title: Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice.
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.
authors: Naomi Berrie Diabetes Center and Department of Medicine, Columbia University, New York, New York 10032, USA.
authors: Ja Young
authors: JY
authors: Kim-Muller
authors: 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.
authors: Jason
authors: J
authors: Fan
authors: Department of Genetics and Integrated Program in Cellular, Molecular and Biomedical Studies, Columbia University, New York, New York 10032, USA.
authors: Young Jung R
authors: YJ
authors: Kim
authors: Naomi Berrie Diabetes Center and Department of Medicine, Columbia University, New York, New York 10032, USA.
authors: Seung-Ah
authors: SA
authors: Lee
authors: Naomi Berrie Diabetes Center and Department of Medicine, Columbia University, New York, New York 10032, USA.
authors: Emi
authors: E
authors: Ishida
authors: Naomi Berrie Diabetes Center and Department of Medicine, Columbia University, New York, New York 10032, USA.
authors: William S
authors: WS
authors: Blaner
authors: Naomi Berrie Diabetes Center and Department of Medicine, Columbia University, New York, New York 10032, USA.
authors: Domenico
authors: D
authors: Accili
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D054337:Cell Dedifferentiation; D045744:Cell Line, Tumor; D002469:Cell Separation; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000473:pathology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000473:pathology; D009154:Mutation; D010085:Oxidative Phosphorylation; D000076226:Rapamycin-Insensitive Companion of mTOR Protein / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000378:metabolism*; D017423:Sequence Analysis, RNA
chemical_list: D015415:Biomarkers; D007328:Insulin; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C525637:rictor protein, mouse; D050697:Retinal Dehydrogenase; C508905:retinaldehyde dehydrogenase 3, mouse