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

Diabetes. 2019 Dec;68(12):2272-2286. doi: 10.2337/db19-0131. Epub 2019 Sep 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / pathology
  • Gas Chromatography-Mass Spectrometry
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Machine Learning
  • Metabolome*
  • Metabolomics
  • Mice
  • Mice, Knockout
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism

Substances

  • Biomarkers
  • Repressor Proteins
  • prohibitin