On the other hand, when stimulated with LPS, there was a significant increase in the secretion of these cytokines. Furthermore, Tessaro et al. Our findings corroborate with previous studies where it was reported that high glucose concentrations 15mM, 25mM do not alter the expression of TNF-α and IL-6 by macrophages, however, when stimulated with LPS, the secretion of these cytokines increase, showing that hyperglycemia it is not a sufficient stimulus for the high production of these cytokines by macrophages 35 , High glucose conditions can cause mitochondrial dysfunction, increase the production of ROS and activates the autophagy pathway 29 , 39 — Furthermore, LC3b protein is involved in mitophagy 42 , a process that removes dysfunctional mitochondria by the autophagic machinery Therefore, we suggest that the high levels of LC3b and beclin-1 expression by ND-BMDM, when compared to D-BMDM identified in this study are due to the normal cellular regulation process in response to stress caused by the hyperglycemic condition, suggesting that the autophagy pathway is impaired in macrophages from diabetic animals, which reinforces that these cells are sensitized when exposed to the hyperglycemic state in vivo 44 — Furthermore, we observed a reduction in LC3b expression by ND-BMDMs and D-BMDMs stimulated and in hyperglycemic conditions.

Our findings corroborate with study that showed a decrease in LC3b expression in THPderived macrophages exposed to high concentrations of glucose with the inflammasome pathway activated However, in this study performed by Dai et al. It was already described that alterations in the autophagy pathway can directly interfere in the inflammatory response of diabetic individuals, making them susceptible to the development of infections 12 49 , Combined with that, nigericin is known to be an inducer of the NLRP3 inflammasome pathway, where the formation of this complex results in the production of IL-1β In our studies, we observed that macrophages from diabetic animals, when stimulated, secreted a greater amount of the cytokine IL-1β, showing that there is an exacerbated production of this cytokine when stimulated by LPS.

Since the relationship between the autophagy process and IL-1β cytokine secretion has been widely studied, it has been reported that this process is responsible for sequestering this cytokine and preventing its secretion 52 , and a negative regulation of this pathway can lead to an increase of IL-1β release 21 , These results suggest that, besides macrophages of diabetic animals being previously sensitized by hyperglycemia, the failure of the autophagy machinery may be contributing to the decompensated secretion of this cytokine.

With the changes observed in our study, we can observe that hyperglycemia plays an essential role in the inflammatory response of BMDMs from diabetic mice, since the high concentration of glucose with LPS stimulation led to significant changes in the secretion of inflammatory mediators and in the autophagy process, having a direct effect on cellular homeostasis.

The high concentration of glucose alters the inflammatory pathways in macrophages after LPS stimulation, disrupting the secretion of pro-inflammatory cytokines by these cells, leading to an impaired inflammatory response against infections.

Furthermore, we observed that the sensitization caused by hyperglycemia in macrophages can downregulate the expression of proteins involved in the autophagy pathway, impairing cellular homeostasis, suggesting the main role of this mechanism over macrophages under diabetic conditions.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. ES and JM conceived and designed the experiments. ES, LQ, JG, KP and RB performed the experiments. ES, LQ, SE and JM analyzed the data.

ES and JM wrote the paper with the assistance and contribution of all the authors. All authors contributed to the article and approved the submitted version. The authors would like to thank Silene Migliorini and Fabiana Teixeira for providing the acquisition, organization of reagents used in this project and assistance at the laboratory.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Watanabe S, Alexander M, Misharin AV, Budinger GRS.

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Mechanism of oxidative stress-induced IR: Chronic exposure of hyperglycemia and hyperlipidemia due to over nutrition leads to the production of oxidative stress via activation of reactive oxygen species.

IKKβ also induces the activation of NF-κB. p38, JNK and IKKβ, further activates the serine phosphorylation of insulin receptor substrate-1 IRS While on the other side, NF-κB also activates the expression of iNOS which also induces the S-nitrosylation of IRS Both S-nitrosylation and serine phosphorylation of IRS-1 suppress the tyrosine phosphorylation of insulin signaling pathways which ultimately results into the induction of IR in liver, adipocytes and skeletal muscles.

Impact of oxidative stress on vital organs of the body. β-cells of pancreatic islets, adipocytes and peripheral tissues are more susceptible to the damaging effects of oxidative stress. Oxidative stress independently exhibit its hazardous effects on these organs due to which impaired insulin secretion occurs in β-cells of pancreatic islets and IR develops in adipocytes and peripheral tissues.

Impaired insulin secretion and IR lead to the development of post prandial hyperglycemia and overt T2DM both of which also acts as feedback mechanism for the development of oxidative stress. Endoplasmic reticulum stress ERS is another mechanism that palys crucial role for the development of IR in adipocytes and peripheral tissues.

ERS just like oxidative stress, is produced by the activation of JNK and inhibitory phosphorylation of IRS-1 in adipose tissues and liver [ 72 ] and induces the pathogenesis of IR in endothelial cells. It has been found that ER is a major site for the production of various proteins such as insulin biosynthesis and act as a place for the lipid and sterol synthesis [ 73 ].

Any kind of abnormality that occurs in ER may lead to the development of ERS which also contribute to induce tissue-specific IR.

It has been revealved from experimental studies that some anti-diabetic agents alos modulate the ERS during the treatment of T2DM [ 74 ] which offer a new therapeutic target for the treatment of ERS-inducced IR and T2DM. NF-κB is a sequence-specific transcriptional mediated factor that primarily regulates various inflammatory responses [ 75 ] and IκB kinase β IKK-β is a central coordinator for these inflammatory responses through the activation of NF-κB [ 76 ].

IKK-β activates NF-κB through phosphorylation of IKK-β [ 77 , 78 ] and thereafter, NF-κB mediates the stimulation of numerous pro-inflammatory mediators such as IL-1β, IL-6, and TNF-α [ 76 , 78 ].

Once these pro-inflammatory cytokines are activated, they ultimately lead to cause IR [ 2 , 14 , 79 , 80 ]. Therefore, NF-κB and IKK-β are considered to be involved in the pathogenesis of IR [ 81 , 82 ].

IKK-β induces inflammatory responses in hepatocytes which massively increase the production of pro-inflammatory cytokines [ 83 ]. These pro-inflammatory cytokines then enter into the blood stream to cause IR in other tissues [ 81 ].

Various studies have investigated that nonsteroidal anti-inflammatory drugs NSAIDs such as cyclooxygenase inhibitors aspirin and salicylates can significantly inhibit the activation of NF-κB and IKK-β [ 84 ] in rodent models and humans [ 84 , 85 ].

These studies suggest that NSAIDs may exhibit their anti-inflammatory effects on myeloid cells rather than in muscle or fat. Expression of IKK-β in myeloid cells significantly suppresses the activation of pro-inflammatory cytokines that promote IR [ 81 ].

In the following sub-sections, role of various transcriptional pathways in the pathogenesis of IR has been briefly described. IR leads to the increased production of insulin from β-cells of pancreatic islets and as result, compensatory hyperinsulinemia within the body occurs.

Toll like receptors TLRs are the important modulators of IR and its comorbidities. Chronic inflammation plays a crucial role in variety of insulin resistant states [ 86 , 87 ] in which various signaling pathways are activated that directly interfere with the normal functioning of the key components of insulin signaling pathways [ 88 ].

Among various pathways, activation of TLRs imparts crucial role for the generation of inflammation. There are two main types of TLRs i. TLR2 and TLR4. TLR4 is an extracellular cell surface receptor that is expressed in β-cells of pancreatic islets, brain, liver skeletal muscle and adipose tissues Fig.

In nomal conditions, TLR4 regulates insulin sensitivity in these tissues, but the activation of TLR4 directly dampen the insulin action through the activation of various pro-inflammatory mediators and ROS, indirectly generates the activation of various pro-inflammatory mediators by inducing various signaling cascades and transcriptional factors notably MyD88, TIRAP, TRIF, IKKs and JNKs that causes the activation of innate immune responses which ultimately leads to the development of IR Fig.

TLR4 plays this role primarly in coordination with the phosphorylation of IRS serine. Expression TLR4 in integrated tissues and organ systems of the body that regulate the insulin sensitivity.

Toll-like receptor 4 TLR4 present in adipocytes, initiates the inflammatory responses that release various pro-inflammatory mediators. Once, produced, these mediators are entred into the blood stream and thereby promote IR.

TLR4, expressed on Kupffer cells and other liver cell components, regulates the various inflammatory responses in liver.

TLR4, expressed in skeletal muscles, has been shown to regulate the substrate metabolism in muscle, favoring glucose oxidation in the absence of insulin. Hypothalamus and mesolimbic area are important sites that modulate the energy expenditure, pancreatic β-cell function and IR in peripheral tissue.

Expression of TLR4 in hypothalamus potentiates various inflammatory responses that contribute to the pathogenesis of IR. Adopted from Kim and Sears Schematic representation of TLR4 signaling cascades. Lipopolysaccharide LPS and its endotoxic moiety have been reported to be the potential activators of TLR4 Fig.

LPS is composed of oligosaccharides and acylated saturated fatty acids SFAs. Besides LPS, SFAs have also been reported to be the activator of TLR4. The expression and signaling of TLR4 are regulated mainly by the adiponectins. Several studies have reported that adiponectin can inhibit LPS-induced activation of TLR4 through the involvement of AMPK, IL, and heme oxygenase-1 [ 90 — 92 ].

Other regulators of TLR4 are peroxisome proliferators-activated receptor gamma PPARγ and sex hormones [ 93 , 94 ]. Taking together, TLR4 is a molecular link for pro-inflamatory mediators, different body organs, and several transcriptional pathways and cascades that modulate the innate immune system by regulating the insulin sensitivity.

In the proceeding sub-sections, role of TLR4 expression in various vital organs of the body for the pathogenesis of IR has been described. Despite of having the ability to act as storage depot for excess calories, adipose tissues secrete large number of hormones, pro-inflammatory cytokines and chemokines that directly influence the metabolism Fig.

Adipose tissues consist of adipocytes, preadipocytes, macrophages, lymphocytes and endothelial cells. Only adipocytes and macrophages are known to release various pro-inflammatory cytokines IL-1β, IL-6, and TNF-α and chemokines such as MCP-1 that potentiate inflammation in several tissues after being released into the systemic circulation [ 95 ].

Besides this, adipocytes are also a rich source of two important hormones namely leptin [ 96 , 97 ] and adiponectin [ 98 ]. Adiponectin, having anti-inflammatory properties, promotes insulin sensitivity whereas, leptin having inflammatory properties, impairs insulin sensitivity in adipocytes [ 87 ].

Several factors such as oxidative stress, increased FFAs flux and hypoxia that are associated with inflammation can induce IR in adipose tissues [ 87 ].

TLRs present in adipose tissues are directly activated by the nutrients [ 99 , ] which play a key role for the initiation of inflammatory responses which ultimately promotes IR in these tissues [ — ].

Nutritional fatty acids can activate the expression of TLR4 in adipocytes that play crucial role for the activation of various pro-inflammatory mediators and transcriptional mediated pathways which ultimately lead to the development of IR in adipocytes. Skeletal muscles have marked significance to regulate the normal glucose homeostasis and development of IR as these are the primary site for insulin-induced glucose uptake and utilization in peripheral tissues.

Skeletal muscles contain myocytes and macrophages in which TLR4 receptors are expressed Fig. Signal transduction of TLR receptors is an underlying mechanism for the development of IR and chronic inflammation in skeletal muscles [ ]. TLR4 expression in skeletal muscle is associated with severity of IR and skeletal muscle metabolism.

The mechanis in the development of IR in skeletal muscles may include the direct effects of intramyocellular FFAs metabolites in skeletal muscles, macrophages and paracrine effects of adipocytes. Recently, it has been experimentally confirmed that disruption of TLR4 expression prevents SFA-induced IR in TLR mutant mice and improves IRS-1 tyrosine phosphorylation and insulin-stimulated glucose uptake.

Moreover, disruption of TLR4 expression has also shown to decrease the JNK1 phosphorylation and IRS-1 serine phosphorylation [ , ].

Liver is the major and vital organ of the body which is composed of heterogenous types of cells notably hepatocytes, immune cells, kupffer cells and endothelial cells. Due to their localization at sinusoids, kupffer cells are in close contact with circulating cytokines, lipids, hormones and postprandial LPS, and hence, kupffer cells are important mediators of inflammation within the liver.

TLR4 expressed on kupffer cells in the liver Fig. It has been found that activated levels of pro-inflammatory AP-1 and NF-κB in liver are directly correlated with IR and oxidative stress [ ].

TLR4 signaling pathway is strongly associated with IR as, it has been found that acute treatment of LPS inhibits the production of hepatic glucose via activation of TLR4 signaling pathway and induces IR in liver [ ]. Several TLRs such as TLR2, TLR3 and TLR4, are also expressed in β-cells of pancreatic islets [ ].

Signal transduction of TLRs in β-cells of pancreatic islets is mainly associated with inflammation in β-cells of pancreatic islets [ — ].

Distruction and malfunctioning of β-cells of pancreatic islets may lead to insufficient secretion of insulin in both types of DM. Expression of TLR4 in pancreatic islets may lead to impaired insulin secretion and promote β-cell apoptosis [ ]. Brain itself palys a central role to regulate glucose homeostasis and metabolism.

In brain, hypothalamus and mesolimbic sites have been considered as important areas that are actively involved in the regulation of insulin sensitivity in peripheral tissues and β-cells secretory functions of pancreatic islets [ ].

TLR4 expression is widely distributed in the body Fig. Vascular endothelial dysfunction is a major complication for induction of IR and pathogenesis of T2DM.

At molecular level, excess amount of nutrient is interlinked with IR through the activation of transcriptional mediated pathways such as IKKβ and NF-κB [ 83 , ]. Augmented levels of FFAs are associated with generation of inflammation and induction of IR in endothelial cells [ , ].

IKKβ and NF-κB are transcriptional mediators of inflammation and TLR4 is implicated as a mediator of IKKβ and NF-κB [ , ]. TLR4 receptors are also expressed in endothelial cells and expression of TLR4 via LPS-stimulated IKKβ and NF-κB activation contributes the dysfunctioning of endothelial cells [ ].

Activation of TLR4 via FFAs can trigger the cellular inflammatory responses in endothelial cells [ , ] whereas, whole body deletion of TLR4 expression has shown to prevent high-fat diet-induced vascular inflammation and IR in mice [ , ].

Similarly, activation of TLR4-dependent IKK and NF-κB indicated impaired insulin signaling and NO production in endothelial cells [ ]. The growing evidence implicates that TLR4 is the major causative factor to induce IR in endothelial cells via activation of various transcriptional mediated pathways and inflammation in endothelial cells.

AMP-activated protein kinase AMPK is an enzyme that is most commonly known as master regulator of energy metabolism [ ] and its activation is based on the energy level of the body.

Upon activation, AMPK resotres the energy levels of the body by stimulating various processes in different body organs Fig. AMPK plays a crucial role between adipose and peripheral tissues, and interferes various metabolic and secretory functions [ ] that are responsible for normoglycemia and glucose homeostasis Fig.

In adipocytes, adipokines exhibit their metabolic effects by activating AMPK which result in the increased β-oxidation in peripheral tissues. Activation of AMPK in peripheral tissues enables skeletal muscles to cope with elevated levels of FFAs.

Keeping in view the active role of AMPK in energy metabolim, it has been found that AMPK activation improves insulin sensitivity and glucose homeostasis. IR is a major hallmark for the pathogenesis of T2DM however, AMPK activation can prevent the pathogenesis of IR and development of T2DM.

Protein kinase C PKC and inhibitor kB kinase IKK are the two main important kinases that play crucial role in pro-inflammatory mediators-induced inflammatory processes in adipocytes and peripheral tissues underlying the development of systemic IR [ — ].

IKK induces IR in peripheral tissues by suppressing the insulin signaling and activating NF-κB [ , ]. Inhibition of IKK activation prevents the secretion of adipokines from adipocytes and improves insulin sensitivity in adipocytes and peripheral tissues [ 81 , , ].

NF-κB is a transcriptional mediated pathway that plays its crucial role in the transcription of signals for te production and release of various pro-inflammatory mediators.

Most importantly, NF-κB plays active role to regulate IL-1β Fig. Once activated, NF-κB targets serval genes to potentiate the release of various pro-inflammatory mediators in adipose tissues and liver [ 81 , 83 , ].

These pro-inflammatory mediators that are produced in response to NF-κB activation induce tissue-specific IR. Glucolipotoxicity is a general term which is collectively used for the combination of glucotoxicity and lipotoxicity.

These two terms are collectively responsible to activate the release of various pro-inflammatory mediators which lead to the development of tissue-specific IR and impaired insulin secretion from β-cells of pancreatic islets Fig.

Adipocytes are the main sites for the storage of fats and energy supplied to the body, is also regulated by the adipocytes. When accumulation of lipids exceeds the energy expenditure, then most of the excess amount is stored in the form of FFAs in adipose and other insulin-sensitive tissues.

When fat storage and energy supply is impaired in adipose tissues, elevation of FFAs levels in plasma occurs which is converted into the triglycerides and stores in non-adipose tissues [ ]. The ectopic storage of FFAs metabolites mostly triglycerides results in lipotoxic effects in peripheral tissues Fig.

In addition to this, elevated levels of FFAs in plasma may also interfere with insulin signaling pathways notably IRS-1 serine phosphorylation in peripheral tissues via activation of PKC and inhibition of IKK and JNK [ ]. Hence, it has been evidenced that glucolipotoxicity is one of the major contributor for the development of tissue-specific IR.

Mechanism of hyperglycemia- and dyslipidemia-induced inflammation for the development of IR and T2DM. Hyperglycemia and dyslipidemia collectively provoke the activation of pro-inflammatory mediators through the involvement of several metabolic pathways.

Once, these pro-inflammatory mediators are released, they induce tissue-specific inflammation due to which IR in peripheral tissues and impaired insulin secretion in pancreatic islets occur that ultimately lead to overt T2DM.

Adapted from Akash et al. Development of IR is one of the major hallmark for pathogenesis of T2DM. To control the propagation of IR is one of the most important targeted treatment. For the development of IR, several factors are involved Fig. Several treatment strategies have been used to overcome the development of IR.

The most important ones have been described here in the following sub-sections. Interleukin-1 receptor antagonist IL-1Ra is naturally occurring anti-inflammatory cytokine of interleukin-1 family. It competitively binds with IL-1RI and prevent the binding of IL-1β and antagonizes its effects.

It has been evidenced from several experimental studies that imbalance between IL-1Ra and IL-1β generates inflammation in various parts of the body where IL-1RI is present [ 4 , 12 ].

Moreover, it has also been found that expression of IL-1Ra is strongly correlated with the development of IR, impaired insulin secretion and T2DM [ 4 , ]. Treatment of human recombinant IL-1Ra improves normoglycemia, insulin sensitivity in adipose and peripheral tissues, and insulin secretion from β-cells of pancreatic islets impairs [ 31 , , ].

This is one of the most important treatment strategy that anti-inflammatory agent might indeed prevent the development of IR and improves glycemia. One of the main shortcoming of IL-1Ra is its short biological half-life and to overcome this problem, high doses with frequent dosing intervals are required to achieve desired therapeutic effects.

To overcome this problem, several treatment strategies have been applied to prolong the biological half-life and therapeutic effects of IL-1Ra [ 29 ]. Salicylates are an important class of anti-inflammatory agents.

They are used in variety of inflammatory diseases and syndromes. Inflammation plays a crucial role for the development of IR and T2DM, therefore, by using salicylates as an alternate treatment strategy, it has been found that salicylates can imporve insulin sensitivity via inhibition of NF-κB and IKKβ [ 82 ] and glucose tolerance [ , ].

In the above sections, it has been briefly described that TNF-α is one of the most important pro-inflammatory mediator that is responsible to induce IR in adipocytes and peripheral tissues.

Inhibition of TNF-α production might be one of the choice to prevent the development of IR and pathogenesis of T2DM [ 4 ]. Recently, infliximab has been demonstrated to improve insulin signaling and inflammation especially in the liver in rodent model of diet-induced IR [ ].

Similarly, using anti-TNF-α antibodies also improve the insulin sensitivity in peripheral tissues [ ]. Lo et al. demonstrated that etanercept therapy can also improve total concentration of adiponectin which is anti-inflammatory adipokine and improved insulin sensitivity [ ].

Keeping in view the decisive role of TNF-α in pathogenesis of IR, several anti-TNF-α treatment strategies have been utilized to prevent the pathogeneis of IR and development of T2DM.

Similarly, anti-TNF-α treatment has also shown to prevent the IR in Sprague—Dawley rats [ ] while neutralization of TNF-α also prevented IR in hepatocytes [ ].

Few controversial studies have also demonstrated that using TNF-α blockade has no effect on IR [ ] which indicates that TNF-α blockade is not a treatment of choice as its production is dependent on the generation of IL-1β and activation of various transcriptional mediated pathways. It has been thought that chemokines activately participate in the development of IR by potentiating the inflammation in adipocytes.

Moreover, genetic inactivation of these chemokine signaling [ 52 , 53 , ] or inhibition of their axis [ , ] by pharmacological approaches have been shown to improve the insulin sensitivity in adipocytes and peripheral tissues. ER stress, as mentioned in the above sections, is a key link between IR and T2DM [ ].

Blockade of ER stress is one of the treatment option to prevent the development of IR and pathogenesis of T2DM. In the recent years, various pharmaceutical chaperones, notably endogenous bile acids and the derivatives of these bile acids such as ursodeoxycholic acid UDCA , 4-phenyl butyric acid PBA have been investigated that have proven to have the ability to modulate the normal functioning of ER and its folding capacity [ 28 ].

Ozcan et al. The results of this study indicated that UDCA significantly improved insulin sensitivity and normoglycemia. Thiazolidinediones also known as glitazones, are one of the most important insulin sensitisers.

They are the agonists of peroxisome proliferator-activated receptors-gamma PPARγ. It has been found that thaizolidinediones have the ability to improve insulin action and decrease IR [ , ]. Inflammatory responses are induced through the activation of various pro-inflammatory and oxidative stress mediators via involment of various transcriptional mediated pathways.

To stop the inflammatory responses in IR development is one of the key treatment strategy. In this areticle, we have comprehensively highlighted the up-to-date scientific knowlesge of role of inflammatory responses in IR development and its treatment strategies.

IR plays a crucial role for the pathogenesis and development of T2DM and its associated complicaitons. Based on the findings mentioned in above sections, anti-inflammatory treatment strategies are one of the best choice to prevent the the pathogenesis of IR, but the studies conducted to investigate the role of anti-inflammatory strategies for the prevention of IR are still in their beginning stages and need to be focused further in future studies for more better and improved clinical outcomes.

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