Project #2 

Tsai  Lab

Mechanism regulating ER protein quality control of mutant proinsulin

     Diabetes Mellitus (DM) affects over 29 million people in the US. It is the 7th leading cause of death in the US and remains a global health concern. As this disease can result from inefficient insulin secretion by pancreatic -cells, proper regulation of this process is vital to prevent DM. Insulin is made as proinsulin in the ER. When proinsulin is properly folded, it exits the ER, transports to the Golgi, and sorts to secretory granules where proinsulin is converted to insulin. Fusion of the secretory granules with the plasma membrane releases insulin to the extracellular milieu, enabling this hormone to execute its physiologic function.

     In this context, 29 genetic mutations in the human insulin gene are known to cause a new genetic metabolic disease called Mutant INS-gene-induced Diabetes of Youth (MIDY), an early onset type 1 DM without islet autoantibodies. Most of these mutations are believed to block proper folding of mutant proinsulin in the ER, thereby impairing their ER exit and eventual secretion. However, the absence of mutant insulin secretion is not directly responsible for disease. Instead, mutant proinsulin is hypothesized to impart a toxic gain-of-function effect on WT insulin secretion by forming aggregated high molecular weight (MW) complexes with WT proinsulin (Figure 2). This prevents proper folding of WT proinsulin in the ER essential for its ER exit, maturation, and secretion. A decrease in insulin secretion leads to hyperglycemia, consequently instructing -cells to upregulate even more mutant and WT proinsulins. The resulting severe ER stress leads to -cell demise. In this scenario, we envision that eliminating mutant proinsulins in the ER would counteract this disease phenotype. This motivates us to examine whether an ER protein quality control pathway exists to degrade the MIDY mutants. If so, we will evalulate if enhancing this pathway might restore WT insulin secretion, thereby alleviating the disease.