Markers and Mechanisms of β-cell Dedifferentiation

Jason Chen Fan

Human and murine diabetes is characterized by pancreatic β-cell dedifferentiation, a process in which β-cells lose expression of markers of maturity and gain those of endocrine progenitors. Failing β-cells inappropriately metabolize lipids over carbohydrates and exhibit impaired mitochondrial oxidative phosphorylation. Therefore, pathways involved in mitochondrial fuel selection and catabolism may represent potential targets for the prevention or reversal of dedifferentiation. In chapter I of this dissertation, we isolated and functionally characterized failing β-cells from various experimental models of diabetes. We found a striking enrichment in the expression of aldehyde dehydrogenase 1 isoform A3 (Aldh1a3) as β-cells become dedifferentiated. Flow-sorted Aldh1a3-expressing (ALDH+) islet cells demonstrate impaired glucose-induced insulin secretion, are depleted of Foxo1 and MafA,...