SENP1 IN ISLET COMPENSATION AND FAILURE DURING HIGH FAT FEEDING

Abstract

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.