Calcineurin/NFAT signalling regulates pancreatic β-cell growth and function

  title={Calcineurin/NFAT signalling regulates pancreatic $\beta$-cell growth and function},
  author={Jeremy J. Heit and {\AA}sa A. Apelqvist and Xueying Gu and Monte M. Winslow and Joel R Neilson and Gerald R. Crabtree and Seung K. Kim},
The growth and function of organs such as pancreatic islets adapt to meet physiological challenges and maintain metabolic balance, but the mechanisms controlling these facultative responses are unclear. Diabetes in patients treated with calcineurin inhibitors such as cyclosporin A indicates that calcineurin/nuclear factor of activated T-cells (NFAT) signalling might control adaptive islet responses, but the roles of this pathway in β-cells in vivo are not understood. Here we show that mice with… 
Transgenic Overexpression of Active Calcineurin in β-Cells Results in Decreased β-Cell Mass and Hyperglycemia
The studies identify calcineurin as an important factor in controlling glucose homeostasis and indicate that chronic depolarization leading to increased calcineURin activity may contribute to β-cell dysfunction and diabetes.
Isx9 Regulates Calbindin D28K Expression in Pancreatic β Cells and Promotes β Cell Survival and Function
Isx9 significantly regulates expression of genes relevant to β cell survival and function, and may be an attractive therapy to treat diabetes and improve islet function post-transplantation.
Calcineurin/NFAT signaling in the β‐cell: From diabetes to new therapeutics
  • J. Heit
  • Biology, Medicine
    BioEssays : news and reviews in molecular, cellular and developmental biology
  • 2007
Recent advances in the understanding of calcineurin and NFAT signaling in the β‐cell are reviewed and novel therapeutic approaches for the treatment of diabetes are discussed.
Calcineurin Signaling Regulates Human Islet β-Cell Survival*
Findings reveal calcineurin as a regulator of human β-cell survival in part through regulation of Irs2, with implications for the pathogenesis and treatment of diabetes following organ transplantation.
CRTC2 is required for β-cell function and proliferation.
It is reported that Crtc2 is essential both for glucose-stimulated insulin secretion and cell survival in the β-cell and promoting this pathway could ameliorate symptoms of new onset diabetes after transplantation.
TGF-β signaling in pancreatic islet β cell development and function.
Findings support the therapeutic utility of targeting TGF-β in diabetes and the role of the various T GF-β pathway ligands in β-cell development, growth and function in normal physiology, and during diabetes pathogenesis is discussed.
Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling.
An engraftment strategy to examine age-associated human islet cell replication competence and reveal mechanisms underlying age-dependent decline of β cell proliferation in human islets finds that exendin-4 (Ex-4), an agonist of the glucagon-like peptide 1 receptor (GLP-1R), stimulates human βcell proliferation in juvenile but not adult islets.
ICA512 signaling enhances pancreatic β-cell proliferation by regulating cyclins D through STATs
It is shown that islet cell autoantigen 512/IA-2, an intrinsic tyrosine phosphatase-like protein of the secretory granules, activates a complementary pathway for β-cell proliferation, identifying ICA512 as a regulator of cyclins D and β- cell proliferation through STATs and may have implication for diabetes therapy.
Role of adenosine signalling and metabolism in β-cell regeneration.


Conditional Expression of Smad7 in Pancreatic β Cells Disrupts TGF-β Signaling and Induces Reversible Diabetes Mellitus
Conditional expression of Smad7 in adult Pdx1 + cells reduced detectable β cell expression of MafA, menin, and other factors that regulate β cell function, revealing that TGF-β signaling is crucial for establishing and maintaining defining features of mature pancreatic β cells.
Intrinsic Regulators of Pancreatic β-Cell Proliferation
Recent advances in understanding of the intrinsic factors and mechanisms that control β-cell cycle progression are reviewed and it is speculated on how these advances may accelerate the discovery of new strategies to treat cancer and diabetes mellitus.
Molecular Control of Cell Cycle Progression in the Pancreatic β-Cell
In this review, the molecular details of cell cycle control as they relate to the pancreatic beta-cell are reviewed and can serve as a common basis and also a roadmap for those interested in developing novel strategies for enhancing beta- cell replication and improving insulin production in animal models as well as in human pancreatic Beta-cells.
PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance.
This study shows that, in postdevelopmental states of beta cell growth, PDX-1 is a critical regulator of Beta cell replication and is required for the compensatory response to insulin resistance.
β cell replication is the primary mechanism for maintaining postnatal β cell mass
It is demonstrated that cyclin D2 is required for the replication of endocrine cells but is expendable for exocrine and ductal cell replication and may provide a target for the development of therapeutic strategies to induce expansion and/or regeneration of β cells.
Cyclins D2 and D1 Are Essential for Postnatal Pancreatic β-Cell Growth
It is shown that cyclins D2 and D1 are essential for normal postnatal islet growth in adult mice, and strategies to tightly regulate D-type cyclin activity in β cells could prevent or cure diabetes.
NFAT regulates insulin gene promoter activity in response to synergistic pathways induced by glucose and glucagon-like peptide-1.
The data suggest that the synergistic action of glucose and GLP-1 to promote insulin gene transcription is mediated through NFAT via PKA- and calcineurin-dependent pathways in pancreatic beta-cells.
Overexpression of c-Myc in beta-cells of transgenic mice causes proliferation and apoptosis, downregulation of insulin gene expression, and diabetes.
It is demonstrated that activation of c-Myc in beta-cells leads to 1) increased proliferation and apoptosis, 2) initial hyperplasia with amorphous islet organization, and 3) selective downregulation of insulin gene expression and the development of overt diabetes.