Identification of individuals with decreased functional β-cell mass is essential for the prevention of diabetes. However, in vivo detection of early asymptomatic β-cell defect remains unsuccessful. Metabolomics has emerged as a powerful tool in providing readouts of early disease states before clinical manifestation. We aimed at identifying novel plasma biomarkers for loss of functional β-cell mass in the asymptomatic prediabetes stage. Nontargeted and targeted metabolomics were applied in both lean β-Phb2-/- (β-cell-specific prohibitin-2 knockout) mice and obese db/db (leptin receptor mutant) mice, two distinct mouse models requiring neither chemical nor dietary treatments to induce spontaneous decline of functional β-cell mass promoting progressive diabetes development. Nontargeted metabolomics on β-Phb2-/- mice identified 48 and 82 significantly affected metabolites in liver and plasma, respectively. Machine learning analysis pointed to deoxyhexose sugars consistently reduced at the asymptomatic prediabetes stage, including in db/db mice, showing strong correlation with the gradual loss of β-cells. Further targeted metabolomics by gas chromatography-mass spectrometry uncovered the identity of the deoxyhexose, with 1,5-anhydroglucitol displaying the most substantial changes. In conclusion, this study identified 1,5-anhydroglucitol as associated with the loss of functional β-cell mass and uncovered metabolic similarities between liver and plasma, providing insights into the systemic effects caused by early decline in β-cells.

Metabolomics identifies a biomarker revealing in vivo loss of functional β-cell mass before diabetes onset

Agazzi A.
Secondo
;
2019

Abstract

Identification of individuals with decreased functional β-cell mass is essential for the prevention of diabetes. However, in vivo detection of early asymptomatic β-cell defect remains unsuccessful. Metabolomics has emerged as a powerful tool in providing readouts of early disease states before clinical manifestation. We aimed at identifying novel plasma biomarkers for loss of functional β-cell mass in the asymptomatic prediabetes stage. Nontargeted and targeted metabolomics were applied in both lean β-Phb2-/- (β-cell-specific prohibitin-2 knockout) mice and obese db/db (leptin receptor mutant) mice, two distinct mouse models requiring neither chemical nor dietary treatments to induce spontaneous decline of functional β-cell mass promoting progressive diabetes development. Nontargeted metabolomics on β-Phb2-/- mice identified 48 and 82 significantly affected metabolites in liver and plasma, respectively. Machine learning analysis pointed to deoxyhexose sugars consistently reduced at the asymptomatic prediabetes stage, including in db/db mice, showing strong correlation with the gradual loss of β-cells. Further targeted metabolomics by gas chromatography-mass spectrometry uncovered the identity of the deoxyhexose, with 1,5-anhydroglucitol displaying the most substantial changes. In conclusion, this study identified 1,5-anhydroglucitol as associated with the loss of functional β-cell mass and uncovered metabolic similarities between liver and plasma, providing insights into the systemic effects caused by early decline in β-cells.
Li, L.; Krznar, P.; Erban, A.; Agazzi, A.; Martin-Levilain, J.; Supale, S.; Kopka, J.; Zamboni, N.; Maechler, P.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/1135373
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