Type 2 diabetes (T2D) occurs when β-cell insulin secretion becomes insufficient in quality and quantity to control blood glucose in the face of insulin resistance. Although β-cell dysfunction is associated with pancreatic inflammation and endoplasmic reticulum (ER) stress, these have not been directly mechanistically linked. Here we present the first evidence that a suite of cytokines, previously not identified as contributors to β-cell dysfunction, induce ER stress, thereby impairing insulin biosynthesis and secretion, whereas another cytokine, IL-22, suppresses ER stress and restores insulin production. Screening a panel of cytokines on cultured MIN6 β-cells and murine pancreatic islets, we found the innate cytokines, IL-23, IL-24 and IL-33, were the most potent inducers of β-cell ER stress, and suppressed insulin secretion in response to glucose. These cytokines were elevated concomitantly with ER stress in the pancreatic islets of mice with high fat diet induced obesity (HFDIO) and in db/db leptin receptor deficient mice. Providing clinical relevance, genes encoding IL-24, IL-33 and the IL-33 receptor are amongst the most highly upregulated genes in a public domain data set comparing human T2D and normal islets. In mice with HFDIO, antibody neutralization of IL-23 or IL-24 for 2 weeks lowered pancreatic ER stress, and significantly improved glucose tolerance. In contrast, by screening combinations of cytokines and chemical ER stressors, we identified IL-22 as a potent suppressor of β-cell ER stress. Systemic administration of recombinant IL-22 to obese mice for 2 weeks eliminated pancreatic ER stress, decreased pancreatic chemokine and cytokine production, restored β-cell insulin stores, reversed fasting hyperinsulinaemia, decreased serum proinsulin by 92%, and completely restored glucose tolerance without altering peripheral insulin resistance. Thus we have identified specific non cell-autonomous regulation of β-cell ER stress by immunity, and shown that therapeutic manipulation of these pathways provides efficacious treatment, reversing the hyperglycaemia that drives diabetes pathology.