving dietary content. These ideas include the inflammation-induced activation of the kynurenine pathway and its role in feeding and metabolism by activation of the aryl hydrocarbon receptor (AHR) and by modulating synaptic transmission in the brain. Evidence for a role of the kynurenine pathway in carcinogenesis then provides a potentially major link between obesity and cancer. A second new hypothesis is based on evidence that serine proteases can deplete cells of the tumour suppressors Deleted in Colorectal Cancer (DCC) and neogenin. These enzymes include mammalian chymotryptic proteases released by pro-inflammatory neutrophils and macrophages. Blood levels of chymotrypsin itself increase in parallel with food intake. The mechanistically similar bacterial enzyme subtilisin is widespread in the environment, animal probiotics, meat processing and cleaning products. Simple public health schemes in these areas, with selective serine protease inhibitors and AHR antagonists and could prevent a range of intestinal and other cancers.

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Section: New Conceptsmentioning

confidence: 99%

Obesity and Cancer: Existing and New Hypotheses for a Causal Connection

2018

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“…Using these criteria, a total of 3344 eligible individuals were included in the final analyses. Individuals with incident diabetes during the followup were identified from the Norwegian prescription database, hospital discharge diagnosis and WENBIT trial follow-up, as previously described in detail [13]. Because information on incident diabetes was collected through 31 December 2009, i.e.…”

Section: Methodsmentioning

confidence: 99%

Ceramide stearic to palmitic acid ratio predicts incident diabetes

et al. 2018

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Aims/hypothesis Ceramide lipids have a role in the development of insulin resistance, diabetes and risk of cardiovascular disease. Here we investigated four ceramides and their ratios to find the best predictors of incident diabetes. Methods A validated mass-spectrometric method was applied to measure Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/ 24:0) and Cer(d18:1/24:1) from serum or plasma samples. These ceramides were analysed in a population-based risk factor study (FINRISK 2002, n = 8045), in a cohort of participants undergoing elective coronary angiography for suspected stable angina pectoris (Western Norway Coronary Angiography Cohort [WECAC], n = 3344) and in an intervention trial investigating improved methods of lifestyle modification for individuals at high risk of the metabolic syndrome (Prevent Metabolic Syndrome [PrevMetSyn], n = 371). Diabetes risk score models were developed to estimate the 10 year risk of incident diabetes. Results Analysis in FINRISK 2002 showed that the Cer(d18:1/18:0)/Cer(d18:1/16:0) ceramide ratio was predictive of incident diabetes (HR per SD 2.23, 95% CI 2.05, 2.42), and remained significant after adjustment for several risk factors, including BMI, fasting glucose and HbA 1c (HR 1.34, 95% CI 1.14, 1.57). The finding was validated in the WECAC study (unadjusted HR 1.81, 95% CI 1.53, 2.14; adjusted HR 1.39, 95% CI 1.16, 1.66). In the intervention trial, the ceramide ratio and diabetes risk scores significantly decreased in individuals who had 5% or more weight loss.Markku J. Savolainen, Ottar Nygård, Veikko Salomaa and Reijo Laaksonen contributed equally to this study.Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-018-4590-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users. * Reijo Laaksonen

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“…Preventing diabetes might be a pathway by which IDO1 lowers the risk of IHD. Previous studies of IDO1 and type 2 diabetes are limited, although some have suggested diabetes up-regulates the tryptophan-kynurenine pathway 36,37 . Given IDO1 has complex and multiple functionality 7,38 , its effects on type 2 diabetes as well as the underlying mechanism, such as via insulin given products of the kynurenine pathway inhibit the synthesis and activity of insulin 39 , needs further investigation.…”

Section: Discussionmentioning

confidence: 99%

Indoleamine 2,3-dioxygenase and ischemic heart disease: a Mendelian Randomization study

Kwok

Fong

et al. 2019

Sci Rep

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Tryptophan is an essential amino acid. Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in the tryptophan-kynurenine pathway, is positively associated with cardiac events, and may be relevant to cancer. We used Mendelian Randomization to obtain unconfounded estimates of the association of IDO1 with ischemic heart disease (IHD), ischemic stroke and their risk factors, all-cancer, cancer of the prostate, lung and bronchus, and breast. We obtained genetic instruments independently and strongly (p-value < 5 × 10 −8 ) predicting plasma IDO1 from a proteome genome-wide association study (GWAS), and applied them to consortia GWAS of the outcomes, including the UK Biobank SOFT CAD GWAS (cases < = 76 014, non-cases < = 264 785) for IHD. Estimates were obtained using inverse variance weighting; with MR-Egger, weighted median and MR-PRESSO as sensitivity analyses. IDO1 was inversely associated with IHD (odds ratio (OR) 0.96 per standard deviation, 95% confidence interval (CI) 0.93 to 1.00, p-value = 0.04), diabetes (OR 0.91, 95% CI 0.85 to 0.97) and prostate cancer (OR 0.96, 95% CI 0.93 to 0.99) with a directionally consistent estimate for stroke (OR 0.98, 95% CI 0.95 to 1.02) but not with blood pressure, or the other cancers considered. IDO1 might be a potential therapeutic target for IHD, diabetes and prostate cancer.

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The kynurenine:tryptophan ratio as a predictor of incident type 2 diabetes mellitus in individuals with coronary artery disease

Cited by 69 publications

References 47 publications

Obesity and Cancer: Existing and New Hypotheses for a Causal Connection

Obesity and Cancer: Existing and New Hypotheses for a Causal Connection

Ceramide stearic to palmitic acid ratio predicts incident diabetes

Indoleamine 2,3-dioxygenase and ischemic heart disease: a Mendelian Randomization study

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