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      High Mobility Group Box-1 and Diabetes Mellitus Complications: State of the Art and Future Perspectives

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          Abstract

          Diabetes mellitus (DM) is an endemic disease, with growing health and social costs. The complications of diabetes can affect potentially all parts of the human body, from the heart to the kidneys, peripheral and central nervous system, and the vascular bed. Although many mechanisms have been studied, not all players responsible for these complications have been defined yet. High Mobility Group Box-1 (HMGB1) is a non-histone nuclear protein that has been implicated in many pathological processes, from sepsis to ischemia. The purpose of this review is to take stock of all the most recent data available on the role of HMGB1 in the complications of DM.

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          Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study.

          J. Spranger, A Kroke, M Möhlig … (2003)
          A subclinical inflammatory reaction has been shown to precede the onset of type 2 (non-insulin-dependent) diabetes. We therefore examined prospectively the effects of the central inflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) on the development of type 2 diabetes. We designed a nested case-control study within the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study including 27,548 individuals. Case subjects were defined to be those who were free of type 2 diabetes at baseline and subsequently developed type 2 diabetes during a 2.3-year follow-up period. A total of 192 cases of incident type 2 diabetes were identified and matched with 384 non-disease-developing control subjects. IL-6 and TNF-alpha levels were found to be elevated in participants with incident type 2 diabetes, whereas IL-1beta plasma levels did not differ between the groups. Analysis of single cytokines revealed IL-6 as an independent predictor of type 2 diabetes after adjustment for age, sex, BMI, waist-to-hip ratio (WHR), sports, smoking status, educational attainment, alcohol consumption, and HbA(1c) (4th vs. the 1st quartile: odds ratio [OR] 2.6, 95% CI 1.2-5.5). The association between TNF-alpha and future type 2 diabetes was no longer significant after adjustment for BMI or WHR. Interestingly, combined analysis of the cytokines revealed a significant interaction between IL-1beta and IL-6. In the fully adjusted model, participants with detectable levels of IL-1beta and elevated levels of IL-6 had an independently increased risk to develop type 2 diabetes (3.3, 1.7-6.8), whereas individuals with increased concentrations of IL-6 but undetectable levels of IL-1beta had no significantly increased risk, both compared with the low-level reference group. These results were confirmed in an analysis including only individuals with HbA(1c) <5.8% at baseline. Our data suggest that the pattern of circulating inflammatory cytokines modifies the risk for type 2 diabetes. In particular, a combined elevation of IL-1beta and IL-6, rather than the isolated elevation of IL-6 alone, independently increases the risk of type 2 diabetes. These data strongly support the hypothesis that a subclinical inflammatory reaction has a role in the pathogenesis of type 2 diabetes.
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            Assembly and localization of Toll-like receptor signalling complexes.

            Nicholas J. Gay, Martyn Symmons, Monique Gangloff … (2014)
            Signal transduction by the Toll-like receptors (TLRs) is central to host defence against many pathogenic microorganisms and also underlies a large burden of human disease. Thus, the mechanisms and regulation of signalling by TLRs are of considerable interest. In this Review, we discuss the molecular basis for the recognition of pathogen-associated molecular patterns, the nature of the protein complexes that mediate signalling, and the way in which signals are regulated and integrated at the level of allosteric assembly, post-translational modification and subcellular trafficking of the components of the signalling complexes. These fundamental molecular mechanisms determine whether the signalling output leads to a protective immune response or to serious pathologies such as sepsis. A detailed understanding of these processes at the molecular level provides a rational framework for the development of new drugs that can specifically target pathological rather than protective signalling in inflammatory and autoimmune disease.
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              Reversing established sepsis with antagonists of endogenous high-mobility group box 1.

              H. Yang, M Ochani, J. LI … (2004)
              Despite significant advances in intensive care therapy and antibiotics, severe sepsis accounts for 9% of all deaths in the United States annually. The pathological sequelae of sepsis are characterized by a systemic inflammatory response, but experimental therapeutics that target specific early inflammatory mediators [tumor necrosis factor (TNF) and IL-1beta] have not proven efficacious in the clinic. We recently identified high mobility group box 1 (HMGB1) as a late mediator of endotoxin-induced lethality that exhibits significantly delayed kinetics relative to TNF and IL-1beta. Here, we report that serum HMGB1 levels are increased significantly in a standardized model of murine sepsis, beginning 18 h after surgical induction of peritonitis. Specific inhibition of HMGB1 activity [with either anti-HMGB1 antibody (600 microg per mouse) or the DNA-binding A box (600 microg per mouse)] beginning as late as 24 h after surgical induction of peritonitis significantly increased survival (nonimmune IgG-treated controls = 28% vs. anti-HMGB1 antibody group = 72%, P < 0.03; GST control protein = 28% vs. A box = 68%, P < 0.03). Animals treated with either HMGB1 antagonist were protected against the development of organ injury, as evidenced by improved levels of serum creatinine and blood urea nitrogen. These observations demonstrate that specific inhibition of endogenous HMGB1 therapeutically reverses lethality of established sepsis indicating that HMGB1 inhibitors can be administered in a clinically relevant time frame.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 11 December 2019
                Publication date Collection: December 2019
                Volume: 20
                Issue: 24
                Electronic Location Identifier: 6258
                Affiliations
                [1 ]U.O.C. Clinica Medica e Malattie Vascolari, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy; g.pecorini@ 123456gmail.com (G.P.); raffaele.landolfi@ 123456unicatt.it (R.L.); andrea.flex@ 123456unicatt.it (A.F.)
                [2 ]Laboratory of Vascular Biology and Genetics, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
                [3 ]Università Cattolica del Sacro Cuore, 00168 Roma, Italy; m.margheritarando@ 123456gmail.com (M.M.R.); elisabetta.nardella@ 123456gmail.com (E.N.); alcech92@ 123456gmail.com (A.L.C.)
                Author notes
                [* ]Correspondence: f.biscetti@ 123456gmail.com ; Tel.: +39-06-3015-4335; Fax: +39-06-3550-7232
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-7449-657X
                Article
                Publisher ID: ijms-20-06258
                DOI: 10.3390/ijms20246258
                PMC ID: 6940913
                PubMed ID: 31835864
                SO-VID: 170e9cf4-c0fc-47fb-9ab8-744653b0c8b7
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 23 November 2019
                Date accepted : 09 December 2019
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: high mobility group box-1 (hmgb1),diabetes mellitus,vascular complications
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: high mobility group box-1 (hmgb1), diabetes mellitus, vascular complications

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