• Author / Creator
    Lin, Haopeng
  • Pancreatic β-cells are paramount for optimizing insulin secretion to metabolic need. The progression from non-diabetes to type 2 diabetes (T2D) is accompanied by β-cell compensation and decompensation. While β-cell decompensation is a hallmark of overt diabetes, β-cell compensation promotes insulin output, either through functional or mass increases, to maintain normoglycemia. The sentrin-specific SUMO protease-1 (SENP1) reverses a post translational modification (PTM) called SUMOylation, and this is required for physiological β-cell function. In contrast, SENP1 exerts a negative effect on β-cell survival under oxidative stress. This dual and opposite effect on function and survival has not been reconciled in the context of metabolic stress, where both β-cell functional and mass compensation are essential to maintain glucose homeostasis.
    The present thesis shows that in short-term HFD exposure, an early stage of compensation where functional compensation is predominant, adaptive glucose-stimulated insulin secretion is accounted for by upregulation of cytosolic reducing signaling via SENP1, redox regulation of which is fine-tuned by a coordinated interaction between Zn2+ and cysteines 603 and 535 of the SENP1 catalytic domain. Loss of β-cell SENP1 impairs intraperitoneal glucose tolerance. Furthermore, under long-term high fat diet (HFD) exposure with decompensated glucose-stimulated insulin secretion and pronounced islet mass expansion, islet and -cell SENP1 is required for maintaining oral glucose tolerance by ensuring robust incretin-stimulated insulin secretion at a point downstream of incretin receptors. Importantly, loss of SENP1 does not have any harmful effect on β-cell mass compensation.
    These findings elucidate the molecular basis of SENP1 redox sensing and provide insights into the mechanisms how β-cell adopts different strategies for functional compensation at different stages of compensation, establishing an indispensable role of SENP1 for β-cell functional compensation to maintain normoglycemia. Targeting SENP1 might emerge as a therapeutic intervention to rescue the β-cell functional decompensation commonly seen in T2D.

  • Subjects / Keywords
  • Graduation date
    Spring 2022
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.