Abstract
Dysfunction or death of pancreatic β cells underlies both types of diabetes. This functional decline begins with β cell stress and de-differentiation. Current drugs for type 2 diabetes (T2D) lower blood glucose levels but they do not directly alleviate β cell stress nor prevent, let alone reverse, β cell de-differentiation. We show here that Urocortin 3 (Ucn3), a marker for mature β cells, is down-regulated in the early stages of T2D in mice and when β cells are stressed in vitro. Using an insulin expression-coupled lineage tracer, with Ucn3 as a reporter for the mature β cell state, we screen for factors that reverse β cell de-differentiation. We find that a small molecule inhibitor of TGFβ receptor I (Alk5) protects cells from the loss of key β cell transcription factors and restores a mature β cell identity even after exposure to prolonged and severe diabetes.
Keywords:
Alk5 inhibitor II; Tgf-beta; Ucn3; beta cells; cell biology; dedifferentiation; developmental biology; diabetes; human; mouse; stem cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biomarkers / metabolism
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Cell Dedifferentiation / drug effects*
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Cytokines / pharmacology
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Diabetes Mellitus, Type 2 / metabolism
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Diabetes Mellitus, Type 2 / pathology
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Humans
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Insulin Resistance
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Insulin-Secreting Cells / pathology*
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Mice, Inbred C57BL
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Nerve Tissue Proteins / metabolism
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / antagonists & inhibitors
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Receptors, Transforming Growth Factor beta / metabolism
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Signal Transduction / drug effects*
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Small Molecule Libraries / pharmacology*
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Stress, Physiological / drug effects
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Transcription Factors / metabolism
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Transforming Growth Factor beta / metabolism*
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Up-Regulation / drug effects
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Urocortins / metabolism
Substances
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Artn protein, mouse
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Biomarkers
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Cytokines
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Nerve Tissue Proteins
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Receptors, Transforming Growth Factor beta
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Small Molecule Libraries
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Transcription Factors
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Transforming Growth Factor beta
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Urocortins
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I
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TGFBR1 protein, human
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Tgfbr1 protein, mouse