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    [Metabolic or immunometabolic syndrome?]. Wysocki Janusz,Skoczyński Szymon,Strózik Agnieszka,Hochuł Beata,Zyguła Magdalena Wiadomosci lekarskie (Warsaw, Poland : 1960) Understanding the risk and pathogenesis of the numerous disorders including the insulin resistance/metabolic syndrome has changed meaningfully in the recent years. The remarkable similarity of the risk factors of cardiovascular disease, type 2 diabetes mellitus, obesity and atherogenic dyslipidemia induced to search for their pathophysiology. The aim of these examinations was to determine if the inflammatory state is a soil of the metabolic syndrome as in atherosclerosis? Increasing number of studies demonstrates a series of statistically significant correlations between the inflammatory markers and diseases present in the metabolic syndrome. It allows for the reasonable basis of hypothesis that chronic, mild inflammatory state underlies not only the cardiovascular disease, but also is the soil of the metabolic syndrome pathologies and its complications development. Both associations between the inflammatory mediators as CRP, fibrinogen, alpha1-glycoproteins, leptin, TNFalpha, PAI-1 and the metabolic syndrome variables, chiefly obesity, seem to suggest that both atherosclerosis and insulin resistance are the results of chronic activation of the nonspecific (innate) immune system. According to this hypothesis, daily stresses as traumas, infections and emotions would lead to primary immune and neuroendocrine systems alterations. By this manner, whole body metabolic disorders and metabolic syndrome component progressive reveal would approach. In this context, metabolic syndrome might be defined as an immunemetabolic disease.
    Obesity: An Immunometabolic Perspective. Ray Indrani,Mahata Sushil K,De Rajat K Frontiers in endocrinology Obesity, characterized by chronic activation of inflammatory pathways, is a critical factor contributing to insulin resistance (IR) and type 2 diabetes (T2D). Free fatty acids (FFAs) are increased in obesity and are implicated as proximate causes of IR and induction of inflammatory signaling in adipose, liver, muscle, and pancreas. Cells of the innate immune system produce cytokines, and other factors that affect insulin signaling and result in the development of IR. In the lean state, adipose tissue is populated by adipose tissue macrophage of the anti-inflammatory M2 type (ATM2) and natural killer (NK) cells; this maintains the insulin-sensitive phenotype because ATM2 cells secrete IL10. In contrast, obesity induces lipolysis and release of pro-inflammatory FFAs and factors, such as chemokine (C-C motif) ligand 2 (CCL2) and tumor necrosis factor alpha (TNF-α), which recruit blood monocytes in adipose tissue, where they are converted to macrophages of the highly pro-inflammatory M1-type (ATM1). Activated ATM1 produce large amounts of pro-inflammatory mediators such as TNF-α, interleukin-1β, IL-6, leukotriene B4, nitric oxide (NO), and resistin that work in a paracrine fashion and cause IR in adipose tissue. In the liver, both pro-inflammatory Kupffer cells (M1-KCs) and recruited hepatic macrophages (Ly6C) contribute to decreased hepatic insulin sensitivity. The present mini-review will update the bidirectional interaction between the immune system and obesity-induced changes in metabolism in adipose tissue and liver and the metabolic consequences thereof. 10.3389/fendo.2016.00157
    Innate Immunity Alterations in Type 2 Diabetes Mellitus: Understanding Infection Susceptibility. de Lourdes Ochoa-González Fátima,González-Curiel Irma E,Cervantes-Villagrana Alberto R,Fernández-Ruiz Julio C,Castañeda-Delgado Julio E Current molecular medicine Diabetes is a chronic disease characterized by marked alterations in the metabolism of glucose and by high concentrations of glucose in the blood due to a decreased insulin production or resistance to the action of this hormone in peripheral tissues. The International Diabetes Federation estimates a global incidence of diabetes of about 10% in the adult population (20 - 79 years old), some 430 million cases reported worldwide in 2018. It is well documented that people with diabetes have a higher susceptibility to infectious diseases and therefore show higher morbidity and mortality compared to the non-diabetic population. Given that the innate immune response plays a fundamental role in protecting against invading pathogens through a myriad of humoral and cellular mechanisms, the present work makes a comprehensive review of the innate immune alterations in patients with type 2 diabetes mellitus (T2D) as well as a brief description of the molecular events leading or associated to such conditions. We show that in these patients a compromised innate immune response increases susceptibility to infections. 10.2174/1566524020999200831124534
    Methionine enkephalin (MENK) regulates the immune pathogenesis of type 2 diabetes mellitus via the IL-33/ST2 pathway. Zhang Keying,Yang Jing,Ao Na,Jin Shi,Qi Ruiqun,Shan Fengping,Du Jian International immunopharmacology The incidence and mortality of type 2 diabetes mellitus (T2DM) rank among the top ten worldwide. Emerging studies indicate pathological roles for the immune system in inflammation, insulin resistance and islet β-cell damage in subjects with T2DM. Methionine enkephalin (MENK) is present in endocrine cells of the pancreas and has been suggested to be an important mediator between the immune and neuroendocrine systems. Therefore, it may play a role in modulating insulin secretion from islet cells. Since little is known about the effect of MENK on T2DM, therefore it was the aim of this study to characterize the role and possible mechanism of action of MENK on plasma glucose and serum insulin levels in T2DM rats and INS-1 cells in vivo and in vitro. MENK significantly decreased the plasma glucose level and increased the serum insulin concentration in T2DM rats. It also increased the serum levels of the cytokines IL-5 and IL-10, while decreased TNF-α and IL-2 levels. We further confirmed that MENK regulated glucose metabolism by upregulating opioid receptor expression and modulating the IL-33/ST2 and MyD88-TRAF6-NF-κB p65 signaling pathways. Based on these results, an intraperitoneal injection of MENK represents a potentially new approach for T2DM. 10.1016/j.intimp.2019.04.054
    Boswellic extracts and 11-keto-ß-boswellic acids prevent type 1 and type 2 diabetes mellitus by suppressing the expression of proinflammatory cytokines. Ammon H P T Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUND:Type 1 diabetes is an autoimmune disease directed to the pancreatic islets where inflammation leads to the death of insulin-producing ß cells and insulin deficiency. Type 2 diabetes, which is closely related to overweight, is characterized by insulin resistance. In both cases, proinflammatory cytokines play an important role by causing insulitis and insulin resistance. The gum resin of Boswellia species and its pharmacologically active compounds, including 11-keto-ß-boswellic acids have been shown to suppress the expression of proinflammatory cytokines in various immune-competent cells. PURPOSE:To review the present evidence of the therapeutic effects of boswellic extracts (BE) and/or 11-keto-ß-boswellic acids in the prevention/treatment of diabetes mellitus and to provide comprehensive insights into the underlying molecular mechanisms. METHODS:This review considers all available informations from preclinical and clinical studies concerning BEs, 11-keto-ß-boswellic acids, proinflammatory cytokines and diabetes mellitus collected via electronic search (PubMed) and related publications of the author. RESULTS:Type 1 diabetes: Studies in mice with autoimmune diabetes revealed that in the model of multiple injections of low doses of streptozotocin (MLD-STZ), an extract of the gum resin of Boswellia serrata and 11-keto-ß-boswellic acid (KBA) suppressed the increase in proinflammatory cytokines in the blood, infiltration of lymphocytes into pancreatic islets and increase in blood glucose. In a second model, i.e. the nonobese diabetic (NOD) mouse, KBA prevented the infiltration of lymphocytes into pancreatic islets. Regarding the clinical effects, a case report provided evidence that BE suppressed the blood levels of tyrosine phosphatase antibody (IA-A), a marker for insulitis, in a patient with late-onset autoimmune diabetes of the adult (LADA). Type 2 diabetes: In a preclinical study in rats where obesity was alimentary induced, the administration of BE significantly reduced food intake, overweight, proinflammatory cytokines such as interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) and ameliorated the parameters of glucose and lipid metabolism. Similar results were obtained in a second animal study, where type 2 diabetes was induced by a combination of a high-fat/high-fructose diet and a single dose of streptozotocin. Two clinical trials with patients with type 2 diabetes receiving the resin of Boswellia serrata demonstrated improvement in the blood glucose, HbA and lipid parameters. CONCLUSION:Preclinical and clinical data suggest that BE and/or 11-keto-ß-boswellic acids by inhibiting the expression of proinflammatory cytokines from immune-competent cells, may prevent insulitis and insulin resistance in type 1 and type 2 diabetes, respectively, and therefore may be an option in the treatment/prevention of type 1 and type 2 diabetes. It is hypothesized that molecularly, BE and 11-keto-ß-boswellic acids act via interference with the IκB kinase/Nuclear Transcription Factor-κB (IKK/NF-κB) signaling pathway through inhibition of the phosphorylation activity of IKK. However, further investigations and well-designed clinical studies are required. 10.1016/j.phymed.2019.153002
    Immunological Characteristics in Type 2 Diabetes Mellitus Among COVID-19 Patients. Han Meifang,Ma Ke,Wang Xiaojing,Yan Weiming,Wang Hongwu,You Jie,Wang Qiuxia,Chen Huilong,Guo Wei,Chen Tao,Ning Qin,Luo Xiaoping Frontiers in endocrinology Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT04365634. Context:Diabetes mellitus was associated with increased severity and mortality of disease in COVID-19 pneumonia. So far the effect of type 2 diabetes (T2DM) or hyperglycemia on the immune system among COVID-19 disease has remained unclear. Objective:We aim to explore the clinical and immunological features of type 2 diabetes mellitus (T2DM) among COVID-19 patients. Design and Methods:In this retrospective study, the clinical and immunological characteristics of 306 hospitalized confirmed COVID-19 patients (including 129 diabetic and 177 non-diabetic patients) were analyzed. The serum concentrations of laboratory parameters including cytokines and numbers of immune cells were measured and compared between diabetic and non-diabetic groups. Results:Compared with non-diabetic group, diabetic cases more frequently had lymphopenia and hyperglycemia, with higher levels of urea nitrogen, myoglobin, D-dimer and ferritin. Diabetic cases indicated the obviously elevated mortality and the higher levels of cytokines IL-2R, IL-6, IL-8, IL-10, and TNF-α, as well as the distinctly reduced Th1/Th2 cytokines ratios compared with non-diabetic cases. The longitudinal assays showed that compared to that at week 1, the levels of IL-6 and IL-8 were significantly elevated at week 2 after admission in non-survivors of diabetic cases, whereas there were greatly reductions from week 1 to week 2 in survivors of diabetic cases. Compared with survival diabetic patients, non-survival diabetic cases displayed distinct higher serum concentrations of IL-2R, IL-6, IL-8, IL-10, TNF-α, and lower Th1/Th2 cytokines ratios at week 2. Samples from a subset of participants were evaluated by flow cytometry for the immune cells. The counts of peripheral total T lymphocytes, CD4 T cells, CD8 T cells and NK cells were markedly lower in diabetic cases than in non-diabetic cases. The non-survivors showed the markedly declined counts of CD8 T cells and NK cells than survivors. Conclusion:The elevated cytokines, imbalance of Th1/Th2 cytokines ratios and reduced of peripheral numbers of CD8 T cells and NK cells might contribute to the pathogenic mechanisms of high mortality of COVID-19 patients with T2DM. 10.3389/fendo.2021.596518
    Induced regulatory T cells suppress Tc1 cells through TGF-β signaling to ameliorate STZ-induced type 1 diabetes mellitus. Zhou Li,He Xuemin,Cai Peihong,Li Ting,Peng Rongdong,Dang Junlong,Li Yue,Li Haicheng,Huang Feng,Shi Guojun,Xie Chichu,Lu Yan,Chen Yanming Cellular & molecular immunology Type 1 diabetes mellitus (T1D) is a chronic autoimmune condition in which the immune system destroys insulin-producing pancreatic β cells. In addition to well-established pathogenic effector T cells, regulatory T cells (Tregs) have also been shown to be defective in T1D. Thus, an increasing number of therapeutic approaches are being developed to target Tregs. However, the role and mechanisms of TGF-β-induced Tregs (iTregs) in T1D remain poorly understood. Here, using a streptozotocin (STZ)-induced preclinical T1D mouse model, we found that iTregs could ameliorate the development of T1D and preserve β cell function. The preventive effect was associated with the inhibition of type 1 cytotoxic T (Tc1) cell function and rebalancing the Treg/Tc1 cell ratio in recipients. Furthermore, we showed that the underlying mechanisms were due to the TGF-β-mediated combinatorial actions of mTOR and TCF1. In addition to the preventive role, the therapeutic effects of iTregs on the established STZ-T1D and nonobese diabetic (NOD) mouse models were tested, which revealed improved β cell function. Our findings therefore provide key new insights into the basic mechanisms involved in the therapeutic role of iTregs in T1D. 10.1038/s41423-020-00623-2
    The Effects of Type 2 Diabetes Mellitus on Organ Metabolism and the Immune System. Daryabor Gholamreza,Atashzar Mohamad Reza,Kabelitz Dieter,Meri Seppo,Kalantar Kurosh Frontiers in immunology Metabolic abnormalities such as dyslipidemia, hyperinsulinemia, or insulin resistance and obesity play key roles in the induction and progression of type 2 diabetes mellitus (T2DM). The field of immunometabolism implies a bidirectional link between the immune system and metabolism, in which inflammation plays an essential role in the promotion of metabolic abnormalities (e.g., obesity and T2DM), and metabolic factors, in turn, regulate immune cell functions. Obesity as the main inducer of a systemic low-level inflammation is a main susceptibility factor for T2DM. Obesity-related immune cell infiltration, inflammation, and increased oxidative stress promote metabolic impairments in the insulin-sensitive tissues and finally, insulin resistance, organ failure, and premature aging occur. Hyperglycemia and the subsequent inflammation are the main causes of micro- and macroangiopathies in the circulatory system. They also promote the gut microbiota dysbiosis, increased intestinal permeability, and fatty liver disease. The impaired immune system together with metabolic imbalance also increases the susceptibility of patients to several pathogenic agents such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thus, the need for a proper immunization protocol among such patients is granted. The focus of the current review is to explore metabolic and immunological abnormalities affecting several organs of T2DM patients and explain the mechanisms, whereby diabetic patients become more susceptible to infectious diseases. 10.3389/fimmu.2020.01582