Pharmacological Targeting of IRE1α Ameliorates Insulin Resistance Through Preservation of the Insulin Receptor Signaling Pathway

Type 2 Diabetes (T2D) is characterized by a combination of factors that ultimately lead to loss of glycemic control. These factors include insulin resistance in insulin-responsive tissues (liver, muscle, and adipose tissues), and a progressive decline in -cell mass and function. In addition, more than half of T2D patients are obese and more than 85% are overweight, which in turn contribute to the observed insulin resistance. It has been reported that obesity induces Endoplasmic Reticulum (ER) stress, which leads to peripheral insulin resistance and ultimately to T2D, yet the underlying mechanisms are not well understood. Using two different mouse models, we found that obesity and a high fat diet induces activation of the bifunctional ER transmembrane kinase/endoribonuclease (RNase)–IRE1– and subsequent insulin desensitization by blunting phosphorylation of AKT. A mono-selective kinase inhibitor that allosterically attenuates IRE1’s RNase activity–KIRA8– prevented hyperglycemia, restored systemic insulin sensitivity, improved blood glucose clearance, enhanced insulin response in the liver and adipose tissues, and preserved pancreatic β-cell mass. Using chemical genetics tools of IRE1α we demonstrate that hyperactivation of IRE1 is sufficient to disrupt the insulin receptor signaling pathway. Our results demonstrate the potential efficacious properties of targeting IRE1α to enhance the adaptive capacity of the ER and prevent both peripheral insulin resistance and pancreatic β-cell loss