TY - JOUR
T1 - Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress
AU - Hasnain, Sumaira Z.
AU - Borg, Danielle J.
AU - Harcourt, Brooke E.
AU - Tong, Hui
AU - Sheng, Yonghua H.
AU - Ng, Choa Ping
AU - Das, Indrajit
AU - Wang, Ran
AU - Chen, Alice C.H.
AU - Loudovaris, Thomas
AU - Kay, Thomas W.
AU - Thomas, Helen E.
AU - Whitehead, Jonathan P.
AU - Forbes, Josephine M.
AU - Prins, Johannes B.
AU - McGuckin, Michael A.
N1 - Funding Information:
We would like to thank the staff of the Mater Research and Translational Research Institute Biological Research Facilities for care of experimental animals, L. Crowley and S. Roy for assistance with confocal microscopy, H. Nielsen for technical assistance with immunofluorescence staining, and A. Bertolotti and D. Serisier for discussions about the manuscript. J.M.F., J.P.W. and M.A.M. are or were supported by Australian National Health and Medical Research Council Senior Research Fellowships. The research was supported by Australian National Health and Medical Research Council Project Grant 1047905 and the Mater Foundation. MIN6N8 cells were a kind gift from J. Miyazaki, Osaka University. F-XBP1∆DBD-venus was a kind gift from M. Miura, University of Tokyo. Anti–IL-23 was a gift from Eli-Lilly.
Publisher Copyright:
© 2015 Nature America, Inc.
PY - 2014/12/1
Y1 - 2014/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/nm.3705
DO - 10.1038/nm.3705
M3 - Article
C2 - 25362253
AN - SCOPUS:84925581887
SN - 1078-8956
VL - 20
SP - 1417
EP - 1426
JO - Nature Medicine
JF - Nature Medicine
IS - 12
ER -