Elucidation of the Mechanism of IL-22-Mediated Suppression of Beta-Cell Stress in Diabetes (2016–2017)
Abstract:
We have discovered that the cytokine IL-22 is a potent endogenous suppressor of oxidative and endoplasmic reticulum (ER) stress in pancreatic ¿¿-cells. Treatment of obese diabetic mice with IL-22 has multiple favourable effects including: full restoration of glucose tolerance, suppression of hyperinsulinaemia and hyperproinsulinaemia, restoration of insulin sensitivity, redistribution of fat to healthy fat pads, and reduced body mass. At the cellular/molecular level these physiological changes are accompanied by reduced oxidative and ER stress in islets in both ¿¿-cells and ¿¿-cells, reduced inflammation in islets, and restoration of biosynthesis and secretion of high quality insulin. Thus we have discovered a novel biological with great promise as a therapy for type 2, and possibly type 1, diabetes. In this project we seek to fully determine the intracellular mechanisms of action of IL-22 using RNA Seq to determine the genes that are regulated by IL-22 that mediate its protective effects. We will then undertake functional studies to further explore which of these genes are most critical to suppression of stress. Deepening understanding of the mechanisms of action of IL-22 will not only expand knowledge of the pathophysiology of type 2 diabetes, but also provide new pathways for therapy in addition to administration of IL-22 as a biological drug. While this project is focused on type 2 diabetes, oxidative and ER stress are considered to be important contributors to autoimmune-mediated death of ¿¿-cells in type 1 diabetes. Thus the insights gained may have relevance for protecting ¿¿-cells in type 1 diabetes. This grant would be best reviewed by assessors with knowledge of endocrinological dysfunction in type 2 diabetes, ¿¿-cell biology and/or gene expression analysis.
