Mammalian metabolism of erythritol: a predictive biomarker of metabolic dysfunction

Ortiz, Semira; Field, Martha S.

doi:10.1097/mco.0000000000000665

Cited by 21 publications

(18 citation statements)

References 28 publications

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“…The precursor of erythrose is erythrose-4phosphate, which is a product of the non-oxidative PPP. The regulation of erythritol synthesis and its role in metabolic homeostasis, however, is poorly understood [17]. Here, we demonstrate that erythritol synthesis is modulated both by glucose availability and oxidative stress.…”

Section: Discussionmentioning

confidence: 73%

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Erythritol synthesis in human cells is elevated in response to oxidative stress and regulated by the non-oxidative pentose phosphate pathway

Ortiz

Heinz

Hiller

et al. 2022

Preprint

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Erythritol is a predictive biomarker of cardiometabolic diseases and is produced from glucose metabolism through the pentose phosphate pathway (PPP). Little is known regarding the regulation of endogenous erythritol synthesis in humans. In the present study, we investigated the stimuli that promote erythritol synthesis in human cells and characterized potential points of regulation along the PPP. Human A549 lung carcinoma cells were chosen for their known ability to synthesize erythritol. A549 cells were treated with potential substrates for erythritol production, including glucose, fructose, and glycerol. Using siRNA knockdown, we assessed the necessity of enzymes G6PD, TKT, TALDO, and SORD for erythritol synthesis. We also used position-specific 13C-glucose tracers to determine whether the carbons for erythritol synthesis are derived directly from glycolysis or through the oxidative PPP. Finally, we assessed if erythritol synthesis responds to oxidative stress using chemical and genetic models. Intracellular erythritol was directly associated with media glucose concentration. In addition, siRNA knockdown of TKT or SORD inhibited erythritol synthesis, whereas siG6PD did not. Both chemically induced oxidative stress and constitutive activation of the antioxidant response transcription factor NRF2 elevated intracellular erythritol. Our findings indicate that erythritol synthesis is proportional to flux through the PPP and is regulated by non-oxidative PPP enzymes.

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Section: Discussionmentioning

confidence: 73%

“…In humans, elevated circulating erythritol is a predictive biomarker of cardiometabolic diseases [17]. Our findings provide a connection between erythritol regulation and hallmarks of cardiometabolic disease: hyperglycemia and oxidative stress [31,32].…”

Section: Discussionmentioning

confidence: 80%

Erythritol synthesis in human cells is elevated in response to oxidative stress and regulated by the non-oxidative pentose phosphate pathway

Ortiz

Heinz

Hiller

et al. 2022

Preprint

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“…2,3 Erythritol is both a prevalent sugar substitute and an endogenously synthesized product of glucose metabolism. 1 Previous studies evaluating the impact of erythritol supplementation on blood glucose and body weight have focused on short-term exposures, most lasting less than two weeks. Here, we characterize the effect of 8 weeks of dietary erythritol consumption on adiposity and glucose homeostasis in mice fed a standard LFD and obesogenic HFD.…”

Section: Discussionmentioning

confidence: 99%

“…Serum levels of one NNS, erythritol, were recently identified as a predictive biomarker of a range of adverse health outcomes. 1 The first association between erythritol and metabolic dysfunction found that young adults that gained central adiposity over their first year of college had baseline serum erythritol levels 15-fold higher than those with stable weight over the same time period. 2 In the larger Atherosclerosis Risk in Communities (ARIC) cohort, serum erythritol was significantly associated with both incident T2DM and cardiovascular disease risk.…”

Section: Introductionmentioning

confidence: 99%

Chronic dietary erythritol exposure elevates fasting plasma erythritol levels but does not cause weight gain or modify glucose homeostasis in mice

Ortiz

Field

2021

Preprint

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ObjectiveErythritol is both a common non-nutritive sweetener (NNS) and an endogenous product of glucose metabolism. Recent reports indicate that elevated plasma erythritol is a predictive biomarker of cardiometabolic disease onset and complications. Although short-term erythritol consumption has been evaluated, the effect of chronically elevated circulating erythritol on adiposity and glucose metabolism has not. This study investigated the effect of longer-term erythritol consumption on weight gain and glucose tolerance, and the interaction between dietary composition and erythritol supplementation on these parameters.Methods8-week-old and 20-week-old C57BL/6J mice were randomized to consume low-fat diet (LFD), high-fat diet (HFD), LFD with 40g/kg erythritol (LFD+ERY), and HFD with 40g/kg erythritol (HFD+ERY) groups. After 8 weeks, plasma erythritol, body weight and composition, food intake, glucose tolerance, and brown adipose tissue (BAT) uncoupling protein 1 (UCP1) expression were measured.ResultsPlasma erythritol was elevated 40-fold in mice consuming LFD+ERY or HFD+ERY relative to mice consuming LFD or HFD, respectively. Liver and kidney tissue contained higher levels of erythritol than adipose. Unexpectedly, there was no effect of erythritol supplementation on body weight or glucose tolerance in 8- or 20-week-old mice fed LFD+ERY, or in 8-week-old mice fed HFD+ERY. In 20-week-old mice fed HFD+ERY, there was a significant interaction between erythritol and body weight (p<0.0001) compared to controls, but the main effect of diet was not significant. We also found no effect of chronic erythritol consumption on BAT UCP1 expression.ConclusionProlonged erythritol consumption did not significantly impact body weight, composition, or glucose tolerance. This suggests that dietary erythritol does not contribute to the development of cardiometabolic disease.

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“…Other primary metabolites of note included 2-deoxytetronic acid, 3,6-anhydro-d-galactose, sugar alcohols (erythritol, xylitol, and myo-inositol), and thymine (Table 4). Isomaltose and erythritol that were originated from dietary resource, have been suggested for the association with disease biomarker, particularly in diabetes 41,42 .…”

Section: Metabolomic Biomarkers In the Mid-trimester Cohort Integratmentioning

confidence: 99%

Metabolomic biomarkers in midtrimester maternal plasma can accurately predict the development of preeclampsia

Lee

Kang

Lee

et al. 2020

Sci Rep

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Early identification of patients at risk of developing preeclampsia (PE) would allow providers to tailor their prenatal management and adopt preventive strategies, such as low-dose aspirin. Nevertheless, no mid-trimester biomarkers have as yet been proven useful for prediction of PE. This study investigates the ability of metabolomic biomarkers in mid-trimester maternal plasma to predict PE. A case–control study was conducted including 33 pregnant women with mid-trimester maternal plasma (gestational age [GA], 16–24 weeks) who subsequently developed PE and 66 GA-matched controls with normal outcomes (mid-trimester cohort). Plasma samples were comprehensively profiled for primary metabolic and lipidomic signatures based on gas chromatography time-of-flight mass spectrometry (GC-TOF MS) and liquid chromatography Orbitrap mass spectrometry (LC-Orbitrap MS). A potential biomarker panel was computed based on binary logistic regression and evaluated using receiver operating characteristic (ROC) analysis. To evaluate whether this panel can be also used in late pregnancy, a retrospective cohort study was conducted using plasma collected from women who delivered in the late preterm period because of PE (n = 13) or other causes (n = 21) (at-delivery cohort). Metabolomic biomarkers were compared according to the indication for delivery. Performance of the metabolomic panel to identify patients with PE was compared also to a commonly used standard, the plasma soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio. In the mid-trimester cohort, a total of 329 metabolites were identified and semi-quantified in maternal plasma using GC-TOF MS and LC-Orbitrap-MS. Binary logistic regression analysis proposed a mid-trimester biomarker panel for the prediction of PE with five metabolites (SM C28:1, SM C30:1, LysoPC C19:0, LysoPE C20:0, propane-1,3-diol). This metabolomic model predicted PE better than PlGF (AUC [95% CI]: 0.868 [0.844–0.891] vs 0.604 [0.485–0.723]) and sFlt-1/PlGF ratio. Analysis of plasma from the at-delivery cohort confirmed the ability of this biomarker panel to distinguish PE from non-PE, with comparable discrimination power to that of the sFlt-1/PlGF ratio. In conclusion, an integrative metabolomic biomarker panel in mid-trimester maternal plasma can accurately predict the development of PE and showed good discriminatory power in patients with PE at delivery.

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Mammalian metabolism of erythritol: a predictive biomarker of metabolic dysfunction

Cited by 21 publications

References 28 publications

Erythritol synthesis in human cells is elevated in response to oxidative stress and regulated by the non-oxidative pentose phosphate pathway

Erythritol synthesis in human cells is elevated in response to oxidative stress and regulated by the non-oxidative pentose phosphate pathway

Chronic dietary erythritol exposure elevates fasting plasma erythritol levels but does not cause weight gain or modify glucose homeostasis in mice

Metabolomic biomarkers in midtrimester maternal plasma can accurately predict the development of preeclampsia

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