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.

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Figure 1: Cytokines regulate oxidative and ER stress in mouse MIN6N8 insulinoma beta cells.
Figure 2: Cytokine-regulated oxidative and ER stress affects islet insulin secretion.
Figure 3: Inflammation and oxidative stress gene expression in mouse obesity and diabetes.
Figure 4: Targeting cytokine-induced ER stress in HFDIO improves glucose tolerance and hyperinsulinemia.
Figure 5: Extended IL-22 treatment in HFDIO restores glucose tolerance and insulin sensitivity, normalizes islet insulin secretion and suppresses oxidative stress, ER stress and inflammation.
Figure 6: IL-22 protects human islets from oxidative stress and ER stress.

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Acknowledgements

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-XBP1ΔDBD-venus was a kind gift from M. Miura, University of Tokyo. Anti–IL-23 was a gift from Eli Lilly.

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S.Z.H., J.M.F., J.P.W., J.B.P. and M.A.M. developed the concept, designed the experiments, interpreted the data and wrote the manuscript. S.Z.H. was involved in all the experimental work and data analysis. D.J.B. conducted studies with mouse islets. B.E.H. conducted the studies in db/db mice. H.T., C.P.N., I.D., R.W. and A.C.-H.C. conducted experiments in HFD mice. T.L., T.W.K. and H.E.T. isolated human islets and contributed to experiments with human islets. Y.H.S. conducted flow cytometry experiments. B.E.H., D.J.B., H.T., Y.H.S., C.P.N., I.D., R.W., A.C.-H.C., T.L., T.W.K. and H.E.T. contributed to redrafting of the manuscript.

Corresponding author

Correspondence to Michael A McGuckin.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Tables 1–5. (PDF 1731 kb)

DHE activation in vehicle control–treated cells.

MIN6N8 cells were loaded with dihydroethidium (DHE) which fluoresces and binds DNA after oxidation by O2 – and the nuclear dye DAPI. Cells were exposed to vehicle only 50 ng mL–1 IL-23 for 30 min ± 50 ng mL–1 IL-22 at the same time or 30 min prior to IL-23. Live cell imaging in MIN6N8 cells was carried out at 37 °C in 5% CO2 in a chamber using an Olympus xcellence rt microscope. Time-lapse imaging (three frames/min for 30 min) was utilized to determine DHEconversion/ fluorescence in cells after treatment. DAPI staining was captured to visualize nuclei. The original TIFF images were compressed into JPG format to prepare the videos to reduce file size. Individual experiment conducted in a single plate at the same time. (MP4 1174 kb)

DHE activation in IL-23–treated cells.

MIN6N8 cells were loaded with dihydroethidium (DHE) which fluoresces and binds DNA after oxidation by O2 – and the nuclear dye DAPI. Cells were exposed to vehicle only 50 ng mL–1 IL-23 for 30 min ± 50 ng mL–1 IL–22 at the same time or 30 min prior to IL-23. Live cell imaging in MIN6N8 cells was carried out at 37 °C in 5% CO2 in a chamber using an Olympus xcellence rt microscope. Time-lapse imaging (three frames/min for 30 min) was utilized to determine DHEconversion/ fluorescence in cells after treatment. DAPI staining was captured to visualize nuclei. The original TIFF images were compressed into JPG format to prepare the videos to reduce file size. Individual experiment conducted in a single plate at the same time. (MP4 6486 kb)

DHE activation in cells concomitantly treated with IL-23 and IL-22.

MIN6N8 cells were loaded with dihydroethidium (DHE) which fluoresces and binds DNA after oxidation by O2 – and the nuclear dye DAPI. Cells were exposed to vehicle only 50 ng mL–1 IL-23 for 30 min ± 50 ng mL–1 IL-22 at the same time or 30 min prior to IL-23. Live cell imaging in MIN6N8 cells was carried out at 37 °C in 5% CO2 in a chamber using an Olympus xcellence rt microscope. Time-lapse imaging (three frames/min for 30 min) was utilized to determine DHEconversion/ fluorescence in cells after treatment. DAPI staining was captured to visualize nuclei. The original TIFF images were compressed into JPG format to prepare the videos to reduce file size. Individual experiment conducted in a single plate at the same time. (MP4 21777 kb)

DHE activation in cells treated with IL-23 following a 30 min pretreatment with IL-22.

MIN6N8 cells were loaded with dihydroethidium (DHE) which fluoresces and binds DNA after oxidation by O2 – and the nuclear dye DAPI. Cells were exposed to vehicle only 50 ng mL–1 IL-23 for 30 min ± 50 ng mL–1 IL-22 at the same time or 30 min prior to IL-23. Live cell imaging in MIN6N8 cells was carried out at 37 °C in 5% CO2 in a chamber using an Olympus xcellence rt microscope. Time-lapse imaging (three frames/min for 30 min) was utilized to determine DHEconversion/ fluorescence in cells after treatment. DAPI staining was captured to visualize nuclei. The original TIFF images were compressed into JPG format to prepare the videos to reduce file size. Individual experiment conducted in a single plate at the same time. (MP4 665 kb)

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Hasnain, S., Borg, D., Harcourt, B. et al. Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress. Nat Med 20, 1417–1426 (2014). https://doi.org/10.1038/nm.3705

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