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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.

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


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.

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