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

Hasnain, Sumaira Z., Borg, Danielle J., Harcourt, Brooke E. , Tong, Hui, Sheng, Yonhua H., Ng, Choa ping, Das, Indrajit, Wang, Ran, Chen, Alice C.-H., Loudovaris, Thomas, Kay, Thomas W., Thomas, Helen E., Whitehead, Jonathan P., Forbes, Josephine M., Prins, Johannes B. and McGuckin, Michael A. (2014) Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress. Nature Medicine, 20 (12). pp. 1417-1426. ISSN 1078-8956

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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. © 2015 Nature America, Inc.

Keywords:insulin, interleukin 22, interleukin 23, interleukin 24, interleukin 33, proinsulin, cytokine, glucose blood level, IL33 protein, human, interleukin derivative, interleukin-22, interleukin-24, interleukin-33, mouse, animal cell, animal experiment, animal model, animal tissue, Article, cell activity, controlled study, endoplasmic reticulum stress, glucose homeostasis, glucose tolerance, glycemic control, human, human cell, hyperglycemia, inflammation, insulin release, insulin resistance, insulin sensitivity, insulin synthesis, mouse, non insulin dependent diabetes mellitus, nonhuman, obesity, oxidative stress, pancreas islet beta cell, priority journal, animal, drug effects, gene expression regulation, immunology, metabolism, pancreas islet, secretion (process), Mus, Animals, Blood Glucose, Cytokines, Diabetes Mellitus, Type 2, Humans, Insulin-Secreting Cells, Interleukin-23, Interleukins, Islets of Langerhans, Mice
Subjects:C Biological Sciences > C730 Metabolic Biochemistry
A Medicine and Dentistry > A100 Pre-clinical Medicine
C Biological Sciences > C130 Cell Biology
Divisions:College of Science > School of Life Sciences
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ID Code:26208
Deposited On:14 Mar 2018 16:47

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