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Metabolic reprogramming drives pancreatic β cell neogenesis from α cells [ATAC-seq]

ABSTRACT: Loss of functional β cells is a hallmark of diabetes, and restoring β cell mass remains a critical goal in the quest for a specific therapy. One potential strategy is to convert non-β cells in the islet, such as α cells, into insulin-producing cells. Although several compounds have been identified to induce β cell-like features in α cells, none have yet been successfully translated into clinical applications. In this study, we identify PRC2 inhibitors as potent inducers of β cell-enriched gene expression in α cells, acting through modulation of the AR-ETV1 complex. AR inhibition suppresses glycogen synthesis and enhances the pentose phosphate pathway (PPP). Direct metabolic reprogramming with methyl esterified 6-phosphogluconate (ME-6-PG), an intermediate metabolite of the PPP, induces β cell-like features in α cells, stimulate β cell regeneration and ameliorates diabetes. Our findings demonstrate that metabolic reprogramming can drive β cell regeneration and highlight a promising therapeutic strategy for diabetes.

ORGANISM(S): Mus musculus

PROVIDER: GSE302785 | GEO | 2026/06/18

REPOSITORIES: GEO

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Project description:The obligatory aerobic acetic acid bacterium Gluconobacter oxydans 621H oxidizes sugars and sugar alcohols primarily in the periplasm and only a small fraction is metabolized in the cytoplasm. The latter can occur either via the Entner-Doudoroff pathway (EDP) or via the pentose phosphate pathway (PPP). The Embden-Meyerhof pathway is non-functional and a cyclic operation of the tricarboxylic acid cycle is prevented by the absence of succinate dehydrogenase. In this work, the cytoplasmic catabolism of fructose formed by oxidation of mannitol was analyzed with a M-NM-^Tgnd mutant lacking the oxidative PPP and a M-NM-^Tedd-eda mutant devoid of the EDP. The growth characteristics of the two mutants under controlled conditions with mannitol as carbon source and enzyme activities showed that the PPP is the main route for cytoplasmic fructose catabolism, whereas the EDP is dispensable and even unfavorable. The M-NM-^Tedd-eda mutant (lacking 6-phosphogluconate dehydratase and 2-keto-3-deoxy-6-phosphogluconate aldolase) formed 24% more cell mass than the reference strain. In contrast, deletion of gnd (6-phosphogluconate dehydrogenase) severely inhibited growth and caused a strong selection pressure for secondary mutations inactivating glucose-6-phosphate dehydrogenase, thus preventing fructose catabolism via the EDP, too. These M-NM-^Tgnd zwf* mutants were almost totally disabled in fructose catabolism, but still produced about 14% of the carbon dioxide of the reference strain, possibly by catabolizing substrates from the yeast extract. Overexpression of gnd in the reference strain improved biomass formation in a similar manner as deletion of edd-eda, further confirming the importance of the PPP for cytoplasmic fructose catabolism. The three transcriptome comparisons of M-NM-^Tupp M-NM-^Tgnd zwf* vs. M-NM-^Tupp and of M-NM-^Tupp M-NM-^Tedd-eda vs. M-NM-^Tupp, and of M-NM-^Tupp M-NM-^Tgnd versus M-NM-^Tupp, were repeated independently three times in biological replicates resulting in 3 x 3 hybridizations as termed by sample 1 to 9.

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Metabolic reprogramming drives pancreatic β cell neogenesis from α cells [ATAC-seq]

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