Mannose is an insulin-regulated metabolite reflecting whole-body insulin sensitivity in man

Ferrannini, Ele; Bokarewa, M.; Brembeck, Petra; Baboota, Ritesh K.; Hedjazifar, Shahram; Andersson, Karin; Baldi, Simona; Campi, Beatrice; Muscelli, Elza; Sterner, I.; Wasén, Caroline; Smith, Ulf

doi:10.1016/j.metabol.2019.153974

Cited by 21 publications

(18 citation statements)

References 24 publications

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“…Our preliminary data on fasting samples document the presence of higher plasma mannose concentrations in type 2 diabetes, par excellence an insulin resistant state, thereby confirming the findings obtained by screening metabolomics [6]. Extensive clinical investigation into the mechanisms of this increase proves that physiological hyperinsulinemia is a potent negative regulator of circulating mannose levels, and that this insulin effect is blunted in patients with type 2 diabetes [24]. Therefore, D-mannose could be further tested a new robust biomarker of insulin resistance and insulin sensitivity in large-scale studies.…”

Section: Discussionsupporting

confidence: 83%

Quantification of d-mannose in plasma: Development and validation of a reliable and accurate HPLC-MS-MS method

Campi

Codini

Bisoli

et al. 2019

Clinica Chimica Acta

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Section: Discussionsupporting

confidence: 83%

Quantification of d-mannose in plasma: Development and validation of a reliable and accurate HPLC-MS-MS method

Campi

Codini

Bisoli

et al. 2019

Clinica Chimica Acta

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“… 40 Recently, it has been reported that mannose is an insulin-regulated metabolite reflecting whole-body insulin sensitivity. 41 In the present study, intracellular mannose level was significantly higher in ANGPTL8/betatrophin knockout HepG2/IR cells, compared to that in the wild type HepG2/IR cells ( p = 0.003), suggesting the more severe insulin resistance in HepG2/IR cells with ANGPTL8/betatrophin knockout. Consistently, it has been reported that insulin upregulates ANGPTL8/betatrophin expression via PI3K/Akt pathway, 19 and ANGPTL8/betatrophin alleviates insulin resistance via the Akt-GSK3β/FoxO1 pathway in HepG2 cells.…”

Section: Discussionsupporting

confidence: 43%

ANGPTL8/Betatrophin Improves Glucose Tolerance in Older Mice and Metabolomic Analysis Reveals Its Role in Insulin Resistance in HepG2 Cells

Xu¹,

Wang²,

Li³

et al. 2021

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Background: Insulin resistance is a determining factor in the pathophysiology of type 2 diabetes mellitus (T2DM). Angiopoietin-like protein 8 (ANGPTL8, also known as betatrophin), associated with glucose homeostasis and lipid metabolism, has attracted attention. But its mechanism in glucose metabolism remains unclear. This study aimed to explore the effect of ANGPTL8/betatrophin on glucose tolerance in Kunming (KM) mice of different ages and metabolic profiles in insulin-resistant HepG2 cells. Our study may provide a new perspective of ANGPTL8/betatrophin in insulin resistance from the metabolic changes. Methods: Oral glucose tolerance test was performed in KM mice of different ages. Insulin concentration was measured by using a quantitative enzyme-linked immunosorbent assay (ELISA). ANGPTL8/betatrophin knockouts in HepG2 cells were established with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) protein 9 (CRISPR/Cas9) system. Cell counting kit-8 (CCK-8) assay was used to determine cell viability after gene knockout. The effect of ANGPTL8/betatrophin on the metabolomic changes was evaluated in high insulin-induced insulin-resistant HepG2 cells by an ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Results: ANGPTL8/betatrophin improved glucose tolerance in older mice not by altering the concentration of insulin. Cell growth was affected in ANGPTL8/betatrophin knockout HepG2. Based on UPLC-MS/MS, compared with wild type insulin-resistant HepG2 cells, we identified 83 differential metabolites in ANGPTL8/betatrophin knockout HepG2 cells after high insulin induction. Among the 14 differential up-regulated metabolites, D-mannose had the highest fold change. In insulin-resistant HepG2 cells, ANGPTL8/betatrophin knockout exerted an effect on the amino acid metabolism, carbohydrate metabolism, metabolism of cofactors and vitamins, lipid metabolism, nucleotide metabolism, and genetic information processing pathway. Conclusion:This study identified the effect of ANGPTL8/betatrophin on glucose tolerance in mice of different ages and metabolic profiles in insulin-resistant HepG2 cells. These findings may contribute to a new understanding of its role in glucose metabolism in the context of insulin resistance.

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“…In contrast, mannose phosphorylation is reduced, so that mannose builds up in the cytoplasm and regurgitates into the plasma. This likely accounts for the close association of plasma mannose with plasma glucose concentrations (r = 0.51, p < 0.0001 in our discovery cohort) and with clamp-based insulin resistance [2]. Both PMM1 and GMPP activities are increased in the liver of obese, insulin resistant subjects; as a consequence, traffic through the N-glycan path is augmented, by increased glycoprotein synthesis, glycoprotein degradation or both.…”

Section: Biological Plausibilitysupporting

confidence: 51%

“…Previous workusing cell-specific analysis of genome-scale metabolic models, transcriptional regulatory networks, and protein-protein interaction networksidentified elevated circulating mannose concentrations as a novel marker of insulin resistance [1]. More recently, studies using the euglycaemic hyperinsulinaemic clamp technique to measure whole-body insulin sensitivity provided direct evidence that plasma mannosequantitated by liquid chromatography and tandem mass spectrometry (HPLC-MS-MS) -is insulin regulatable and closely tracks in vivo insulin resistance [2]. Moreover, in epidemiological cohorts higher plasma mannose concentrations have been associated not only with insulin resistance but also with risk of developing diabetes, diabetic kidney disease, and cardiovascular disease (CVD) [3].…”

Section: Introductionmentioning

confidence: 99%

Mannose as a biomarker of coronary artery disease: Angiographic evidence and clinical significance

Ferrannini

Andreini

Campi

et al. 2022

International Journal of Cardiology

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Background: High mannose has previously associated with insulin resistance and cardiovascular disease (CVD). Our objective is to establish whether mannose is associated with anatomical evidence of coronary artery disease (CAD). Methods: Plasma mannose concentrations were measured by liquid chromatography/tandem mass spectrometry in a discovery cohort (n = 513) and a validation cohort (n = 221) of carefully phenotyped individuals. In both cohorts CAD was quantitated using state-of-the-art imaging techniques (coronary computed coronary tomography angiography (CCTA), invasive coronary angiography and optical coherence tomography). Information on subsequent CVD events/death was collected. Associations of mannose with angiographic variables and biomarkers were tested using univariate and multivariate regression models. Survival analysis was performed using the Kaplan-Meier estimator. Results: Mannose was related to indices of CAD and features of plaque vulnerability. In the discovery cohort, mannose was a marker of quantity and quality of CCTA-proven CAD and subjects with a mannose level in the top quartile had a significantly higher risk of CVD events/death (p = 3.6e-5). In the validation cohort, mannose was significantly associated with fibrous cap thickness < 65 μm (odds ratio = 1.32 per each 10 μmol/L mannose change [95% confidence interval, 1.05-1.65]) and was an independent predictor of death (hazard ratio for mannose≥vs < 84.6 μmol/L: 4.0(95%CI, 1.4-11.3), p = 0.006). Conclusion:The current data add novel evidence that high mannose is a signature of CAD with a vulnerable plaque phenotype, consistently across measures of severity of vessel involvement and independent of the traditional correlates of CVD, and that it is an independent predictor of incident adverse outcomes.

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Mannose is an insulin-regulated metabolite reflecting whole-body insulin sensitivity in man

Cited by 21 publications

References 24 publications

Quantification of d-mannose in plasma: Development and validation of a reliable and accurate HPLC-MS-MS method

Quantification of d-mannose in plasma: Development and validation of a reliable and accurate HPLC-MS-MS method

ANGPTL8/Betatrophin Improves Glucose Tolerance in Older Mice and Metabolomic Analysis Reveals Its Role in Insulin Resistance in HepG2 Cells

Mannose as a biomarker of coronary artery disease: Angiographic evidence and clinical significance

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