Rheumatoid arthritis (RA) has been associated with an elevated risk of developing disorders related to glucose metabolism, including decreased insulin secretion, impaired glucose tolerance, and type 2 diabetes mellitus. The previse mechanisms underlying this association remain incompletely elucidated. In this study, we utilized a cohort of fifty Wistar female rats, establishing a type II collagen-induced arthritis (CIA) model (n = 30). Out observations indicated abnormal glucose and inulin levels in the CIA rats, accompanied by diminished β cell function. Additionally, we detected elevated cytokines levels and increased apoptosis within the pancreatic tissue of the CIA rats. It is hypothesized that the heightened apoptosis may be induced by cytokines, potentially leading to reduced insulin synthesis and dysregulated glucose metabolism. Through transcriptomic and proteomic analyses, we identified differential expression of genes and proteins involved in pathways that directly or indirectly regulate glycolysis in the CIA rats. Notably, we discovered novel differentially expressed enzymes implicated in the glycolysis pathway, such as hexokinase and fructose-bisphosphate aldolase, within the CIA rat model, which may serve as new markers for the diagnosis of RA or provide new perspectives to treat RA or RA-related glucose metabolism disorder.

Physical exercise is critical for preventing and managing chronic conditions, such as cardiovascular disease, type 2 diabetes, hypertension, and sarcopenia. Regular physical activity significantly reduces cardiovascular and all-cause mortality. Exercise also enhances metabolic health by promoting muscle growth, mitochondrial biogenesis, and improved nutrient storage while preventing age-related muscle dysfunction. Key metabolic benefits include increased glucose uptake, enhanced fat oxidation, and the release of exercise-induced molecules called myokines, which mediate interorgan communication and improve overall metabolic function. These myokines and other exercise-induced signaling molecules hold promise as therapeutic targets for aging and obesity-related conditions.

Interleukin-6 (IL-6) knockout mice and humans treated with IL-6 receptor blockade gain adipose tissue mass. This study investigates whether basal IL-6 activity (resting IL-6 levels) influences fat storage during fasting and postprandial states. Using stable-isotope tracer techniques and IL-6 receptor blockade with tocilizumab, we examine fat kinetics in humans. Blocking basal IL-6 activity reduces fasting whole-body lipolysis, decreases hormone-sensitive lipase (HSL) phosphorylation and fatty acid release in adipose tissue, and impairs postprandial fatty acid uptake in the leg. These results suggest diminished fatty acid uptake and oxidation in skeletal muscle, along with enhanced fatty acid entrapment in adipose tissue, which may account for the increased adiposity in the absence of IL-6 activity. Additionally, IL-6 blockade increases the escape of meal-derived fatty acids into the bloodstream. Whether this affects fatty acid storage and lipotoxicity in other tissues warrants further investigation. This study was registered at ClinicalTrials.gov (NCT04687540).

The bidirectional correlation between diabetes and periodontitis positions the latter as the most prevalent complication of the former. Rehabilitation of the periodontal tissues damaged by diabetic periodontitis presents a significant clinical challenge. The multifaceted nature of the pathogenesis of diabetic periodontitis necessitates a comprehensive approach in its treatment to mitigate its adverse effects. To address this, a temperature-sensitive hydrogel containing phlorotannins (PL) and antimicrobial peptide LL-37 was developed to shift the microenvironment of diabetic periodontitis from an exacerbated high-glycemic inflammatory state to a regenerative one. The addition of PL significantly enhanced the antimicrobial properties, stability, and safety of LL-37. Vitro experiments confirmed that PL/LL-37 had good biocompatibility and promoted osteogenic differentiation of bone. PL/LL-37 demonstrated antioxidant properties by scavenging DPPH free radicals and inhibiting NO production. Furthermore, PL/LL-37 effectively modulated macrophage polarization from a M1 phenotype to an M2 phenotype through NF-κB P-p65 inflammatory pathway, thereby reducing the release of pro-inflammatory cytokines and promoting the secretion of anti-inflammatory cytokines. Interestingly, it could downregulate the AGE-RAGE signaling pathway, exerting a protective effect against diabetes. In addition, PL/LL-37 could attenuate inflammation levels, inhibit osteoclast production, promote bone regeneration, inhibit apoptosis and decrease RAGE levels in a rat model of diabetic periodontitis. These combined features synergistically accelerate diabetic periodontal bone regeneration. Consequently, PL/LL-37 emerges as a promising candidate for clinical treatment of diabetic periodontitis.

Background/Objectives: Obesity is associated with chronic systemic inflammation and elevated levels of inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and C-reactive protein (CRP). Weight loss through lifestyle interventions can reduce inflammation in adults with obesity. Time-restricted eating (TRE) and calorie restriction (CR) are two popular diet interventions that can produce clinically significant weight loss. However, to date, no studies have directly compared the effects of TRE versus CR on inflammatory cytokines in adults with obesity. Methods: Here, we performed a secondary analysis on a recently published study to compare the long-term (12-month) effects of TRE versus CR on key inflammatory cytokines. Results: We found that while TRE and CR produced similar amounts of weight loss (4-5% from baseline), no statistically significant changes in circulating levels of TNF-alpha, IL-6, and CRP were noted in the TRE or CR groups, compared to the controls, by month 12. However, we did observe that circulating CRP levels were positively related to body weight, visceral fat mass, and insulin resistance, while IL-6 and TNF-alpha were not related to any metabolic marker. Conclusions: Thus, TRE and CR may not affect key inflammatory mediators with 4-5% weight loss, but more research is warranted.

Despite persisting health disparities between Black and White individuals, racial differences in inflammation have yet to be comprehensively examined.

To determine if significant differences in circulating levels of inflammatory markers between Black and White populations exist.

Studies were identified through systematic searches of four electronic databases in January 2022. Additional studies were identified via reference lists and e-mail contact.

Eligible studies included full-text empirical articles that consisted of Black and White individuals and reported statistics for inflammatory markers for each racial group. Of the 1368 potentially eligible studies, 84 (6.6 %) representing more than one million participants met study selection criteria.

Risk of bias was assessed via meta regressions that considered relevant covariates. Data heterogeneity was tested using both the Cochrane Q-statistic and the standard I2 index. Random effects models were used to calculate estimates of effect size from standardized mean differences.

Outcome measures included 12 inflammatory markers, including C-reactive protein (CRP), Fibrinogen, Interleukin-6 (IL-6), Tumor necrosis factor-alpha (TNF-α), and soluble intercellular adhesion molecule 1 (sICAM-1).

Several markers had robust sample sizes for analysis, including CRP (White N = 934,594; Black N = 55,234), Fibrinogen (White N = 80,880; Black N = 18,001), and IL-6 (White N = 20,269; Black N = 14,675). Initial results indicated significant effects on CRP (k = 56, pooled Hedges' g = 0.24), IL-6 (k = 33, g = 0.15), and Fibrinogen (k = 19, g = 0.49), with Black individuals showing higher levels. Results also indicated significant effects on sICAM-1 (k = 6, g = -0.46), and Interleukin-10 (k = 4, g = -0.18), with White individuals showing higher levels. Sensitivity analyses confirmed robust effects for CRP, IL-6, Fibrinogen, and sICAM-1 while also revealing significant effects on TNF-α (k = 18, g = -0.17) and Interleukin-8 (k = 5, g = -0.19), with White individuals showing higher levels of both.

Current meta-analytic results provide evidence for marked racial differences in common circulating inflammatory markers and illustrate the complexity of the inflammatory profile differences between Black and White individuals. Review Pre-Registration: PROSPERO Identifier - CRD42022312352.

The biology of schizophrenia is highly complex and multifaceted. Numerous efforts have been made over the years to disentangle the heterogeneity of the disease, gradually leading to a more detailed understanding of its underlying pathogenic mechanisms. Two cardinal elements in the pathophysiology of schizophrenia are neuroinflammation and alterations of neurotransmission. The kynurenine (KYN) pathway (KP) is of particular importance because it is inducted by systemic low-grade inflammation in peripheral tissues, producing metabolites that are neuroactive (i.e., modulating glutamatergic and cholinergic neurotransmission), neuroprotective, or neurotoxic. Consequently, the KP is at the crossroads between two primary systems involved in the pathogenesis of schizophrenia. It bridges the central nervous system (CNS) and the periphery, as KP metabolites can cross the blood-brain barrier and modulate neuronal activity. Metabolic syndrome plays a crucial role in this context, as it frequently co-occurs with schizophrenia, contributing to a sub-inflammatory state able to activate the KP. This narrative review provides valuable insights into these complex interactions, offering a framework for developing targeted therapeutic interventions or precision psychiatry approaches of the disorder.

Metformin is an anti-diabetic drug used to control blood glucose levels. The effects of metformin on insulin sensitivity in inflammation-induced adipocytes are not fully understood.This study aimed to explore the mechanism of metformin on insulin sensitivity enhancement in the coculture of LPS-induced 3T3-L1 adipocytes and RAW 264.7 macrophages.

Insulin resistance was induced in coculture cells using Lipopolysaccharide, followed by adding 25, 50, and 100 µg/ml of metformin for 24 h of incubation. Glucose consumption, GLUT-4, IRS-1, and IL-6 mRNA expressions were quantified.

Metformin, starting at a concentration of 25 µg/ml, enhanced glucose consumption, upregulated GLUT-4 mRNA expression, and stimulated the expression of IRS-1 mRNA in coculture cells at 100 µg/ml of concentration. Additionally, Metformin inhibited inflammation by reducing IL-6 mRNA expression in coculture cells up to 100 µg/ml.

These findings suggest that metformin attenuated inflammation and improved insulin sensitivity in inflammation-induced adipocytes that may be mediated by the IRS-1/GLUT-4 pathway.

This cross-sectional study, as a preliminary part of an ongoing project, aimed to investigate the effect of apical peridontitis (AP) on glycated hemoglobin (HbA1c) and systemic inflammatory markers in diabetic individuals.

A total of 280 individuals (140 with type 2 diabetes mellitus [T2DM] and 140 healthy) with and without AP were enrolled. Sixty-four age-, gender-, and body mass index-matched participants each in T2DM with AP group (DAP), T2DM without apical periodontitis (D), systemically healthy controls with apical periodontitis (CAP), and without apical periodontitis (C) groups were evaluated. Radiologic and clinical oral examination was performed for confirming the diagnosis of AP and periapical index scoring (PAI). Blood analyses were carried out for interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, high-sensitivity C-reactive protein (hsCRP), and HbA1c assessment.

Significantly higher levels of IL-1β, TNF-α, and hsCRP were observed in patients with AP in both diabetes and control groups (P < .05). In the diabetes group, AP contributed to significantly raised levels of HbA1c compared with T2DM group patients without AP. After controlling for possible confounders, partial corelation coefficients revealed positive corelation of presence of AP as well as size of the periapical lesion with HbA1c and serum levels of inflammatory markers in both diabetic and healthy individuals. Multivariate linear regression analysis revealed both presence of AP (P < .05) as well as the size of lesion (P < .001) were found to significantly predict the HbA1c levels as well as the levels of IL-1β, IL-6, TNF-α, and hsCRP in both diabetic and non-diabetic individuals.

These findings suggest that both presence of AP and size of periapical lesion was associated with glycemic control and systemic inflammatory burden in patients with T2DM.

Periodontitis, a chronic multifactorial inflammatory condition of the periodontium, is originated by a dysbiotic oral microbiota and is negatively correlated with several systemic diseases. The low-chronic burden of gingival inflammation not only exacerbates periodontitis but also predisposes individuals to a spectrum of age-related conditions, including cardiovascular diseases, neurodegenerative disorders, and metabolic dysfunction, especially related to ageing. In this regard, over the local periodontal treatment, lifestyle modifications and adjunctive therapies may offer synergistic benefits in ameliorating both oral and systemic health in ageing populations. Elucidating the intricate connections between periodontitis and senescence is important for understanding oral health's systemic implications for ageing and age-related diseases. Effective management strategies targeting the oral microbiota and senescent pathways may offer novel avenues for promoting healthy ageing and preventing age-related morbidities. This review will analyze the current literature about the intricate interplay between periodontitis, oral dysbiosis, and the processes of senescence, shedding light on their collective impact on the modulation and accelerated ageing and age-related diseases. Lastly, therapeutic strategies targeting periodontitis and oral dysbiosis to mitigate senescence and its associated morbidities will be discussed.

It is critical to sustain the diversity of the microbiota to maintain host homeostasis and health. Growing evidence indicates that changes in gut microbial biodiversity may be associated with the development of several pathologies, including type 2 diabetes mellitus (T2DM). Metformin is still the first-line drug for treatment of T2DM unless there are contra-indications. The drug primarily inhibits hepatic gluconeogenesis and increases the sensitivity of target cells (hepatocytes, adipocytes and myocytes) to insulin; however, increasing evidence suggests that it may also influence the gut. As T2DM patients exhibit gut dysbiosis, the intestinal microbiome has gained interest as a key target for metabolic diseases. Interestingly, changes in the gut microbiome were also observed in T2DM patients treated with metformin compared to those who were not. Therefore, the aim of this review is to present the current state of knowledge regarding the association of the gut microbiome with the antihyperglycemic effect of metformin. Numerous studies indicate that the reduction in glucose concentration observed in T2DM patients treated with metformin is due in part to changes in the biodiversity of the gut microbiota. These changes contribute to improved intestinal barrier integrity, increased production of short-chain fatty acids (SCFAs), regulation of bile acid metabolism, and enhanced glucose absorption. Therefore, in addition to the well-recognized reduction of gluconeogenesis, metformin also appears to exert its glucose-lowering effect by influencing gut microbiome biodiversity. However, we are only beginning to understand how metformin acts on specific microorganisms in the intestine, and further research is needed to understand its role in regulating glucose metabolism, including the impact of this remarkable drug on specific microorganisms in the gut.

To meet the prodigious bioenergetic demands of the photoreceptors, glucose and other nutrients must traverse the retinal pigment epithelium (RPE), a polarised monolayer of cells that lie at the interface between the outer retina and the choroid, the principal vascular layer of the eye. Recent investigations have revealed a metabolic ecosystem in the outer retina where the photoreceptors and RPE engage in a complex exchange of sugars, amino acids, and other metabolites. Perturbation of this delicate metabolic balance has been identified in the aging retina, as well as in age-related macular degeneration (AMD), the leading cause of blindness in the Western world. Also common in the aging and diseased retina are elevated levels of cytokines, oxidative stress, advanced glycation end-products, increased growth factor signalling, and biomechanical stress - all of which have been associated with metabolic dysregulation in non-retinal cell types and tissues. Herein, we outline the role of these factors in retinal homeostasis, aging, and disease. We discuss their effects on glucose, mitochondrial, lipid, and amino acid metabolism in tissues and cell types outside the retina, highlighting the signalling pathways through which they induce these changes. Lastly, we discuss promising avenues for future research investigating the roles of these pathological conditions on retinal metabolism, potentially offering novel therapeutic approaches to combat age-related retinal disease.

Cell culture plays a crucial role in addressing fundamental research questions, particularly in studying insulin resistance (IR) mechanisms. Multiple in vitro models are utilized for this purpose, but their technical distinctions and relevance to in vivo conditions remain unclear. This study aims to assess the effectiveness of existing in vitro models in inducing IR and their ability to replicate in vivo IR conditions.

Insulin resistance (IR) is a cellular condition linked to metabolic disorders. Despite the utility of cell culture in IR research, questions persist regarding the suitability of various models. This study seeks to evaluate these models' efficiency in inducing IR and their ability to mimic in vivo conditions. Insights gained from this research could enhance our understanding of model strengths and limitations, potentially advancing strategies to combat IR and related disorders.

1- Investigate the technical differences between existing cell culture models used to study molecular mediators of insulin resistance (IR). 2- Compare the effectiveness of present in vitro models in inducing insulin resistance (IR). 3- Assess the relevance of the existing cell culture models in simulating the in vivo conditions and environment that provoke the induction of insulin resistance (IR).

In vitro, eight sets of 3T3-L1 cells were cultured until they reached 90% confluence. Subsequently, adipogenic differentiation was induced using a differentiation cocktail (media). These cells were then divided into four groups, with four subjected to normal conditions and the other four to hypoxic conditions. Throughout the differentiation process, each cell group was exposed to specific factors known to induce insulin resistance (IR). These factors included 2.5 nM tumor necrosis factor-alpha (TNFα), 20 ng/ml interleukin-6 (IL-6), 10 micromole 4-hydroxynonenal (4HNE), and high insulin (HI) at a concentration of 100 nM. To assess cell proliferation, DAPI staining was employed, and the expression of genes associated with various metabolic pathways affected by insulin resistance was investigated using Real-Time PCR. Additionally, insulin signaling was examined using the Bio-plex Pro cell signaling Akt panel.

We induced insulin resistance in 3T3-L1 cells using IL-6, TNFα, 4HNE, and high insulin in both hypoxic and normoxic conditions. Hypoxia increased HIF1a gene expression by approximately 30% (P<0.01). TNFα reduced cell proliferation by 10-20%, and chronic TNFα treatment significantly decreased mature adipocytes due to its cytotoxicity. We assessed the impact of insulin resistance (IR) on metabolic pathways, focusing on genes linked to branched-chain amino acid metabolism, detoxification, and chemotaxis. Notably, ALDH6A1 and MCCC1 genes, related to amino acid metabolism, were significantly affected under hypoxic conditions. TNFα treatment notably influenced MCP-1 and MCP-2 genes linked to chemotaxis, with remarkable increases in MCP-1 levels and MCP-2 expression primarily under hypoxia. Detoxification-related genes showed minimal impact, except for a significant increase in MAOA expression under acute hypoxic conditions with TNFα treatment. Additional genes displayed varying effects, warranting further investigation. To investigate insulin signaling's influence in vitro by IRinducing factors, we assessed phospho-protein levels. Our results reveal a significant p-Akt induction with chronic high insulin (10%) and acute TNFα (12%) treatment under hypoxia (both P<0.05). Other insulin resistance-related phospho-proteins (GSK3B, mTOR, PTEN) increased with IL-6, 4HNE, TNFα, and high insulin under hypoxia, while p-IRS1 levels remained unaffected.

In summary, different in vitro models using inflammatory, oxidative stress, and high insulin conditions under hypoxic conditions can capture various aspects of in vivo adipose tissue insulin resistance (IR). Among these models, acute TNFα treatment may offer the most robust approach for inducing IR in 3T3-L1 cells.

Smoking and nicotine impose detrimental health effects including adipose tissue dysfunction. Despite extensive physiological evidence, the cellular mechanisms remain poorly understood, with few studies examining the effects of cigarette smoke extract (CSE) or nicotine on adipocyte differentiation.

Primary human bone marrow-derived mesenchymal stromal cells (MSCs) were exposed to CSE or nicotine (50-500 ng/ml) during adipogenic differentiation. Cell viability and metabolic activity were assessed via MTT assay. Lipid droplet accumulation was evaluated using Sudan III staining and quantitative image analysis. Adiponectin, IL6, and IL8 concentrations were measured after 35 days using ELISA.

At these doses, CSE and nicotine do not immediately affect cell viability but inhibit undifferentiated cell proliferation. Notably, both agents at 50 ng/ml significantly increased lipid accumulation during adipogenesis, while higher CSE doses nearly completely inhibited this process. Additionally, CSE dose-dependently decreased adiponectin secretion and increased IL6 and IL8, indicating a shift towards an inflammatory state. Nicotine alone primarily increased IL6 secretion with less pronounced effects.

The study highlights the complex impact of CSE and nicotine on adipocyte function during early differentiation from MSCs. Dose-dependent changes in lipid accumulation, cytokine, and adiponectin secretion induced by CSE and nicotine can partly explain smoking-related adipose tissue dysfunction.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterised by insulin resistance, hyperglycaemia, and inflammation, with oxidative stress contributing to its progression. Curcumin (CUR), known for its anti-inflammatory, antioxidant, and insulin sensitising effects, has shown potential for the treatment of T2DM but is limited by low solubility and bioavailability. This study investigated long-circulating curcumin-loaded liposomes (CUR-LPs) to improve curcumin stability, solubility, and circulation and assessed their effect on insulin resistance in a murine model of T2DM.

CUR-LPs were prepared using the ethanol injection method and characterized for morphology, particle size, zeta potential, encapsulation efficiency, drug-loading capacity, and in vitro release. Cell viability was tested on murine L929 cells. In a T2DM murine model, after four weeks of CUR-LP treatment, inflammatory markers TNF-α and IL-6 were measured by real-time polymerase chain reaction, and liver tissues were analyzed for glutathione (GSH) and superoxide dismutase (SOD) via colorimetry.

CUR-LPs were spherical, with an average diameter of (249 ± 2.3) nm and a zeta potential of (-33.5 ± 0.8) mV. They exhibited an encapsulation efficiency of (99.2 ± 0.5) %and a drug-loading capacity of (1.63 ± 0.02) %. CUR embedding in liposomes significantly maintained CUR release. In L929 cells, over 80% viability was maintained at 12 uM CUR concentration after 24 h. In HFD/STZ-induced T2DM mice, CUR-LPs improved blood glucose and insulin levels more efficiently than free CUR, and CUR-LPs also reduced hepatic inflammation (TNF-α, IL-6), enhanced hepatic GSH and SOD, and attenuated liver injury.

CUR-LPs improved glucose metabolism and insulin resistance in HFD/STZ-induced T2DM mice, which may be associated with a decrease in liver inflammation and oxidative stress.

Decrements in energy were found in 67% of women who underwent breast cancer surgery. However, no information is available on chronic decrements in energy and associations with inflammation. Purposes were to identify latent classes of patients with distinct average energy profiles from prior to through 12 months after breast cancer surgery; evaluate for differences in demographic and clinical characteristics between the two extreme average energy classes; and evaluate for polymorphisms for cytokine genes associated with membership in the Low energy class.

Women (n = 397) completed assessments of energy prior to and for 12 months following breast cancer surgery. Growth mixture modeling was used to identify classes of patients with distinct average energy profiles. Eighty-two single nucleotide polymorphisms (SNPs) among 15 cytokine genes were evaluated.

Three distinct energy profiles were identified (ie, Low [27.0%], Moderate [54.4%], Changing [18.6%]). Data from patients in the Low and Moderate energy classes were used in the candidate gene analyses. Five SNPs and one haplotype in six different genes remained significant in logistic regression analyses (ie, interleukin [IL]-1β rs1143623, IL1 receptor 1 rs3917332 IL4 rs2243263, IL6 HapA1 [that consisted of rs1800795, rs2069830, rs2069840, rs1554606, rs2069845, rs2069849, and rs2069861], nuclear factor kappa beta subunit 1 rs170731, tumor necrosis factor rs1799964). For several SNPs for IL6, expression quantitative trait locis were identified in subcutaneous and visceral adipose tissue and thyroid tissue. In addition, skeletal muscle was identified as an expression quantitative trait loci for nuclear factor kappa beta subunit 1.

Findings suggest that cytokine genes are involved in the mechanisms that underlie chronic decrements in energy in women following breast cancer surgery. Given the roles of subcutaneous and visceral adipose and thyroid tissues in metabolism and energy balance, the findings related to IL6 suggest that these polymorphisms may have a functional role in the development and maintenance of chronic decrements in energy.

Background: Gestational diabetes mellitus (GDM) is a pregnancy-related diabetic condition that may cause serious complications. However, its pathogenesis remains unclear. Placental damage due to GDM may lead to several health issues that cannot be ignored. Thus, we aimed to identify the mechanisms underlying GDM by screening differentially expressed genes (DEGs) related to vascular endothelial cells in the GDM databases and verify the expression of these DEGs in the placentas of women afflicted by GDM. Methods: We used GDM microarray datasets integrated from the Gene Expression Omnibus (GEO) database. Functional annotation and protein-protein interaction (PPI) analyses were used to screen DEGs. Placental tissues from 20 pregnant women with GDM and 20 healthy pregnant women were collected, and differential gene expression in the placental tissues was verified via qRT-PCR, western blotting, and immunofluorescence. Results: Bioinformatics analysis revealed three significant DEGs: SNAIL2, PAPP-A, and TGFβ1. These genes were all predicted to be underexpressed in patients with GDM. The results of qRT-PCR, western blot, and immunofluorescence analyses indicated that SNAIL2 and PAPP-A in the placenta tissue of patients with GDM were significantly underexpressed. However, TGFβ1 in the placenta tissues of GDM was significantly overexpressed. Conclusion: SNAIL2, TGFβ1, and PAPP-A may affect the placentas of pregnant women with GDM, warranting further investigation.

Brain insulin resistance has recently been described as a metabolic abnormality of brain glucose homeostasis that has been proven to downregulate insulin receptors, both in astrocytes and neurons, triggering a reduction in glucose uptake and glycogen synthesis. This condition may generate a mismatch between brain's energy reserve and expenditure, ??mainly during high metabolic demand, which could be involved in the chronification of migraine and, in the long run, at least in certain subsets of patients, in the prodromic phase of Alzheimer's disease, along a putative metabolic physiopathological continuum. Indeed, the persistent disruption of glucose homeostasis and energy supply to neurons may eventually impair protein folding, an energy-requiring process, promoting pathological changes in Alzheimer's disease, such as amyloid-β deposition and tau hyperphosphorylation. Hopefully, the "neuroenergetic hypothesis" presented herein will provide further insight on there being a conceivable metabolic bridge between chronic migraine and Alzheimer's disease, elucidating novel potential targets for the prophylactic treatment of both diseases.

Ovarian carcinoma (OC) is a fatal malignancy, with most patients experiencing recurrence and resistance to chemotherapy. In contrast to hematogenous metastasizing tumors, ovarian cancer cells disseminate within the peritoneal cavity, especially the omentum. Previously, we reported omental crown-like structure (CLS) number is associated with poor prognosis of advanced-stage OC. CLS that have pathologic features of a dead or dying adipocyte was surrounded by several macrophages is well known a histologic hallmark for inflammatory adipose tissue. In this study, we attempted to clarify the interaction between metastatic ovarian cancer cells and omental CLS, and to formulate a therapeutic strategy for advanced-stage ovarian cancer.

A three-cell (including OC cells, adipocytes and macrophages) coculture model was established to mimic the omental tumor microenvironment (TME) of ovarian cancer. Caspase-1 activity, ATP and free fatty acids (FFA) levels were detected by commercial kits. An adipocyte organoid model was established to assess macrophages migration and infiltration. In vitro and in vivo experiments were performed for functional assays and therapeutic effect evaluations. Clinical OC tissue samples were collected for immunochemistry stain and statistics analysis.

In three-cell coculture model, OC cells-derived IL-6 and IL-8 could induce the occurrence of pyroptosis in omental adipocytes. The pyroptotic adipocytes release ATP to increase macrophage infiltration, release FFA into TME, uptake by OC cells to increase chemoresistance. From OC tumor samples study, we demonstrated patients with high gasdermin D (GSDMD) expression in omental adipocytes is highly correlated with chemoresistance and poor outcome in advanced-stage OC. In animal model, by pyroptosis inhibitor, DSF, effectively retarded tumor growth and prolonged mice survival.

Omental adipocyte pyroptosis may contribute the chemoresistance in advanced stage OC. Omental adipocytes could release FFA and ATP through the GSDMD-mediate pyroptosis to induce chemoresistance and macrophages infiltration resulting the poor prognosis in advanced-stage OC. Inhibition of adipocyte pyroptosis may be a potential therapeutic modality in advanced-stage OC with omentum metastasis.

Patients with triple negative breast cancer (TNBC) and comorbid Type 2 Diabetes (T2D), characterized by insulin resistance of adipose tissue, have higher risk of metastasis and shorter survival. Adipocytes are the main non-malignant cells of the breast tumor microenvironment (TME). However, adipocyte metabolism is usually ignored in oncology and mechanisms that couple T2D to TNBC outcomes are poorly understood. Here we hypothesized that exosomes, small vesicles secreted by TME breast adipocytes, drive epithelial-to-mesenchymal transition (EMT) and metastasis in TNBC via miRNAs. Exosomes were purified from conditioned media of 3T3-L1 mature adipocytes, either insulin-sensitive (IS) or insulin-resistant (IR). Murine 4T1 cells, a TNBC model, were treated with exosomes in vitro (72h). EMT, proliferation and angiogenesis were elevated in IR vs. control and IS. Brain metastases showed more mesenchymal morphology and EMT enrichment in the IR group. MiR-145a-3p is highly differentially expressed between IS and IR, and potentially regulates metastasis.

IR adipocyte exosomes modify TME, increase EMT and promote metastasis to distant organs, likely through miRNA pathways. We suggest metabolic diseases such as T2D reshape the TME, promoting metastasis and decreasing survival. Therefore, TNBC patients with T2D should be closely monitored for metastasis, with metabolic medications considered.

Obesity and related metabolic syndromes have been recognized as important disease risks, in which the role of adipokines cannot be ignored. Adiponectin (ADP) is one of the key adipokines with various beneficial effects, including improving glucose and lipid metabolism, enhancing insulin sensitivity, reducing oxidative stress and inflammation, promoting ceramides degradation, and stimulating adipose tissue vascularity. Based on those, it can serve as a positive regulator in many metabolic syndromes, such as type 2 diabetes (T2D), cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), sarcopenia, neurodegenerative diseases, and certain cancers. Therefore, a promising therapeutic approach for treating various metabolic diseases may involve elevating ADP levels or activating ADP receptors. The modulation of ADP genes, multimerization, and secretion covers the main processes of ADP generation, providing a comprehensive orientation for the development of more appropriate therapeutic strategies. In order to have a deeper understanding of ADP, this paper will provide an all-encompassing review of ADP.

Arsenic-contaminated drinking water can induce various disorders by disrupting lipid and glucose metabolism in adipose tissue, leading to insulin resistance. It inhibits adipocyte development and exacerbates insulin resistance, though the precise impact on lipid synthesis and lipolysis remains unclear. This review aims to explore the processes and pathways involved in adipogenesis and lipolysis within adipose tissue concerning arsenic-induced diabetes. Although arsenic exposure is linked to type 2 diabetes, the specific role of adipose tissue in its pathogenesis remains uncertain. The review delves into arsenic's effects on adipose tissue and related signaling pathways, such as SIRT3-FOXO3a, Ras-MAP-AP-1, PI(3)-K-Akt, endoplasmic reticulum stress proteins, CHOP10, and GPCR pathways, emphasizing the role of adipokines. This analysis relies on existing literature, striving to offer a comprehensive understanding of different adipokine categories contributing to arsenic-induced diabetes. The findings reveal that arsenic detrimentally impacts white adipose tissue (WAT) by reducing adipogenesis and promoting lipolysis. Epidemiological studies have hinted at a potential link between arsenic exposure and obesity development, with limited research suggesting a connection to lipodystrophy. Further investigations are needed to elucidate the mechanistic association between arsenic exposure and impaired adipose tissue function, ultimately leading to insulin resistance.

The increasing prevalence of type 2 diabetes, has become a global concern, making it imperative to control. Chemical drugs commonly recommended for diabetes treatment cause many complications and drug resistance over time.

The polyphenol tyrosol has many health benefits, including anti-diabetes properties. Tyrosol's efficacy can be significantly increased when it is used as a niosome in the treatment of diabetes. In this study, Tyrosol and nano-Tyrosol are examined for their effects on genes implicated in type 2 diabetes in streptozotocin-treated rats. Niosome nanoparticles containing 300 mg surfactant (span60: tween60) and 10 mg cholesterol were hydrated in thin films with equal molar ratios. After 72 hours, nano-niosomal formulas were assessed for their physicochemical properties. MTT assays were conducted on HFF cells to assess the cellular toxicity of the nano niosome contacting optimal Tyrosol. Finally, the expression of PEPCK, GCK, TNF-ɑ, IL6, GLUT2 and GLUT9 was measured by real-time PCR. Physiochemical properties of the SEM images of niosomes loaded with Tyrosol revealed the nanoparticles had a vehicular structure.

In this study, there were two stages of release: initial release (8 hours) and sustainable release (72 hours). Meanwhile, free-form drugs were considerably more toxic than niosomal drugs in terms of their cellular toxicity. An in vivo comparison of oral Tyrosol gavage with nano-Tyrosol showed a significant increase in GCK (P < 0.001), GLUT2 (P < 0.001), and GLUT9 (P < 0.001). Furthermore, nano-Tyrosol decreased the expression of TNF-ɑ (P < 0.05), PEPCK (P < 0.001), and IL-6 (P < 0.05) which had been increased by diabetes mellitus. The results confirmed nano-Tyrosol's anti-diabetes and anti-inflammatory effects.

These findings suggest that nano-Tyrosol has potential applications in diabetes treatment and associated inflammation. Further research is needed to better understand the mechanism of action.

Charcot Neuroarthropathy (CN) is a complex and incapacitating disorder characterized by neuropathy, progressive deformity, and joint destruction. It is of substantial interest within the diabetic population as this ailment chiefly affects individuals with diabetes. The pathophysiology of CN is multidimensional, connecting peripheral neuropathy, repetitive trauma, and autonomic dysfunction. The review analyses the mechanisms directing the development of CN, emphasizing the influence of diabetes in individuals who lean toward this condition. Clinical presentation and diagnosis of CN in diabetic patients present unique challenges. Complex clinical features have also been discussed, including joint deformities, insidious onset, and painless swelling, which mimic other musculoskeletal conditions. The diagnostic approaches, involving clinical examination and radiological imaging, are analyzed for early and accurate diagnosis. Risk factors and epidemiology emphasize the prevalence of CN within the diabetic population and draw attention to common risk factors contributing to its development. Significant factors such as glycemic control, duration of the disease, and type of diabetes are important in estimating an individual's risk for CN. Complications, such as foot ulcers and amputations, provide an understanding of the severe outcome of this condition on patients' quality of life. Management approaches and treatment involving conservative and surgical approaches are reviewed in depth. A multidisciplinary approach to patient care is emphasized, given the complex nature of CN and the comorbidities existing in diabetic individuals. Prognosis and prevention comprise approaches for mitigating the risk of CN in diabetic patients, such as glycemic control, regular foot examinations, and patient education. This thorough review aims to outline the intricate relationship between CN and diabetes, offering an understanding of pathophysiology, clinical complexities, diagnostic nuances, treatment modalities, and prevention strategies.

Interleukin (IL)-6 elicits both anticancer and procancer effects depending on the context, which we have termed the 'exercise IL-6 enigma'. IL-6 is released from skeletal muscles during exercise to regulate short-term energy availability. Exercise-induced IL-6 provokes biological effects that may protect against cancer by improving insulin sensitivity, stimulating the production of anti-inflammatory cytokines, mobilising immune cells, and reducing DNA damage in early malignant cells. By contrast, IL-6 continuously produced by leukocytes in inflammatory sites drives tumorigenesis by promoting chronic inflammation and activating tumour-promoting signalling pathways. How can a molecule have such opposing effects on cancer? Here, we review the roles of IL-6 in chronic inflammation, tumorigenesis, and exercise-associated cancer prevention and define the factors that underpin the exercise IL-6 enigma.

Diabetes mellitus (DM) is a very serious disease, the incidence of which has been increasing worldwide. The beginning of diabetic research can be traced back to the 17th century. Since then, animals have been experimented on for diabetic research. However, the greatest development of diabetes research occurred in the second half of the last century, along with the development of laboratory techniques. Information obtained by monitoring patients and animal models led to the finding that there are several types of DM that differ significantly from each other in the causes of the onset and course of the disease. Through different types of animal models, researchers have studied the pathophysiology of all types of diabetic conditions and discovered suitable methods for therapy. Interestingly, despite the unquestionable success in understanding DM through animal models, we did not fully succeed in transferring the data obtained from animal models to human clinical research. On the contrary, we have observed that the chances of drug failure in human clinical trials are very high. In this review, we will summarize the history and presence of animal models in the research of DM over the last hundred years. Furthermore, we have summarized the new methodological approaches, such as "organ-on-chip," that have the potential to screen the newly discovered drugs for human clinical trials and advance the level of knowledge about diabetes, as well as its therapy, towards a personalized approach.

Adipose tissue inflammation has been implicated in various chronic inflammatory diseases and cancer. Perivascular adipose tissue (PVAT) surrounds the aorta as an extra layer and was suggested to contribute to atherosclerosis development. PVAT regulates the function of endothelial and vascular smooth muscle cells in the aorta and represent a reservoir for various immune cells which may participate in aortic inflammation. Recent studies demonstrate that adipocytes also express various cytokine receptors and, therefore, may directly respond to inflammatory stimuli. Here we will summarize current knowledge on immune mechanisms regulating adipocyte activation and the crosstalk between myeloid cells and adipocytes in pathogenesis of atherosclerosis.

Researches and practice of traditional Chinese medicine indicated that Agrimonia pilosa Ledeb could improve insulin resistance (IR) and treat type 2 diabetes (T2DM). To reveal its underling mechanisms, we isolated Flavonoid component (FC) from Agrimonia pilosa Ledeb and elucidated its effects on glucose metabolism to improve IR by suppressing oxidative stress and inflammation.

Adipocytes or mice IR model was established with overdosed glucose and insulin or high-fat diet. The uptake of 2-NBDG and glucose consumption were measured to verify insulin sensitivity in vitro and vivo. Reactive oxidative species (ROS) were detected by flow cytometry, and superoxide dismutase (SOD) activity as well as the malondialdehyde (MDA) content were also measured. Meanwhile, factors associated with insulin signal pathway including PPARγ, insulin receptor substrate-1 (IRS-1), GLUT4, and oxidative stress including NF-E2-related factor 2 (Nrf2), as well as the related inflammatory cytokines such as NF-κB, IL-1β, IL-6 and TNF-α were tested. Furthermore, the JNK/PI3K/Akt signal pathway was also explored.

FC extracted from Agrimonia pilosa Ledeb ameliorated the impaired glucose metabolism significantly. Further study indicated that FC could regulate the insulin signal pathway to improve insulin resistance. Moreover, it could upregulate PPARγ with the similar efficacy as pioglitazone (Piog) straightway. FC also decreased the endogenous ROS and MDA content, increased SOD activity and Nrf2 expression to facilitate oxidative homeostasis. It attenuated expression and secretion of inflammatory cytokines obviously. At last, our results indicated JNK/PI3K/Akt pathway was regulated by FC in adipocytes and adipose tissue.

FC could ameliorate glucose metabolism and improve IR. It exerted these effects by suppressing oxidative stress and inflammation. FC from Agrimonia pilosa Ledeb has a good prospect to be drugs or functional foods for IR and T2DM.

Oestrogens are sex steroid hormones that have gained prominence over the years owing to their crucial roles in human health and reproduction functions which have been preserved throughout evolution. One of oestrogens actions, and the focus of this review, is their ability to determine adipose tissue distribution, function and adipose tissue 'health'. Body fat distribution is sexually dimorphic, affecting males and females differently. These differences are also apparent in the development of the metabolic syndrome and other chronic conditions where oestrogens are critical. In this review, we summarize the different molecular mechanisms, pathways and resulting pathophysiology which are a result of oestrogens actions in and on adipose tissues. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part I)'.

The discovery of leptin in the 1990s led to a reconsideration of adipose tissue (AT) as not only a fatty acid storage organ, but also a proper endocrine tissue. AT is indeed capable of secreting bioactive molecules called adipokines for white AT or batokines for brown/beige AT, which allow communication with numerous organs, especially brain, heart, liver, pancreas, and/or the vascular system. Adipokines exert pro or anti-inflammatory activities. An equilibrated balance between these two sets ensures homeostasis of numerous tissues and organs. During the development of obesity, AT remodelling leads to an alteration of its endocrine activity, with increased secretion of pro-inflammatory adipokines relative to the anti-inflammatory ones, as shown in the graphical abstract. Pro-inflammatory adipokines take part in the initiation of local and systemic inflammation during obesity and contribute to comorbidities associated to obesity, as detailed in the present review.

Chronic low-grade inflammation is associated with a state of diet-induced obesity that impacts systemic tissues and can cross the blood-brain barrier to act directly on the brain. The extent to which pro-inflammatory cytokines released in these conditions affect dopamine presynaptic neurotransmission has not been previously investigated. The purpose of this study was to examine how dopamine terminals are affected by pro-inflammatory cytokines, and to determine if dietary fat consumption potentiates cytokine effects on dopamine release and reuptake rate in the nucleus accumbens (NAc). Male and female C57BL/6J mice were fed high, medium, or low-fat diets (60%, 30%, or 10% total kcals from fat, respectively) for six weeks. Fast scan cyclic voltammetry (FSCV) was used to measure dopamine release and reuptake rate in the NAc core from ex vivo coronal brain slices. Electrically evoked dopamine release and the maximal rate of dopamine reuptake (Vmax) were significantly lower in mice fed the 30% and 60% high-fat diets compared to the 10% low-fat group (p < 0.05). IL-6 5 or 10 nM or TNFα 30 or 300 nM was added to artificial cerebrospinal fluid (aCSF) bathed over brain slices during FSCV. No effect on dopamine release or Vmax was observed with lower concentrations. However, 10 nM IL-6 and 300 nM TNFα significantly reduced dopamine release in the 60% fat group (p < 0.05). No effect of added cytokine was observed on Vmax. Overall, these data provide evidence that dietary fat increases neural responsiveness to cytokines, which may help inform comorbidities between diet-induced obesity and depression or other mood disorders.

Type 2 diabetes (T2D) is known to be associated with chronic inflammation, but the inflammatory regulators/markers are not exactly defined and the link between them remains undetermined. The objective of this study is to identify these markers by testing traditional (IL6 & IL8) and non-traditional (TREM1 & uPAR) inflammatory markers.

Data and blood samples were obtained from 114 T2D and 74 non-diabetic Kuwaiti subjects attending health facilities in Kuwait. Chemical analyzers were used to measure glycemic and lipid profiles, while ELISA was used to measure plasma levels of insulin and several inflammatory markers.

Showed that the IL-6 and TREM1 were significantly higher in T2D compared to non-diabetic controls, and the uPAR level was borderline higher in T2D but significantly correlated with IL-6 levels. Unexpectedly, IL8 was significantly below normal in T2D and IL6/IL8 ratio was significantly higher in T2D patients. Unlike other tested markers, uPAR was in addition strongly correlated with insulin levels and HOMA-IR index.

Raised levels of IL6, TREMI, IL6/IL8 ratio, and the strong positive correlation of plasma levels of uPAR with IL-6, insulin, and HOMA-IR index, are reliable spectators of chronic inflammation in T2D patients. The reduced level of IL-8 in T2D was a peculiar observation that needs further explanation. Finally, the consequences and impact of the sustained rise of these inflammatory regulators in diabetic tissues need to be meticulously explored.

Intrauterine growth restriction (IUGR) arises when maternal stressors coincide with peak placental development, leading to placental insufficiency. When the expanding nutrient demands of the growing fetus subsequently exceed the capacity of the stunted placenta, fetal hypoxemia and hypoglycemia result. Poor fetal nutrient status stimulates greater release of inflammatory cytokines and catecholamines, which in turn lead to thrifty growth and metabolic programming that benefits fetal survival but is maladaptive after birth. Specifically, some IUGR fetal tissues develop enriched expression of inflammatory cytokine receptors and other signaling cascade components, which increases inflammatory sensitivity even when circulating inflammatory cytokines are no longer elevated after birth. Recent evidence indicates that greater inflammatory tone contributes to deficits in skeletal muscle growth and metabolism that are characteristic of IUGR offspring. These deficits underlie the metabolic dysfunction that markedly increases risk for metabolic diseases in IUGR-born individuals. The same programming mechanisms yield reduced metabolic efficiency, poor body composition, and inferior carcass quality in IUGR-born livestock. The ω-3 polyunsaturated fatty acids (PUFA) are diet-derived nutraceuticals with anti-inflammatory effects that have been used to improve conditions of chronic systemic inflammation, including intrauterine stress. In this review, we highlight the role of sustained systemic inflammation in the development of IUGR pathologies. We then discuss the potential for ω-3 PUFA supplementation to improve inflammation-mediated growth and metabolic deficits in IUGR offspring, along with potential barriers that must be considered when developing a supplementation strategy.

Adipose tissue (AT) acts as a highly active endocrine organ, which secretes a wide range of adipokine hormones. In the past few years, several adipokines (leptin, adiponectin, resistin etc.) have been discovered showing metabolic consequences in relation to insulin resistance (IR), obesity and diabetes. These adipokines are considered to be an important component playing an important role in the regulation of energy metabolism. They have been shown to be involved in the pathogenesis of metabolic syndrome (MetS) and cardiac diseases. The current article provides a holistic summary of recent knowledge on adipokines and emphasizes their importance in association with IR, obesity, diabetes and MetS. Adipokines such as leptin, adiponectin, resistin and tumor necrosis factor-alpha (TNF-α) have been involved in the regulation of an array of metabolic functions and disease associated with it, e.g. appetite and energy balance of the body, suppression of atherosclerosis and liver fibrosis, obesity with type 2 diabetes (T2D) and IR. An important adipokine, Interleukin-6 (IL-6), also correlates positively with human obesity and IR and also the elevated level of IL-6 predicts development of T2D. All of these hormones have important correlation with energy homeostasis, glucose and lipid metabolism, cardiovascular function and immunity. All the possible connections have extended the biological emphasis of AT secreted adipokines as an investigator in the development of MetS, and are now no longer considered as only an energy storage site.

Maintaining systemic homeostasis requires the coordination of different organs and tissues in the body. Our bodies rely on complex inter-organ communications to adapt to perturbations or changes in metabolic homeostasis. Consequently, the liver, muscle, and adipose tissues produce and secrete specific organokines such as hepatokines, myokines, and adipokines in response to nutritional and environmental stimuli. Emerging evidence suggests that dysregulation of the interplay of organokines between organs is associated with the pathophysiology of obesity and type 2 diabetes (T2D). Strategies aimed at remodeling organokines may be effective therapeutic interventions. Diet modification and exercise have been established as the first-line therapeutic intervention to prevent or treat metabolic diseases. This review summarizes the current knowledge on organokines secreted by the liver, muscle, and adipose tissues in obesity and T2D. Additionally, we highlighted the effects of diet/nutrition and exercise on the remodeling of organokines in obesity and T2D. Specifically, we investigated the ameliorative effects of caloric restriction, selective nutrients including ω3 PUFAs, selenium, vitamins, and metabolites of vitamins, and acute/chronic exercise on the dysregulation of organokines in obesity and T2D. Finally, this study dissected the underlying molecular mechanisms by which nutrition and exercise regulate the expression and secretion of organokines in specific tissues.

Type 2 diabetes mellitus (T2DM) and depression are significant public health and socioeconomic issues. They commonly co-occur, with T2DM occurring in 11.3% of the US population, while depression has a prevalence of about 9%, with higher rates among youths. Approximately 31% of patients with T2DM suffer from depressive symptoms, with 11.4% having major depressive disorders, which is twice as high as the prevalence of depression in patients without T2DM. Additionally, over 80% of people with T2DM are overweight or obese. This review describes how T2DM and depression can enhance one another, using the same molecular pathways, by synergistically altering the brain's structure and function and reducing the reward obtained from eating. In this article, we reviewed the evidence that eating, especially high-caloric foods, stimulates the limbic system, initiating Reward Deficiency Syndrome. Analogous to other addictive behaviors, neurochemical changes in those with depression and/or T2DM are thought to cause individuals to increase their food intake to obtain the same reward leading to binge eating, weight gain and obesity. Treating the symptoms of T2DM, such as lowering HbA1c, without addressing the underlying pathways has little chance of eliminating the disease. Targeting the immune system, stress circuit, melatonin, and other alterations may be more effective.

Brain death (BD) and steatosis are both risk factors for organ dysfunction or failure in liver transplantation (LT).

Here, we examine the role of interleukin 6 (IL- 6) and IL-10 in LT of both non-steatotic and steatotic liver recovered from donors after brain death (DBDs), as well as the molecular signaling pathways underlying the effects of such cytokines.

BD reduced IL-6 levels only in nonsteatotic grafts, and diminished IL-10 levels only in steatotic ones. In both graft types, BD increased IL-1β, which was associated with hepatic inflammation and damage. IL-6 administration reduced IL-1β only in non-steatotic grafts and protected them against damage and inflammation. Concordantly, IL-1β inhibition via treatment with an IL-1 receptor antagonist caused the same benefits in non-steatotic grafts. Treatment with IL-10 decreased IL-1β only in steatotic grafts and reduced injury and inflammation specifically in this graft type. Blockading the IL-1β effects also reduced damage and inflammation in steatotic grafts. Also, blockade of IL-1β action diminished hepatic cAMP in both types of livers, and this was associated with a reduction in liver injury and inflammation, then pointing to IL-1β regulating cAMP generation under LT and BD conditions. Additionally, the involvement of nitric oxide (NO) in the effects of interleukins was evaluated. Pharmacological inhibition of NO in LT from DBDs prompted even more evident reductions of IL-6 or IL-10 in non-steatotic and steatotic grafts, respectively. This exacerbated the already high levels of IL-1β seen in LT from DBDs, causing worse damage and inflammation in both graft types. The administration of NO donors to non-steatotic grafts potentiated the beneficial effects of endogenous NO, since it increased IL-6 levels, and reduced IL-1β, inflammation, and damage. However, treatment with NO donors in steatotic grafts did not modify IL-10 or IL-1β levels, but induced more injurious effects tan the induction of BD alone, characterized by increased nitrotyrosine, lipid peroxidation, inflammation, and hepatic damage.

Our study thus highlights the specificity of new signaling pathways in LT from DBDs: NO-IL-6-IL-1β in non-steatotic livers and NO-IL-10-IL-1β in steatotic ones. This opens up new therapeutic targets that could be useful in clinical LT.

The excessive intake of fructose in the regular human diet could be related to global increases in metabolic disorders. Sugar-sweetened soft drinks, mostly consumed by children, adolescents, and young adults, are the main source of added fructose. Dietary high-fructose can increase intestinal permeability and circulatory endotoxin by changing the gut barrier function and microbial composition. Excess fructose transports to the liver and then triggers inflammation as well as de novo lipogenesis leading to hepatic steatosis. Fructose also induces fat deposition in adipose tissue by stimulating the expression of lipogenic genes, thus causing abdominal adiposity. Activation of the inflammatory pathway by fructose in target tissues is thought to contribute to the suppression of the insulin signaling pathway producing systemic insulin resistance. Moreover, there is some evidence that high intake of fructose negatively affects both male and female reproductive systems and may lead to infertility. This review addresses dietary high-fructose-induced deteriorations that are obvious, especially in gut permeability, microbiota, abdominal fat accumulation, insulin signaling, and reproductive function. The recognition of the detrimental effects of fructose and the development of relevant new public health policies are necessary in order to prevent diet-related metabolic disorders.

Objective: Telmisartan is an angiotensin receptor blocker (ARB) that specifically blocks angiotensin II type-1 receptors (AT1R). Telmisartan has been proven to have antidiabetic effects via a variety of mechanisms, and it can be utilized in some diabetic patients due to its dual benefit for hypertensive patients with type 2 DM (T2DM) and when the other oral antidiabetic medications are intolerable or contraindicated. However, its precise underlying hypoglycemic mechanism is still obscure. Aim of work: We sought to establish a link between telmisartan administration and myostatin expression in skeletal muscles of T2DM rat model as a potential hypoglycemic mechanism of telmisartan. Materials and Methods: 32 male albino rats were included in the study; 8 rats served as controls (group I). T2DM was inducted in the other 24 rats, which were then randomly subdivided into 3 groups (8 in each): (group II) the Diabetic group and (groups III and IV) which were treated with either telmisartan (8 mg/kg/day) or metformin (250 mg/kg/day) respectively via oral gavage for a 4-week period. Results: Telmisartan administration resulted in a significant improvement in OGTT, HOMA-IR, glucose uptake, and muscle mass/body ratios in Telmisartan group as compared to Diabetic group (p < 0.05). Additionally, telmisartan induced a significant boost in adiponectin and IL-10 serum levels with a substantial drop in TNF-α and IL-6 levels in Telmisartan group compared to diabetic rats (p < 0.05). Moreover, telmisartan significantly boosted SOD and GSH, and decreased MDA levels in the skeletal muscles of telmisartan group. Furthermore, a significant downregulation of myostatin and upregulation of insulin receptor, IRS-1, and IRS-3 genes in the skeletal muscles of Telmisartan group were also detected. Histologically, telmisartan attenuated the morphological damage in the skeletal muscle fibers compared to diabetic rats, as evidenced by a considerable decrease in the collagen deposition area percentage and a reduction in NF-kB expression in the muscle tissues of group III. Conclusion: Telmisartan administration dramatically reduced myostatin and NF-kB expressions in skeletal muscles, which improved insulin resistance and glucose uptake in these muscles, highlighting a novel antidiabetic mechanism of telmisartan in treating T2DM.

In recent years, there has been an increasing incidence of metabolic syndrome, type 2 diabetes, and cardiovascular events related to insulin resistance. As one of the target organs for insulin, adipose tissue is essential for maintaining in vivo immune homeostasis and metabolic regulation. Currently, the specific adipose tissue mechanisms involved in insulin resistance remain incompletely understood. There is increasing evidence that the process of insulin resistance is mostly accompanied by a dramatic increase in the number and phenotypic changes of adipose tissue macrophages (ATMs). In this review, we discuss the origins and functions of ATMs, some regulatory factors of ATM phenotypes, and the mechanisms through which ATMs mediate insulin resistance. We explore how ATM phenotypes contribute to insulin resistance in adipose tissue. We expect that modulation of ATM phenotypes will provide a novel strategy for the treatment of diseases associated with insulin resistance.

The innate cytokine system is involved in the response to excessive food intake. In this review, we highlight recent advances in our understanding of the physiological role of three prominent cytokines, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF), in mammalian metabolic regulation. This recent research highlights the pleiotropic and context-dependent functions in the immune-metabolic interplay. IL-1β is activated in response to overloaded mitochondrial metabolism, stimulates insulin secretion, and allocates energy to immune cells. IL-6 is released by contracting skeletal muscle and adipose tissue and directs energy from storing tissues to consuming tissues. TNF induces insulin resistance and prevents ketogenesis. Additionally, the therapeutic potential of modulating the activity of each cytokine is discussed.

Hyperinsulinemia, hyperglucagonemia, and low-grade inflammation are frequently presented in obesity and type 2 diabetes (T2D). The pathogenic regulation between hyperinsulinemia/insulin resistance (IR) and low-grade inflammation is well documented in the development of diabetes. However, the cross-talk of hyperglucagonemia with low-grade inflammation during diabetes progression is poorly understood. In this study, we investigated the regulatory role of proinflammatory cytokine interleukin-6 (IL-6) on glucagon secretion.

The correlations between inflammatory cytokines and glucagon or insulin were analyzed in rhesus monkeys and humans. IL-6 signaling was blocked by IL-6 receptor-neutralizing antibody tocilizumab in obese or T2D rhesus monkeys, glucose tolerance was evaluated by intravenous glucose tolerance test (IVGTT). Glucagon and insulin secretion were measured in isolated islets from wild-type mouse, primary pancreatic α-cells and non-α-cells sorted from GluCre-ROSA26EYFP (GYY) mice, in which the enhanced yellow fluorescent protein (EYFP) was expressed under the proglucagon promoter, by fluorescence-activated cell sorting (FACS). Particularly, glucagon secretion in α-TC1 cells treated with IL-6 was measured, and RNA sequencing was used to screen the mediator underlying IL-6-induced glucagon secretion. SLC39A5 was knocking-down or overexpressed in α-TC1 cells to determine its impact in glucagon secretion and cytosolic zinc density. Dual luciferase and chromatin Immunoprecipitation were applied to analyze the signal transducer and activator of transcription 3 (STAT3) in the regulation of SLC39A5 transcription.

Plasma IL-6 correlate positively with plasma glucagon levels, but not insulin, in rhesus monkeys and humans. Tocilizumab treatment reduced plasma glucagon, blood glucose and HbA1c in spontaneously obese or T2D rhesus monkeys. Tocilizumab treatment also decreased glucagon levels during IVGTT, and improved glucose tolerance. Moreover, IL-6 significantly increased glucagon secretion in isolated islets, primary pancreatic α-cells and α-TC1 cells. Mechanistically, we found that IL-6-activated STAT3 downregulated the zinc transporter SLC39A5, which in turn reduced cytosolic zinc concentration and ATP-sensitive potassium channel activity and augmented glucagon secretion.

This study demonstrates that IL-6 increases glucagon secretion via the downregulation of zinc transporter SLC39A5. This result revealed the molecular mechanism underlying the pathogenesis of hyperglucagonemia and a previously unidentified function of IL-6 in the pathophysiology of T2D, providing a potential new therapeutic strategy of targeting IL-6/glucagon to preventing or treating T2D.