Human and mouse non‐targeted metabolomics identify 1,5‐anhydroglucitol as SGLT2‐dependent glycemic marker

Kappel, B.; Moellmann, Julia; Thiele, Kirsten; Rau, Matthias; Artati, Anna; Adamski, Jerzy; Ghesquière, Bart; Schuett, Katharina; Romeo, Francesco; Stoehr, Robert; Federici, Massimo; Lehrke, Michael

doi:10.1002/ctm2.470

Cited by 9 publications

(10 citation statements)

References 10 publications

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“…The interaction between SGs and 1,5-AHG has also been confirmed in a metabolomic study by Kappel et al, where they report that the observed decrease in 1,5-AHG may be due to a decrease in its renal reabsorption [109]. Because of this phenomenon, its use as a glycemic marker in individuals treated with SGLT-2i is not recommended [108,109]. Furthermore, 1,5-AHG can be used as a marker of remission in patients with T2DM treated with insulin.…”

Section: 5-anhydroglucitolmentioning

confidence: 58%

“…It has been reported that SGLT-2i treatment can interfere with the measurement of 1,5-AHG, resulting in a falsely low value in patients with controlled blood glucose levels [108]. The interaction between SGs and 1,5-AHG has also been confirmed in a metabolomic study by Kappel et al, where they report that the observed decrease in 1,5-AHG may be due to a decrease in its renal reabsorption [109]. Because of this phenomenon, its use as a glycemic marker in individuals treated with SGLT-2i is not recommended [108,109].…”

Section: 5-anhydroglucitolmentioning

confidence: 86%

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Recent Developments in Biomarkers for Diagnosis and Screening of Type 2 Diabetes Mellitus

et al. 2022

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Purpose of Review Diabetes mellitus is a complex, chronic illness characterized by elevated blood glucose levels that occurs when there is cellular resistance to insulin action, pancreatic β-cells do not produce sufficient insulin, or both. Diabetes prevalence has greatly increased in recent decades; consequently, it is considered one of the fastest-growing public health emergencies globally. Poor blood glucose control can result in long-term micro- and macrovascular complications such as nephropathy, retinopathy, neuropathy, and cardiovascular disease. Individuals with diabetes require continuous medical care, including pharmacological intervention as well as lifestyle and dietary changes. Recent Findings The most common form of diabetes mellitus, type 2 diabetes (T2DM), represents approximately 90% of all cases worldwide. T2DM occurs more often in middle-aged and elderly adults, and its cause is multifactorial. However, its incidence has increased in children and young adults due to obesity, sedentary lifestyle, and inadequate nutrition. This high incidence is also accompanied by an estimated underdiagnosis prevalence of more than 50% worldwide. Implementing successful and cost-effective strategies for systematic screening of diabetes mellitus is imperative to ensure early detection, lowering patients' risk of developing life-threatening disease complications. Therefore, identifying new biomarkers and assay methods for diabetes mellitus to develop robust, non-invasive, painless, highly-sensitive, and precise screening techniques is essential. Summary This review focuses on the recent development of new clinically validated and novel biomarkers as well as the methods for their determination that represent cost-effective alternatives for screening and early diagnosis of T2DM.

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Section: 5-anhydroglucitolmentioning

confidence: 58%

Section: 5-anhydroglucitolmentioning

confidence: 86%

Recent Developments in Biomarkers for Diagnosis and Screening of Type 2 Diabetes Mellitus

et al. 2022

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“…Patients with diabetes mellitus type 2 as well as cardiovascular disease (reduced LV‐EF by ischemic cardiomyopathy with no coronary event in the past three months) were recruited at RWTH Aachen University hospital between 12/2015 and 07/2016 as described before (NCT03131232, approved by the ethics committee of the RWTH Aachen Medical Faculty; all patients gave informed consent). 8 , 9 Serum collection, recording of clinical data, and echocardiography were performed at baseline. Fortytwo patients were included, 17 individuals had to be excluded from the metabolomics analysis due to lack of serum collection, lack of echocardiography, or withdrawal of consent.…”

Section: Methodsmentioning

confidence: 99%

“…Patients hospitalized for ST‐segment elevation myocardial infarction or non‐ST‐segment elevation myocardial infarction were included in this cohort between 02/2015 and 04/2016 at Tor Vergata University of Rome, Italy. 9 All subjects gave written informed consent. Forty patients were enrolled in the study; 3 patients had to be excluded to various reasons.…”

Section: Methodsmentioning

confidence: 99%

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Non‐targeted metabolomics identify polyamine metabolite acisoga as novel biomarker for reduced left ventricular function

et al. 2021

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Aims Chronic heart failure with reduced ejection fraction remains a major health issue. To date, no reliable biomarker is available to predict reduced left ventricular ejection fraction (LV-EF). We aimed to identify novel circulating biomarkers for reduced left ventricular function using untargeted serum metabolomics in two independent patient cohorts. Methods and resultsEchocardiography and non-targeted serum metabolomics were conducted in two patient cohorts with varying left ventricular function: (1) 25 patients with type 2 diabetes with established cardiovascular disease or high cardiovascular risk (LV-EF range 20-66%) (discovery cohort) and (2) 37 patients hospitalized for myocardial infarction (LV-EF range 25-60%) (validation cohort). In the discovery cohort, untargeted metabolomics revealed seven metabolites performing better than N-terminal pro-B-type natriuretic peptide in the prediction of impaired left ventricular function shown by LV-EF. For only one of the metabolites, acisoga, the predictive value for LV-EF could be confirmed in the validation cohort (r = À0.37, P = 0.02). In the discovery cohort, acisoga did not only correlate with LV-EF (r = À60, P = 0.0016), but also with global circumferential strain (r = 0.67, P = 0.0003) and global longitudinal strain (r = 0.68, P = 0.0002). Similar results could be detected in the discovery cohort in a 6 month follow-up proofing stability of these results over time. With an area under the curve of 0.86 in the receiver operating characteristic analysis, acisoga discriminated between patients with normal EF and LV-EF < 40%. Multivariate analysis exposed acisoga as independent marker for impairment of LV-EF (Beta = À0.71, P = 0.004). Conclusions We found the polyamine metabolite acisoga to be elevated in patients with impaired LV-EF in two independent cohorts. Our analyses suggest that acisoga may be a valuable biomarker to detect patients with heart failure with reduced ejection fraction.

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SGLT5 is the renal transporter for 1,5-anhydroglucitol, a major player in two rare forms of neutropenia

Diederich,

Mounkoro,

Tirado

et al. 2023

Cell. Mol. Life Sci.

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Neutropenia and neutrophil dysfunction in glycogen storage disease type 1b (GSD1b) and severe congenital neutropenia type 4 (SCN4), associated with deficiencies of the glucose-6-phosphate transporter (G6PT/SLC37A4) and the phosphatase G6PC3, respectively, are the result of the accumulation of 1,5-anhydroglucitol-6-phosphate in neutrophils. This is an inhibitor of hexokinase made from 1,5-anhydroglucitol (1,5-AG), an abundant polyol in blood. 1,5-AG is presumed to be reabsorbed in the kidney by a sodium-dependent-transporter of uncertain identity, possibly SGLT4/SLC5A9 or SGLT5/SLC5A10. Lowering blood 1,5-AG with an SGLT2-inhibitor greatly improved neutrophil counts and function in G6PC3-deficient and GSD1b patients. Yet, this effect is most likely mediated indirectly, through the inhibition of the renal 1,5-AG transporter by glucose, when its concentration rises in the renal tubule following inhibition of SGLT2. To identify the 1,5-AG transporter, both human and mouse SGLT4 and SGLT5 were expressed in HEK293T cells and transport measurements were performed with radiolabelled compounds. We found that SGLT5 is a better carrier for 1,5-AG than for mannose, while the opposite is true for human SGLT4. Heterozygous variants in SGLT5, associated with a low level of blood 1,5-AG in humans cause a 50–100% reduction in 1,5-AG transport activity tested in model cell lines, indicating that SGLT5 is the predominant kidney 1,5-AG transporter. These and other findings led to the conclusion that (1) SGLT5 is the main renal transporter of 1,5-AG; (2) frequent heterozygous mutations (allelic frequency > 1%) in SGLT5 lower blood 1,5-AG, favourably influencing neutropenia in G6PC3 or G6PT deficiency; (3) the effect of SGLT2-inhibitors on blood 1,5-AG level is largely indirect; (4) specific SGLT5-inhibitors would be more efficient to treat these neutropenias than SGLT2-inhibitors.

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Human and mouse non‐targeted metabolomics identify 1,5‐anhydroglucitol as SGLT2‐dependent glycemic marker

Cited by 9 publications

References 10 publications

Recent Developments in Biomarkers for Diagnosis and Screening of Type 2 Diabetes Mellitus

Recent Developments in Biomarkers for Diagnosis and Screening of Type 2 Diabetes Mellitus

Non‐targeted metabolomics identify polyamine metabolite acisoga as novel biomarker for reduced left ventricular function

SGLT5 is the renal transporter for 1,5-anhydroglucitol, a major player in two rare forms of neutropenia

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