title: Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress.
abstract: In type 2 diabetes, hyperglycemia is present when an increased demand for insulin, typically due to insulin resistance, is not met as a result of progressive pancreatic beta cell dysfunction. This defect in beta cell activity is typically characterized by impaired insulin biosynthesis and secretion, usually accompanied by oxidative and endoplasmic reticulum (ER) stress. We demonstrate that multiple inflammatory cytokines elevated in diabetic pancreatic islets induce beta cell oxidative and ER stress, with interleukin-23 (IL-23), IL-24 and IL-33 being the most potent. Conversely, we show that islet-endogenous and exogenous IL-22, by regulating oxidative stress pathways, suppresses oxidative and ER stress caused by cytokines or glucolipotoxicity in mouse and human beta cells. In obese mice, antibody neutralization of IL-23 or IL-24 partially reduced beta cell ER stress and improved glucose tolerance, whereas IL-22 administration modulated oxidative stress regulatory genes in islets, suppressed ER stress and inflammation, promoted secretion of high-quality efficacious insulin and fully restored glucose homeostasis followed by restitution of insulin sensitivity. Thus, therapeutic manipulation of immune regulators of beta cell stress reverses the hyperglycemia central to diabetes pathology.
authors.affiliation: Mucosal Diseases Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Sumaira Z
authors.initials: SZ
authors.lastname: Hasnain
authors.affiliation: Glycation &Diabetes Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Danielle J
authors.initials: DJ
authors.lastname: Borg
authors.affiliation: Glycation &Diabetes Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Harcourt
authors.affiliation: Mucosal Diseases Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Hui
authors.initials: H
authors.lastname: Tong
authors.affiliation: Mucosal Diseases Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Yonghua H
authors.initials: YH
authors.lastname: Sheng
authors.affiliation: Metabolic Medicine Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Choa Ping
authors.initials: CP
authors.lastname: Ng
authors.affiliation: Mucosal Diseases Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Indrajit
authors.initials: I
authors.lastname: Das
authors.affiliation: Mucosal Diseases Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Ran
authors.initials: R
authors.lastname: Wang
authors.affiliation: Mucosal Diseases Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Alice C-H
authors.initials: AC
authors.lastname: Chen
authors.affiliation: St. Vincent's Research Institute, Melbourne, Victoria, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Loudovaris
authors.affiliation: St. Vincent's Research Institute, Melbourne, Victoria, Australia.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kay
authors.affiliation: St. Vincent's Research Institute, Melbourne, Victoria, Australia.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Thomas
authors.affiliation: 1] Metabolic Medicine Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia. [2] School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Whitehead
authors.affiliation: 1] Glycation &Diabetes Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia. [2] School of Medicine, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Forbes
authors.affiliation: 1] Metabolic Medicine Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia. [2] School of Medicine, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Johannes B
authors.initials: JB
authors.lastname: Prins
authors.affiliation: 1] Mucosal Diseases Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia. [2] School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia. [3] School of Medicine, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McGuckin
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D016207:Cytokines / Q000276:immunology*; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000378:metabolism; D053759:Interleukin-23 / Q000276:immunology; D000067596:Interleukin-33; D007378:Interleukins / Q000276:immunology / Q000494:pharmacology; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology; D000097043:Interleukin-22; D000099180:Interleukin-24
chemical_list: D001786:Blood Glucose; D016207:Cytokines; D007328:Insulin; D053759:Interleukin-23; D000067596:Interleukin-33; D007378:Interleukins; D000097043:Interleukin-22; D000099180:Interleukin-24; C506536:IL33 protein, human; C506535:Il33 protein, mouse