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.

Chronic fractalkine administration improves glucose tolerance and pancreatic endocrine function

“…This was accompanied by increased β cell mass and the expression of the genes involved in β cell differentiation and function. It should be noted that chronic FKN-Fc administration began at 10 weeks of HFD, at which point β cell dysfunction and dedifferentiation already exist (46,47).…”

Evidence for Loss in Identity, De-Differentiation, and Trans-Differentiation of Islet β-Cells in Type 2 Diabetes

“…Thus, upregulated ALDH1A3 levels (normally only produced in progenitors during embryogenesis) were observed in adult islet β-cells from FoxO (1, 3a, 4) triple knockout mice, and also found in the dysfunctional β-cell populations in db / db, Nkx6.1 , and MafA -deficient mouse models (Taylor et al, 2013; Hang et al, 2014; Kim-Muller et al, 2016). Sorted ALDH1A3 + cells were less glucose responsive than cells lacking ALDH1A3, had reduced levels of mature β-cell markers (e.g., Glucokinase, MafA ), concomitant increases in progenitor markers (e.g., Rfx6, Rfx7, Mlxipl ), and mitochondrial dysfunction (Kim-Muller et al, 2016). Although still unclear, some evidence suggests that ALDH1A3 also does not directly cause β-cell dysfunction.…”

“…Inactivation likely involves mechanisms that result in loss/reduction β-cell identity marker expression (e.g., MafA, Nkx6.1, Pdx1, insulin) as well induction of cell failure signatures (e.g., ALDH1A3; Kim-Muller et al, 2016). β1–4 cells represent at least some of the functionally distinct β-cell populations in human islets, with our model suggesting that failing T2D islets will be composed of several (e.g., β3 and β4; Dorrell et al, 2016).…”

“…A newly defined biomarker of “failing” T2D cells appears to involve induction of aldehyde dehydrogenase 1 isoform A3 ( ALDH1A3 ) (Kim-Muller et al, 2016). Thus, upregulated ALDH1A3 levels (normally only produced in progenitors during embryogenesis) were observed in adult islet β-cells from FoxO (1, 3a, 4) triple knockout mice, and also found in the dysfunctional β-cell populations in db / db, Nkx6.1 , and MafA -deficient mouse models (Taylor et al, 2013; Hang et al, 2014; Kim-Muller et al, 2016).…”

The undoing and redoing of the diabetic β-cell

“…Kim-Mueller et al (42) advanced these studies further by identifying the stem cell marker aldehyde dehydrogenase 1a3 to be increased in β-cells of a variety of diabetic mouse models, including mice lacking FoxO1, 3a and 4 selectively in β-cells. While adlh1a3 did not appear to confer the de-differentiated state of diabetic β-cells, it served as a marker, which allowed to selectively enrich de-differentiated β-cells by fluorescent sorting for further transcriptomic analyses, which reflected changes in gene expression pattern broadly consistent with oxidative and mitochondrial stress, and suggest that increased oxidiative damage to β-cells as a consequence to increased metabolic demand may be a principal driver of β-cell de-differentiation (42).…”