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

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          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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          Endoplasmic reticulum stress in liver disease.

          Harmeet Malhi, Randal Kaufman (2011)
          The unfolded protein response (UPR) is activated upon the accumulation of misfolded proteins in the endoplasmic reticulum (ER) that are sensed by the binding immunoglobulin protein (BiP)/glucose-regulated protein 78 (GRP78). The accumulation of unfolded proteins sequesters BiP so it dissociates from three ER-transmembrane transducers leading to their activation. These transducers are inositol requiring (IRE) 1α, PKR-like ER kinase (PERK), and activating transcription factor (ATF) 6α. PERK phosphorylates eukaryotic initiation factor 2 alpha (eIF2α) resulting in global mRNA translation attenuation, and concurrently selectively increases the translation of several mRNAs, including the transcription factor ATF4, and its downstream target CHOP. IRE1α has kinase and endoribonuclease (RNase) activities. IRE1α autophosphorylation activates the RNase activity to splice XBP1 mRNA, to produce the active transcription factor sXBP1. IRE1α activation also recruits and activates the stress kinase JNK. ATF6α transits to the Golgi compartment where it is cleaved by intramembrane proteolysis to generate a soluble active transcription factor. These UPR pathways act in concert to increase ER content, expand the ER protein folding capacity, degrade misfolded proteins, and reduce the load of new proteins entering the ER. All of these are geared toward adaptation to resolve the protein folding defect. Faced with persistent ER stress, adaptation starts to fail and apoptosis occurs, possibly mediated through calcium perturbations, reactive oxygen species, and the proapoptotic transcription factor CHOP. The UPR is activated in several liver diseases; including obesity associated fatty liver disease, viral hepatitis, and alcohol-induced liver injury, all of which are associated with steatosis, raising the possibility that ER stress-dependent alteration in lipid homeostasis is the mechanism that underlies the steatosis. Hepatocyte apoptosis is a pathogenic event in several liver diseases, and may be linked to unresolved ER stress. If this is true, restoration of ER homeostasis prior to ER stress-induced cell death may provide a therapeutic rationale in these diseases. Herein we discuss each branch of the UPR and how they may impact hepatocyte function in different pathologic states. Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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            The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation.

            Holly K. Bryan, Adedamola Olayanju, Christopher E. Goldring … (2013)
            The transcription factor Nrf2 (NF-E2-related factor 2) plays a vital role in maintaining cellular homeostasis, especially upon the exposure of cells to chemical or oxidative stress, through its ability to regulate the basal and inducible expression of a multitude of antioxidant proteins, detoxification enzymes and xenobiotic transporters. In addition, Nrf2 contributes to diverse cellular functions including differentiation, proliferation, inflammation and lipid synthesis and there is an increasing association of aberrant expression and/or function of Nrf2 with pathologies including cancer, neurodegeneration and cardiovascular disease. The activity of Nrf2 is primarily regulated via its interaction with Keap1 (Kelch-like ECH-associated protein 1), which directs the transcription factor for proteasomal degradation. Although it is generally accepted that modification (e.g. chemical adduction, oxidation, nitrosylation or glutathionylation) of one or more critical cysteine residues in Keap1 represents a likely chemico-biological trigger for the activation of Nrf2, unequivocal evidence for such a phenomenon remains elusive. An increasing body of literature has revealed alternative mechanisms of Nrf2 regulation, including phosphorylation of Nrf2 by various protein kinases (PKC, PI3K/Akt, GSK-3β, JNK), interaction with other protein partners (p21, caveolin-1) and epigenetic factors (micro-RNAs -144, -28 and -200a, and promoter methylation). These and other processes are potentially important determinants of Nrf2 activity, and therefore may contribute to the maintenance of cellular homeostasis. Here, we dissect evidence supporting these Keap1-dependent and -independent mechanisms of Nrf2 regulation. Furthermore, we highlight key knowledge gaps in this important field of biology, and suggest how these may be addressed experimentally. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Thioredoxin-interacting protein mediates ER stress-induced β cell death through initiation of the inflammasome.

              Christine M Oslowski, Takashi Hara, Bryan O'Sullivan-Murphy … (2012)
              Recent clinical and experimental evidence suggests that endoplasmic reticulum (ER) stress contributes to the life-and-death decisions of β cells during the progression of type 1 and type 2 diabetes. Although crosstalk between inflammation and ER stress has been suggested to play a significant role in β cell dysfunction and death, a key molecule connecting ER stress to inflammation has not been identified. Here we report that thioredoxin-interacting protein (TXNIP) is a critical signaling node that links ER stress and inflammation. TXNIP is induced by ER stress through the PERK and IRE1 pathways, induces IL-1β mRNA transcription, activates IL-1β production by the NLRP3 inflammasome, and mediates ER stress-mediated β cell death. Collectively, our results suggest that TXNIP is a potential therapeutic target for diabetes and ER stress-related human diseases such as Wolfram syndrome. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Nat. Med.
                Title: Nature medicine
                ISSN (Electronic): 1546-170X
                ISSN (Print): 1078-8956
                Publication date (Electronic): Dec 2014
                Volume: 20
                Issue: 12
                Affiliations
                [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.
                Article
                Publisher Item ID: nm.3705
                DOI: 10.1038/nm.3705
                PubMed ID: 25362253
                SO-VID: 7defba01-5b2f-4f53-916d-354db7763df5
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