IL-22 is a thought to function mainly in the skin and mucosae where it boosts barrier function and wound repair. However, the IL-22 receptor (IL-22R1) is most highly expressed in the pancreas. In murine MIN6N8 β-cells IL-22 potently suppresses ER stress induced by palmitate, inflammatory cytokines or tunicamycin. Healthy murine islets cultured in IL-22R1 antibody showed increased ER stress and decreased glucose-stimulated insulin secretion (GSIS), demonstrating that IL-22-IL-22R1 signalling is a component of normal islet function. Healthy islets exposed to ER stress-inducing cytokines or tunicamycin had diminished GSIS, however co-culture with IL-22 prevented ER stress and normalised GSIS. In contrast, in islets from mice with high fat diet induced obesity (HFDIO) which showed chronic ER stress and hypersecretion of insulin, IL-22 suppressed ER stress and reduced GSIS to that seen in non-obese islets. HFDIO mice treated with IL-22 normalised random fed blood glucose within 7 days and showed normal glucose tolerance and fasting insulin by 2 weeks, at which time insulin resistance was unchanged. However, by 4 weeks of treatment insulin sensitivity was largely restored. Islets from IL-22-treated mice showed greatly reduced proinsulin secretion in response to challenge with glucose and GLP-1. IL-22 treated islets also had near complete suppression of ER stress and inflammation, increased stored insulin and decreased proinsulin. Taken together these data suggest that IL-22 is a natural regulator of β-cell insulin biosynthesis and secretion, protecting the β-cell from ER stress and preventing the hypersecretion of poor quality insulin seen in obesity.