Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice

Nat Commun. 2016 Aug 30;7:12631. doi: 10.1038/ncomms12631.

Abstract

Insulin-producing β cells become dedifferentiated during diabetes progression. An impaired ability to select substrates for oxidative phosphorylation, or metabolic inflexibility, initiates progression from β-cell dysfunction to β-cell dedifferentiation. The identification of pathways involved in dedifferentiation may provide clues to its reversal. Here we isolate and functionally characterize failing β cells from various experimental models of diabetes and report a striking enrichment in the expression of aldehyde dehydrogenase 1 isoform A3 (ALDH(+)) as β cells become dedifferentiated. Flow-sorted ALDH(+) islet cells demonstrate impaired glucose-induced insulin secretion, are depleted of Foxo1 and MafA, and include a Neurogenin3-positive subset. RNA sequencing analysis demonstrates that ALDH(+) cells are characterized by: (i) impaired oxidative phosphorylation and mitochondrial complex I, IV and V; (ii) activated RICTOR; and (iii) progenitor cell markers. We propose that impaired mitochondrial function marks the progression from metabolic inflexibility to dedifferentiation in the natural history of β-cell failure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Cell Dedifferentiation*
  • Cell Line, Tumor
  • Cell Separation
  • Diabetes Mellitus / genetics
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus / pathology*
  • Disease Models, Animal
  • Flow Cytometry
  • Gene Expression Profiling
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / pathology*
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / pathology
  • Mutation
  • Oxidative Phosphorylation
  • Rapamycin-Insensitive Companion of mTOR Protein / metabolism
  • Retinal Dehydrogenase / metabolism*
  • Sequence Analysis, RNA

Substances

  • Biomarkers
  • Insulin
  • Rapamycin-Insensitive Companion of mTOR Protein
  • rictor protein, mouse
  • Retinal Dehydrogenase
  • retinaldehyde dehydrogenase 3, mouse