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Nat Med. 2014 Dec;20(12):1417-26. doi: 10.1038/nm.3705. Epub 2014 Nov 2.

Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress.

Author information

1
Mucosal Diseases Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
2
Glycation &Diabetes Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
3
Metabolic Medicine Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
4
St. Vincent's Research Institute, Melbourne, Victoria, Australia.
5
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.
6
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.
7
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.
8
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.

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.

PMID:
25362253
DOI:
10.1038/nm.3705
[Indexed for MEDLINE]

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