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

Ja Young Kim-Muller, Jason Fan, Young Jung R. Kim, Seung-Ah Lee, Emi Ishida, William S. Blaner and Domenico Accili ()
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Ja Young Kim-Muller: Columbia University
Jason Fan: Columbia University
Young Jung R. Kim: Molecular and Biomedical Studies, Columbia University
Seung-Ah Lee: Columbia University
Emi Ishida: Columbia University
William S. Blaner: Columbia University
Domenico Accili: Columbia University

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12631

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