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

Elife. 2014 Sep 16;3:e02809. doi: 10.7554/eLife.02809.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Cell Dedifferentiation / drug effects*
  • Cytokines / pharmacology
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Humans
  • Insulin Resistance
  • Insulin-Secreting Cells / pathology*
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / metabolism
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction / drug effects*
  • Small Molecule Libraries / pharmacology*
  • Stress, Physiological / drug effects
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta / metabolism*
  • Up-Regulation / drug effects
  • Urocortins / metabolism

Substances

  • Artn protein, mouse
  • Biomarkers
  • Cytokines
  • Nerve Tissue Proteins
  • Receptors, Transforming Growth Factor beta
  • Small Molecule Libraries
  • Transcription Factors
  • Transforming Growth Factor beta
  • Urocortins
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human
  • Tgfbr1 protein, mouse