IRE1 alpha inhibitors for type 2 diabetes

DESCRIPTION provided by applicant The American Diabetes Association has declared type diabetes T D a public health crisis T D begins as a state of compensated insulin resistance frank disease develops when of insulin producing pancreatic islet cells of affected individuals undergo cell death Endoplasmic reticulum ER stress has emerged as a central underlying mechanism that drives the progression from obesity to T D In the periphery obesity induced ER stress can impair proper insulin signaling In pancreatic islets glucotoxicity and lipotoxicity induced ER stress contributes to cell dysfunction and apoptosis We have identified IRE as the master unfolded protein response regulator that determines cell fate under ER stress and have demonstrated that IRE inhibitors we call KIRAs Kinase Inhibitor RNase Attenuators block ER stress driven cell dysfunction and apoptosis in vivo We believe that KIRAs will also act to reduce peripheral insulin resistance and propose proof of concept experiments addressing insulin signaling in the liver We will demonstrate that KIRAs can correct faulty insulin signaling in ER stress challenged liver cells and optimize their profile to support subsequent development in T D We believe a drug intervention that addresses both peripheral insulin resistance and pancreatic cell dysfunction and apoptosis has great disease modifying potential The specific aims of the proposal are Demonstrate that KIRAs can correct insulin signaling in a cellular model of insulin resistance and Optimize KIRAs to impart a profile that supports development in T D PUBLIC HEALTH RELEVANCE Type diabetes affects over million Americans with healthcare and lost producitivty costs exceeding $ billion per year We are proposing new strategies that have the potential to improve both insulin resistance and cell function and longevity These efforts represent significant steps towards the development of a novel oral treatment to improve glycemic control in type diabetics with the unique potential to modify disease progression