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

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

Author information

1
Naomi Berrie Diabetes Center and Department of Medicine, Columbia University, New York, New York 10032, USA.
2
Department of Genetics and Integrated Program in Cellular, Molecular and Biomedical Studies, Columbia University, New York, New York 10032, USA.

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.

PMID:
27572106
PMCID:
PMC5013715
DOI:
10.1038/ncomms12631
[Indexed for MEDLINE]
Free PMC Article

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