Beta Cell Function (Co-Leaders: Maike Sander and Orian Shirihai)

Studies on the development and functions of beta cells represent important areas in both Type 1 and 2 diabetes. We have made important advances in both the clinical and basic science arenas. Highlights include the following.


  1. ECM Signaling Regulates Collective Cellular Dynamics to Control Pancreas Branching Morphogenesis by DRC member Sander and others in Cell Reports (2016). Sander and colleagues employed time-lapse microscopy and fluorescent labeling of cells to show that outer bud cells adjacent to the basement membrane are pleomorphic and rearrange frequently; dependent on cell contacts with the basement membrane, which induce actomyosin cytoskeleton remodeling via integrin-mediated activation of FAK/Src signaling. Thus, regulation of cell motility and adhesion by local niche cues initiates pancreas branching morphogenesis.
  2. The IRE1α/XBP1s Pathway Is Essential for the Glucose Response and Protection of β Cells, by DRC member Kaufman and others in PLOS Biology (2015). Kaufman and colleagues demonstrate that glucose activates the unfolded protein response transducer inositol-requiring enzyme 1 α (IRE1α) to initiate Xbp1 mRNA splicing in adult primary beta cells. Beta cell failure upon Ire1α deletion was primarily due to reduced proinsulin mRNA revealing that glucose activates IRE1α-mediated Xbp1 splicing to expand the secretory capacity of the beta cell for increased proinsulin synthesis and to limit oxidative stress that leads to beta cell failure.
  3. ERRγ Is Required for the Metabolic Maturation of Therapeutically Functional Glucose-Responsive β Cells by DRC member Evans and others in Cell Metabolism (2016). Evans and colleagues identify estrogen-related receptor α (ERRα) expression as a hallmark of adult, but not neonatal beta cells. Forced expression of ERRα in iPSC-derived β-like cells enables glucose-responsive secretion of human insulin, obviating in vivo maturation to achieve functionality, and offering a scalable approach for in vitro generation of functional human beta cells.
  4. Vitamin D switches BAF complexes to protect β cells,by DRC member Evans and others in Cell(2018). The vitamin D receptor (VDR) is a key modulator of inflammation and β cell survival. Alternative recognition of an acetylated lysine in VDR by bromodomain proteins BRD7 and BRD9 directs association to
    PBAF and BAF chromatin remodeling complexes, respectively. Importantly, pharmacological inhibition of
    BRD9 promotes PBAF-VDR association to restore β cell function and ameliorate hyperglycemia in murine T2Dmodels. These studies reveal an unrecognized VDR-dependent transcriptional program underpinning β cellsurvival and identifies the VDR:PBAF/BAF association as a potential therapeutic target for T2D.