A Smad Signaling Network Regulates Islet Cell Proliferation

  1. George Gittes1
  1. 1Division of Pediatric Surgery, Department of Surgery, Children’s Hospital of Pittsburgh, Pittsburgh, PA
  2. 2Department of Internal Medicine, St. Elizabeth Health Center, Youngstown, OH
  3. 3Department of Surgery, School of Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, TX
  4. 4Division of Neonatology, Department of Pediatrics, Children’s Hospital of Pittsburgh, Pittsburgh, PA
  5. 5Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
  6. 6Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC
  1. Corresponding author: George Gittes, george.gittes{at}
  1. Y.E. and S.T. contributed equally to the manuscript.


Pancreatic β-cell loss and dysfunction are critical components of all types of diabetes. Human and rodent β-cells are able to proliferate, and this proliferation is an important defense against the evolution and progression of diabetes. Transforming growth factor-β (TGF-β) signaling has been shown to affect β-cell development, proliferation, and function, but β-cell proliferation is thought to be the only source of new β-cells in the adult. Recently, β-cell dedifferentiation has been shown to be an important contributory mechanism to β-cell failure. In this study, we tie together these two pathways by showing that a network of intracellular TGF-β regulators, smads 7, 2, and 3, control β-cell proliferation after β-cell loss, and specifically, smad7 is necessary for that β-cell proliferation. Importantly, this smad7-mediated proliferation appears to entail passing through a transient, nonpathologic dedifferentiation of β-cells to a pancreatic polypeptide–fold hormone-positive state. TGF-β receptor II appears to be a receptor important for controlling the status of the smad network in β-cells. These studies should help our understanding of properly regulated β-cell replication.


  • Received March 17, 2013.
  • Accepted September 21, 2013.

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