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Reversal of ? cell de-differentiation by a small molecule inhibitor of the TGF? pathway.

ABSTRACT: Dysfunction or death of pancreatic ? cells underlies both types of diabetes. This functional decline begins with ? cell stress and de-differentiation. Current drugs for type 2 diabetes (T2D) lower blood glucose levels but they do not directly alleviate ? cell stress nor prevent, let alone reverse, ? cell de-differentiation. We show here that Urocortin 3 (Ucn3), a marker for mature ? cells, is down-regulated in the early stages of T2D in mice and when ? cells are stressed in vitro. Using an insulin expression-coupled lineage tracer, with Ucn3 as a reporter for the mature ? cell state, we screen for factors that reverse ? cell de-differentiation. We find that a small molecule inhibitor of TGF? receptor I (Alk5) protects cells from the loss of key ? cell transcription factors and restores a mature ? cell identity even after exposure to prolonged and severe diabetes.

SUBMITTER: Blum B

PROVIDER: S-EPMC4204634 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway.

Blum Barak B Roose Adam N AN Barrandon Ornella O Maehr René R Arvanites Anthony C AC Davidow Lance S LS Davis Jeffrey C JC Peterson Quinn P QP Rubin Lee L LL Melton Douglas A DA

eLife 20140916

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 insul ...[more]

PMID: 25233132

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