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.
Highlights
Insulin-producing b cells become dedifferentiated during diabetes progression
We have shown that genetic ablation of Foxo function in b-cells impairs metabolic flexibility, that is, the ability to switch from glucose to lipids as a source of acetyl-CoA for mitochondrial oxidative phosphorylation, paving the way for b-cell dedifferentiation[6,7,8,9]
We report the discovery of an isoform of the enzyme aldehyde dehydrogenase 1 isoform A3 (ALDH1A3) as a biomarker of dysfunctional b cells
Summary
Insulin-producing b cells become dedifferentiated during diabetes progression. An impaired ability to select substrates for oxidative phosphorylation, or metabolic inflexibility, initiates progression from b-cell dysfunction to b-cell dedifferentiation. Abnormalities of islet cell function in diabetes include an impaired insulin response to stimulus, a reduced number of b cells, and an inappropriate glucagon response[4] This occurs despite the fact that reversal of hyperglycemia can partly restore b-cell function, even in patients with advanced disease[5]. We have shown that genetic ablation of Foxo function in b-cells impairs metabolic flexibility, that is, the ability to switch from glucose to lipids as a source of acetyl-CoA for mitochondrial oxidative phosphorylation, paving the way for b-cell dedifferentiation[6,7,8,9] These two processes bookend b-cell failure, but we do not know what happens in between. The significance of this work consists in the discovery of a biomarker of b-cell dysfunction that can be used to isolate failing cells; and in the identification of a pathogenic mechanism and a narrow set of potential effectors that can be tested for therapeutic relevance
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