PKR inhibitors suppress endoplasmic reticulum stress and subdue glucolipotoxicitymediated impairment of insulin secretion in pancreatic beta cells

Abstract

Type 2 diabetes mellitus is characterized by insulin resistance and hypersecretion of insulin from the pancreas to compensatefor decreased insulin sensitivity in the peripheral tissues. In later stages of the disease insulin-secreting beta cell degeneration commencesand patients require insulin replacement therapy in order to accomplish proper regulation of their blood glucose. Endoplasmicreticulum (ER) stress in the beta cells is one of the factors contributing to this detrimental effect. Protein kinase R (PKR) is a cellularstress kinase activated by ER stress and contributing to degeneration of pancreatic islets. In order to determine whether inhibition ofPKR activation by specific small molecule inhibitors of PKR ameliorates pancreatic insulin secretion capacity, we treated beta cells withtwo imidazole/oxindole-derived inhibitors of PKR kinase, imoxin (C16) and 2-aminopurine (2-AP), in the presence of ER stress. Ourresults demonstrate that PKR inhibition suppresses tunicamycin-mediated ER stress without altering the insulin production capacityof the cells. Palmitic acid-mediated suppression of insulin secretion, however, was subdued significantly by PKR inhibitor treatmentthrough an ER stress-related mechanism. We suggest that PKR inhibitor treatment may be used to increase the insulin secretion capacityof the pancreas in later stages of diabetes.