Targeting Diabetes with a Novel Small Molecule Activator of Sarco/endoplasmic Reticulum Ca2+‐ATPase (SERCA)

Abstract

Diabetes represents an enormous burden due to the risk of complications and impact on mortality and morbidity. Endoplasmic reticulum (ER) stress has been shown to be a causative factor in diabetic pathophysiology. A major cause of ER stress is disturbed calcium homeostasis caused by dysfunctional Sarco/ER Ca2+‐ATPase (SERCA). Using novel screening methodology, we have developed a series of novel, drug‐like small molecules that activate SERCA and rescue various cell lines from ER stress‐induced cell death. Among our SERCA allosteric agonists, CDN1163 (CDN) significantly reduced the plasma levels of glucose and triglyceride in obese diabetic mice. Interestingly, the obese mice maintained a lower glucose level, identical to lean mice, for over 6 weeks after CDN has been administered. CDN also decreased hepatic steatosis and the expression of genes involved in gluconeogenesis and lipogenesis, and attenuated ER stress via PERK and IRE1a pathways independent of change in the expression of chaperones. Furthermore, CDN improved mitochondrial function through increased mitochondrial biogenesis and oxidative phosphorylation, upregulated the expression of antioxidant enzymes and attenuated ER stress‐induced apoptosis. Taken together, our data demonstrate that developing drug therapy that directly activates endogenous SERCA may constitute a novel therapeutic potential to treat diabetes. (NIH HL097357)