Coping with stress: IL-22 and cytokines in beta cell function

Abstract

b-cell dysfunction in type 2 diabetes is accompanied by adverse cellular responses to high concentrations of lipids/glucose, oxidative stress, endoplasmic reticulum (ER) stress and local inflammation, although the relative contribution of these inter-related factors has remained unclear. Here we present the first evidence that a suite of cytokines, previously not identified as contributors to b-cell dysfunction, induce ER stress, thereby impairing insulin biosynthesis and secretion, whereas another cytokine, IL-22, suppresses ER stress and restores insulin production. The IL-22 receptor (IL-22R1) is most highly expressed by islet secretory cells and IL-22 directly acted to down-regulate pro-oxidant genes and up-regulates anti-oxidant genes in murine MIN6N8 b-cells and islets, and human islets. IL- 22R1 neutralising antibodies induce oxidative/ER stress in healthy mouse and human islets, demonstrating that IL-22-IL-22R1 signalling maintains islet homeostasis. Islets from mice with high fat diet-induced obesity show immune activation, chronic ER stress and hypersecretion of insulin. Ex-vivo exposure to IL-22 suppresses ER stress and chemokine production, and reduces glucose-stimulated insulin secretion. Systemic administration of recombinant IL-22 to diabetic mice eliminated pancreatic ER stress and decreased pancreatic inflammation, while reversing b-cell abnormalities. IL- 22 promoted high quality insulin production (decreased serum proinsulin by 92%), which restored glucose homeostasis without altering peripheral insulin sensitivity. However, after 4 weeks treatment serum proinsulin returned to normal levels and insulin sensitivity was restored. Taken together these data suggest that IL-22 is a natural regulator of b-cell insulin biosynthesis and secretion, protecting the b-cell from stress, preventing hypersecretion of poor quality insulin, and suppressing innate islet inflammation.L720731462015-11-20 <br />