Potential Diabetes Drug Works by Relieving Endoplasmic Reticulum Stress

A recent paper linked stress affecting the endoplasmic reticulum (ER) to the development of several chronic diseases including diabetes, retinitis pigmentosa, cystic fibrosis, Huntington's disease, and Alzheimer's disease.

The ER plays a critical role in protein, lipid, and glucose metabolism as well as cellular calcium signaling and homeostasis. Disruptions of ER function and chronic ER stress have been associated with many disease states ranging from diabetes and neurodegenerative diseases to cancer and inflammation. Although ER targeting shows therapeutic promise in preclinical models of obesity and other diseases, available drugs generally lack the specificity and other pharmacological properties required for effective clinical use.

To gain a better understanding of how the ER connects to disease development, investigators at Harvard University Medical School (Boston, MA, USA) designed and chemically and genetically validated two high-throughput functional screening systems that independently measured the free chaperone content and protein-folding capacity of the ER in living cells.

Using these screening platforms they characterized a small-molecule compound, azoramide (N-{2-[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]ethyl}butanamide), which improved ER protein-folding ability and activated ER chaperone capacity to protect cells against ER stress in multiple systems.

They further reported in the June 17, 2015, online edition of the journal Science Translational Medicine that azoramide exhibited potent anti-diabetic efficacy in two independent mouse models of obesity by improving insulin sensitivity and pancreatic beta cell function.

"While we and others had previously discovered the central role that ER stress plays in diabetes and metabolic disease, efforts to translate that knowledge into clinically effective ways to improve ER function have had limited success so far," said senior author, Dr. Gokhan S. Hotamisligil, professor of genetics and complex diseases at Harvard University Medical School. "These results show the broad potential for azoramide or drugs with similar functions targeted at the endoplasmic reticulum. ER dysfunction is implicated in many other disease processes such as cystic fibrosis, Huntington's disease, and Alzheimer's, which makes this novel screening strategy an exciting new tool that can be applied by multiple labs to discover new drug candidates for diseases that are linked to ER stress."

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Harvard University Medical School