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Islet Studies

Metabolomics Identifies a Biomarker Revealing In Vivo Loss of Functional β-Cell Mass Before Diabetes Onset

  1. Lingzi Li1,2,
  2. Petra Krznar3,4,
  3. Alexander Erban5,
  4. Andrea Agazzi6,
  5. Juliette Martin-Levilain1,2,
  6. Sachin Supale1,2,
  7. Joachim Kopka5,
  8. Nicola Zamboni3⇑ and
  9. Pierre Maechler1,2⇑
  1. 1Department of Cell Physiology and Metabolism, University of Geneva Medical Centre, Geneva, Switzerland
  2. 2Faculty Diabetes Centre, University of Geneva Medical Centre, Geneva, Switzerland
  3. 3Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland
  4. 4PhD Program in Systems Biology, Life Science Zurich Graduate School, Zurich, Switzerland
  5. 5Max Planck Institute of Molecular Plant Physiology, Potsdam, Germany
  6. 6Theoretical Physics Department, University of Geneva, Geneva, Switzerland
  1. Corresponding authors: Pierre Maechler, pierre.maechler{at}unige.ch, and Nicola Zamboni, zamboni{at}imsb.biol.ethz.ch
  1. L.L. and P.K. contributed equally to this work.

Diabetes 2019 Dec; 68(12): 2272-2286. https://doi.org/10.2337/db19-0131
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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.

Footnotes

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db19-0131/-/DC1.

  • Received February 7, 2019.
  • Accepted September 10, 2019.
  • © 2019 by the American Diabetes Association.
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December 2019, 68(12)
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Metabolomics Identifies a Biomarker Revealing In Vivo Loss of Functional β-Cell Mass Before Diabetes Onset
Lingzi Li, Petra Krznar, Alexander Erban, Andrea Agazzi, Juliette Martin-Levilain, Sachin Supale, Joachim Kopka, Nicola Zamboni, Pierre Maechler
Diabetes Dec 2019, 68 (12) 2272-2286; DOI: 10.2337/db19-0131

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Metabolomics Identifies a Biomarker Revealing In Vivo Loss of Functional β-Cell Mass Before Diabetes Onset
Lingzi Li, Petra Krznar, Alexander Erban, Andrea Agazzi, Juliette Martin-Levilain, Sachin Supale, Joachim Kopka, Nicola Zamboni, Pierre Maechler
Diabetes Dec 2019, 68 (12) 2272-2286; DOI: 10.2337/db19-0131
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© 2019 by the American Diabetes Association. Diabetes Print ISSN: 0012-1797, Online ISSN: 1939-327X.