Elsevier

Clinica Chimica Acta

Volume 462, 1 November 2016, Pages 77-89
Clinica Chimica Acta

Review
Tissue resident macrophages: Key players in the pathogenesis of type 2 diabetes and its complications

https://doi.org/10.1016/j.cca.2016.08.015Get rights and content

Highlights

  • Tissue-resident macrophages play a major role in regulation of tissue inflammation.

  • Macrophages have a role in development of insulin resistance and β cell dysfunction.

  • Macrophages contribute to T2D complications such as nephropathy and retinopathy.

  • Here we focus on the role of macrophages in the pathogenesis of T2D and its complications.

Abstract

There is increasing evidence showing that chronic inflammation is an important pathogenic mediator of the development of type 2 diabetes (T2D). It is now generally accepted that tissue-resident macrophages play a major role in regulation of tissue inflammation. T2D-associated inflammation is characterized by an increased abundance of macrophages in different tissues along with production of inflammatory cytokines. The complexity of macrophage phenotypes has been reported from different human tissues. Macrophages exhibit a phenotypic range that is intermediate between two extremes, M1 (pro-inflammatory) and M2 (anti-inflammatory). Cytokines and chemokines produced by macrophages generate local and systemic inflammation and this condition leads to pancreatic β-cell dysfunction and insulin resistance in liver, adipose and skeletal muscle tissues. Data from human and animal studies also suggest that macrophages contribute to T2D complications such as nephropathy, neuropathy, retinopathy and cardiovascular diseases through cell–cell interactions and the release of pro-inflammatory cytokines, chemokines, and proteases to induce inflammatory cell recruitment, cell apoptosis, angiogenesis, and matrix protein remodeling. In this review we focus on the functions of macrophages and the importance of these cells in the pathogenesis of T2D. In addition, the contribution of macrophages to diabetes complications such as nephropathy, neuropathy, retinopathy and cardiovascular diseases is discussed.

Introduction

Type 2 diabetes (T2D) is a serious health problem that is estimated to affect more than 300 million people by 2013 worldwide [1]. Insulin resistance and β-cell dysfunction are hallmarks of T2D. Insulin resistance leads to impairments in insulin-mediated suppression of hepatic glucose production, skeletal muscle glucose disposal and inhibition of lipolysis in adipose tissue [2]. These conditions result in a relative hyperglycemia and increased plasma free fatty acids (FFAs). To compensate for insulin resistance, pancreatic β-cells produce more insulin. However, overtime β-cells fail to compensate for the increasing demand for insulin and eventually diabetes develops [2].

Several factors including genetics, environmental, physical inactivity and obesity have been suggested to play role in the development of insulin resistance and β-cell dysfunction. In particular, obesity seems to be the major contributor to insulin resistance and T2D, as almost 80% of subjects with T2D are classified as overweight or obese [3]. It is now commonly accepted that low grade inflammation is the link between obesity and insulin resistance in diabetic patients. Obesity-associated inflammation is characterized by an increased abundance and activation of innate and adaptive immunity cells in adipose tissue along with an increased release of inflammatory factors and chemokines locally and systemically. These inflammatory factors can then impair the insulin signaling in adipose, liver and skeletal muscle tissues [4]. Among the innate and immunity cells present in adipose tissue, macrophages and their infiltration into the tissue seems to be the key mediator of the inflammatory process. In addition, tissue-resident macrophages in the liver and skeletal muscle tissues have been demonstrated to activate inflammatory process leading to insulin resistance in these tissues [5].

Islet inflammation has also been demonstrated in T2D patients. Islet inflammation is characterized by the presence of amyloid deposits, fibrosis, and infiltration of macrophages along with increased levels of pro-inflammatory cytokines and chemokines [6]. It is now well known that interleukin 1β (IL-1β) is the main pro-inflammatory cytokine in the islets that causes an increased local expression of pro-inflammatory cytokines and chemokines leading to macrophage recruitment to the islets. This local inflammation decreases insulin secretion and induces β-cell apoptosis that eventually results in islet mass reduction [6].

Diabetic patients are at the risk for long-term complications such as macrovascular (coronary artery disease, peripheral arterial disease, and stroke) and microvascular complications (nephropathy, neuropathy, and retinopathy). It has long been evident that macrophages are a major component of atherosclerotic plaques. Similarly, diabetic nephropathy is considered an inflammatory disease. Infiltration of immune cells including macrophages cells into the kidney has been reported to be involved in both the development and progression of the disease [7].

Although, other immune cells, such as T and B cells have been shown to accumulate in tissues, macrophages as mentioned earlier, are the main players in regulating the local immune response. Therefore, in this review, we only focus on the role of macrophage cells in the pathogenesis of T2D and its complications. In particular we will discuss about the role of tissue-resident macrophages in the development and progression of muscle, adipose and liver insulin resistance, pancreatic β-cell dysfunction and complications of T2D such as nephropathy, retinopathy, atherosclerosis and neuropathy.

Inflammation is a series of cellular and molecular events that help to defend the body from infection. Various immune cells are involved in inflammation. Neutrophils are the first line of immune defense against infectious diseases [5], [8]. Once neutrophils recognize the pathogens, they produce chemokines leading to recruitment of other immune cells to the site of the infection. Macrophages are recruited first, and then lymphocytes are recruited. The infiltrating immune cells then kill and remove the infected cells, after which the inflammation resolves and tissue healing starts. Finally, B cells mediate the transition from innate immunity to adaptive immunity [5]. Therefore, in general, inflammation is characterized by enhanced local and systemic cytokine production along with increase in infiltration of the immune cells into the local sites. Accordingly, any dysregulation of this process can result in an uncontrolled inflammation leading to unwanted outcomes, such as septic shock. Inflammation has mainly been studied in infectious models but it is now well understood that its dysregulation has as major role in the pathogenesis of several pathological states such as T2D, rheumatoid arthritis, atherosclerosis, asthma and other autoimmune diseases.

Macrophages, the innate immunity cells, are derived from bone marrow hematopoietic stem cells [9]. After differentiation of hematopoietic stem cells into monocyte, they are released from the bone marrow into the circulation. In the case of infection, monocytes migrate into the local inflammatory sites, where they can differentiate into macrophages [5], [9]. A key function of macrophages in these sites is to protect the body from infection by removing and killing infected cells via phagocytosis and cytokines, respectively. Macrophages also promote wound repair and tissue remodeling by producing extracellular matrix [10]. In addition to the role of macrophages in classical inflammation, they are also believed to play important roles in regulation of chronic inflammation. In most chronic diseases such as atherosclerosis and T2D, macrophages produce chemokines that recruit other immune cells into the local inflammatory sites. They are also able to produce pro-inflammatory cytokines that polarize and activate other immune cells [11], [12].

We now know that macrophages are found in many tissues, where they respond to metabolic signals and produce pro- and/or anti-inflammatory mediators to modulate the inflammatory responses. Tissue macrophages have a broad role in the maintenance of tissue homeostasis, through the clearance of senescent cells and the remodeling and repair of tissues [13]. Macrophage numbers in the tissues depends on the influx of monocytes/differentiation of macrophages and the proliferation of macrophages at the local sites [14]. Accordingly, it is expectable that resident macrophages show the expression profiles distinct from those of recruited macrophages responding to systemic cues. Macrophages are not a uniform population of the cells rather they are morphologically very complex. The macrophages in different tissues show very different properties and are therefore labeled with different names: alveolar macrophages in lung, Kupffer cells in liver, microglia in neural tissue, and osteoclasts in bone [15]. Even within one tissue, the macrophages can be classified into different subtypes based on their surface markers and functions [12].

As mentioned above, macrophages are generally considered to be derived from circulating monocytes and have a high degree of heterogeneity. Human monocytes are subdivided into three populations depending on cell surface CD14 and CD16 expression: classical monocytes that express high levels of CD14 and no CD16 (CD14++ CD16), intermediate monocytes that have intermediate expression of CD14 and CD16 (CD14++ CD16+) and non-classical monocytes that express very low levels of CD14 and high levels of CD16 (CD14 CD16+) [16]. These populations have diverse functions and have been suggested to play both anti and pro-inflammatory roles in a variety of diseases including atherosclerosis and sarcoidosis. It has been suggested that CD14++ CD16 and CD14++ CD16+ monocytes resemble mouse Ly6C+ monocyte subset, whereas CD14+ CD16++ monocytes may resemble Ly6C monocytes [5]. Ly6C+ is known to be inflammatory monocytes and macrophage precursors, whereas Ly6C monocytes are considered to be less inflammatory [17].

The molecular mechanisms underlying the recruitment of macrophages into the tissues are not well understood. However, it has been suggested that an increased production of some chemokines in inflammation local site play a crucial role in this process. Studies in recent years have revealed that CC chemokine ligand 2 (CCL2) [also known as monocyte chemoattractant protein 1 (MCP-1)] and its receptor CC chemokine receptor 2 (CCR2) have an important role in macrophage recruitment [18]. The data from animal studies support the role of these factors in the recruitment of macrophages into inflamed tissues. CCR2-knockout mice showed a reduced macrophage accumulation and chronic inflammation [19], whereas its overexpression led to an increased macrophage infiltration in adipose tissue [20]. In addition, a decrease in macrophage infiltration along with improved insulin sensitivity was observed in MCP-1 knockout mice [20]. In contrast, adipose-specific overexpression of MCP-1 caused insulin resistance and hepatic steatosis in mice [21]. In is worth to note that other studies have failed to repeat these findings and found no effect of MCP-1 or CCL2 deletion on total macrophage recruitment [22], [23]. Thus, it appears that the molecular mechanism regulating the macrophage recruitment in inflammation is more complex than the early studies and a number of additional factors might be involved in this process.

The functional diversity is one of the main characteristics of the macrophages. This functional diversity enables macrophages to differently respond to various micro-environmental cues. Accordingly, two main macrophage phenotypes including the classically activated (or M1) macrophages and the alternatively activated (or M2) macrophages have been recognized [24]. T helper 1 (Th1)-related cytokines such as interferon γ (IFN-γ) and microbicidal product such as lipopolysaccharides (LPS) polarize macrophages to an M1 phenotype. Classical activation results in a population of macrophages with enhanced microbicidal capacity and increased secretion of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), IFN-γ and inducible nitric oxide synthase (iNOS) to further strengthen the cell-mediated adaptive immunity [25]. The alternatively activated macrophages (M2) are more diverse and are induced by Th2 cytokines such as interleukin 4 (IL-4) and IL-13. M2 macrophages are characterized by the expression of arginase-1, CD163, mannose receptor and anti-inflammatory cytokines (e.g., IL-10) [25] (Fig. 1). These cells play a key role in the immune response to parasites, allergy, wound healing, and tissue remodeling [26]. Several other stimuli such as glucocorticoid hormones, apoptotic cells and immune complexes have also been suggested to induce macrophages to an M2-like phenotype [27]. Although this classification of macrophages was established in vitro, it can also simply be used to classify macrophages in vivo. For example, in atherosclerosis and obesity which are pro-inflammatory states, the predominant macrophage phenotypes are often classified as M1 macrophages. However, due to the complexity of in vivo conditions and multiplicity of micro-environmental cues, a mixture of both M1 and M2 phenotypes to varying extent would be expected in different tissues. This idea can be supported by the presence of both M1 and M2 in the adipose tissue of obese subjects [28].

Obesity is associated with a chronic low-grade inflammation as determined by increased plasma levels of C-reactive protein, interleukin-6 (IL-6), IL-8, and TNF-α in humans and different animal models of obesity [29]. The main origin of this systemic inflammatory response seems to be the adipose tissue. The adipose tissue itself consists of a variety of cell types including adipocytes, immune cells (macrophages and lymphocytes), pre-adipocytes, and endothelial cells. Several cytokines and chemokines such as MCP1, IL-6, IL-1β, macrophage migration inhibitory factor (MIF), and TNF-α are released by adipocytes and macrophages [30].

Adipose tissue inflammation probably results from a complex crosstalk between adipocytes, macrophages and other immune cells [31]. Among different cells in adipose tissue, macrophages are the major source of pro-inflammatory cytokines that can act in paracrine and endocrine manner leading to development of local and systemic inflammation. The first evidence for the presence of macrophages in adipose tissue was reported by Bornstein et al. in 2000 by immunohistochemical analysis of the human white adipose tissue using anti-CD68 antibody [32]. In 2003, two publications by Xu et al. [11] and Weisberg et al. [33] emphasized the key role of macrophage infiltration into expanding adipose tissue, causing inflammation and linking obesity to insulin resistance. They showed that obesity increases adipose tissue macrophage (ATM) numbers and those ATMs, not adipocytes, produce the majority of cytokines in response to obesity. Xu et al. performed microarray analyses on various tissues of genetic mouse models (ob/ob and db/db) and the diet-induced obesity model. They found that many of the most significantly upregulated genes in white adipose tissue were not known to be involved in adipocyte biology; instead, they could be broadly categorized as macrophage- or inflammation-related genes [11]. Histologically, there was evidence of significant infiltration of macrophages but not of neutrophils and lymphocytes into the white adipose tissue of the obese mice. In another study, Weisberg et al. demonstrated an increased macrophage number through microarray analyses of various mouse models of obesity. This study showed that the content of these macrophages in a given adipose tissue depot is positively correlated with the degree of obesity. They estimated that the percentage of macrophages in adipose tissue ranges from under 10% in lean mice and humans to over 50% in extremely obese, leptin-deficient mice and nearly 40% in obese humans [33]. In addition, this study clearly showed that ATMs are responsible for almost all adipose tissue TNF-α expression and significant amounts of iNOS and IL-6 expression [19]. These cytokines can then induce local (adipose) and systemic (liver and skeletal muscle) insulin resistance by interfering with the insulin receptor signaling pathway. Taken together, these two studies concluded that ATMs numbers increase in obesity and participate in inflammatory pathways that are activated in adipose tissues of obese individuals. Increased infiltration of macrophages into the obese adipose tissue has subsequently been verified in several human and animal studies [34], [35], [36]. It has also been shown the loss of weight or thiazolidinedione treatment decrease ATM numbers along with an improvement in insulin resistance [37].

Although macrophage infiltration in adipose tissue is now generally accepted, the source of the ATMs and the specific cellular mechanisms linking adiposity to increased macrophages numbers in obesity has not been completely defined. Jenkins et al. have reported the proliferation of M2 macrophages under the control of T-helper 2 activation [38] , however, this does not seem to be a major process in obesity, as the most of ATMs are of the M1 variety. In another study Morinaga et al. showed that only a small pool of macrophages proliferate in the obese adipose tissue and the majority of these CD11c+ macrophages were newly recruited CCR2+ monocytes [39]. In a recent study Nagareddy et al. suggested a continuous recruitment of blood monocytes into the adipose tissue, where they mature into macrophages. They proposed that a feed-forward mechanism exists in obesity such that inflamed adipose tissue can signal to the bone marrow hematopoietic progenitor cells to proliferate, expand, and increase production of myeloid cells. In this regard, obesity induces the expression of Il-1β in macrophages. IL-1β then travels to the bone marrow to induce proliferation of hematopoietic progenitor cells via interleukin-1 receptor (IL-1R), ultimately resulting in monocytosis and neutrophilia [13]. Therefore, it appears that many of the inflammatory origins of obesity may derive from bone marrow pools that give rise to circulating monocytes.

One of the most important questions concerning ATMs is the underlying mechanism promoting the accumulation of these cells in adipose tissue. Among different cells in adipose tissue, it is clear that adipocytes are an important initiator of the inflammatory response. Different mechanisms including hypoxia, adipocyte cell death and augmented chemokine secretion have been suggested to be the initiators of macrophage infiltration [5]. Activation of these mechanisms leads to production and secretion of pro-inflammatory molecules from adipocytes that regulate the recruitment and activation of immune cell populations (Fig. 2).

The increase in the mass of adipose tissue during the development of obesity can arise through an increase in cell size, an increase in cell number, or both. Adipocyte hypertrophy might lead to a local hypoxia during the early stages of expansion and this results in upregulation of a variety of pro-inflammatory adipokines [31], [40]. The response to hypoxia is the activation of the c-Jun. N-terminal kinase (JNK), nuclear factor κB (NF-κB) and hypoxia-inducible factor (HIF) pathways leading to increased expression of genes involved in inflammation and endoplasmic reticulum stress. Activation of these pathways leads to chemokine release and subsequent recruitment of macrophages into the adipose tissue, where they form ring-like structures around large, dying adipocytes [18]. The primary purpose of these recruited macrophages is the removal of cell debris and tissue remodeling. In addition, once recruited, pro-inflammatory macrophages themselves secrete additional chemokines, initiating a feed-forward loop and potentiating the inflammatory responses.

As discussed, during the development of obesity, nutrient excess leads to development of a more inflammatory adipocyte state, including the secretion of different chemoattractants. In this regard, the expression of chemokines such as MCP-1, MIP-1α, MCP-2, RANTES (regulated on activation normal T cell expressed and secreted) and chemokine receptors such as CCR2 and CCR5 are increased in the adipose tissue of obese mice [29]. This elevated expression has been demonstrated to play a major role in recruitment of macrophages to adipose tissue in obesity.

MCP-1 and its receptor, CCR2, are the most studied chemokines for macrophage recruitment to adipose tissue. It has been reported that serum concentration of MCP-1 is increased after 4 weeks of high fat diet feeding in mice [41]. In support of the role MCP-1 in macrophage recruitment, transgenic mice overexpressing MCP-1 in the adipose tissue show enhanced plasma MCP-1 concentration, increased macrophage accumulation in adipose tissue and impaired insulin sensitivity [21]. Furthermore, insulin resistance, hepatic steatosis, and macrophage accumulation in adipose tissue induced by a high-fat diet were reduced extensively in MCP-1 knockout mice [20]. In addition, both acute and chronic systemic infusion of MCP-1 led to insulin resistance in mice [42]. In agreement with these findings, knockout of CCR2 or neutralization of MCP-1 leads to a reduction in the levels of inflammatory monocytes in the circulation, decrease of macrophage recruitment to adipose tissue and protection from high-fat diet-induced insulin resistance [19], [20]. However, some studies did not confirm above findings, as MCP-1 and CCR2 deficiency did not decrease macrophage numbers in adipose tissue and these animals were not protected from high-fat diet-induced insulin resistance and macrophage accumulation [41], [43]). The reasons for these discrepancies are unclear. A possible explanation for the different findings regarding these chemokines can be related to the structure of CCR2. CCR2 is a functional receptor for several other chemokines including MCP-2, MCP-3, CC chemokine ligand 7 (CCL7) and CC chemokine ligand 7 (CCL8), which are all expressed in obese adipose tissue [25].

In keeping with these findings, the role of other chemokines in macrophage recruitment into adipose tissue has been identified. For example, MIP-1α-deficient mice are not protected against high-fat diet induced macrophage infiltration into adipose tissue [44]. Chemokine (C-X-C motif) ligand 14 (CXCL14) and the receptor chemokine (C-X-C motif) receptor 2 (CXCR2) were reported to play a role in macrophage recruitment to adipose tissue [25], [45]. In humans, CCL5 (also known as RANTES) was demonstrated to positively correlate with inflammatory gene expression in visceral adipose tissue [46]. In addition, CCR5 knockout mice were protected from insulin resistance induced by high fat feeding through both reduction in ATM accumulation and induction of anti-inflammatory M2 shift in those cells [47]. The chemoattractant leukotriene B4 (LTB4) and its specific receptor leukotriene B4 type 1 receptor (BLT1) have also been implicated in macrophage recruitment to inflamed adipose tissue. It has been reported that targeting the LTB4-BLT1 axis more specifically, protects mice from obesity-induced inflammation and insulin resistance [48]. Taken together, these findings indicate that multiple chemoattractants might have a role in recruitment of macrophages and monocytes into the adipose tissue. However, a chemokine-independent mechanism for macrophage recruitment to adipose tissue should be considered, since deficiency or antagonism of chemokines or chemokine receptors has not completely abolished macrophage accumulation in adipose tissue [25].

High levels of free fatty acids (FFAs) have been suggested to be one of the key regulators of macrophage recruitment into adipose tissue. It is believed that obesity causes an increase in basal lipolysis, and the resultant increase in local extracellular FFA concentrations could provide a chemotactic stimulus for entry and accumulation of macrophages [9]. Basal lipolysis is chronically elevated in adipose tissue of obese compared with the lean subjects [49]. In support of this hypothesis, supplementation with palmitate, one of the major FFAs released from the adipose tissue, caused recruitment of monocytes to hypertrophied adipocytes by inducing MCP-1 production via JNK and NF-κB activation [3]. Similarly, palmitate increased inflammatory gene expression in human macrophages by an NF-κB-dependent mechanism [50]. An important component of these FFA–induced activation events are the pattern recognition receptors, toll-like receptor-2 (TLR2) and TLR4. Activation of inflammation is prevented in macrophages and adipocytes that are deficient in TLR2, TLR4, or TLR2/TLR4 [51], [52]. In line with this, TLR4-knockout mice are protected against lipid- and obesity-induced insulin resistance [53]. Interestingly, the expression of TLR2/TLR4 are increased in macrophages that are triply positive for F4/80, CD11b, and CD11c [51], thus providing an additional mechanism of feed-forward activation of inflammation within macrophages and the surrounding adipocytes.

As discussed earlier, macrophages are very heterogeneous, which suggests that ATMs may also be very heterogeneous. The first evidence of ATM heterogeneity was reported when a “crown-like structures” was detected from adipose tissue of obese animals, whereas these structures were rarely observed in adipose tissue of lean control animals [11], [33]. Later studies using macrophage-pulse labeling revealed two categories of ATMs, namely newly recruited macrophages (M1) and the residential macrophages (M2) [36]. New macrophages recruited to adipose tissue during the onset of obesity were highly pro-inflammatory and showed increased expression of genes involved in macrophage adhesion, migration, and inflammation [36]. In contrast, the macrophages reside in lean adipose tissue are anti-inflammatory before high-fat feeding [36]. These two groups of macrophage are phenotypically and functionally different. M2 macrophages express CD11b, F4/80, CD301, and CD206 and promote local insulin sensitivity through production of anti-inflammatory cytokines, such as IL-10 [4]. In contrast, M1 macrophages express CD11c in addition to CD11b and F4/80 and secrete inflammatory factors including TNF-α, IL-1β, IL-6, and nitric oxide (NO) [36]. It is important to point that this classification is an oversimplification and ATMs are a heterogeneous population and display plasticity and can alter or “switch” phenotypes in response to changes in the local microenvironment. There are reports indicating a mixed M1/M2 phenotype for macrophages in adipose tissue. In the line with this concept, flow cytometry analyses showed the presence of both CD11c (M1) and CD301 (M2) markers on macrophages of adipose tissue [54] and this suggests that individual ATMs can bear both M1 and M2 characteristics simultaneously. In this regard, obesity induces the polarization of ATMs from M2 phenotypes into M1 phenotypes, characterized by a reduction in anti-inflammatory IL-10 and arginase production and an increase in pro-inflammatory TNF-α production [36]. Increase in M1 ATM is due to either a ‘phenotypic switch’ from M2 to M1 or additional recruitment of M1 macrophages from blood vessels. It has been suggested that in obese state, inflammatory mediators released from adipose tissue, such as saturated FFAs, cytokines, and IFN-γ, induce recruitment of monocytes and/or their differentiation into M1-like macrophages [55]. Further studies showed that macrophages are also capable of undergoing a phenotypic switch from an M1 state to the M2 state. For instance, switching mice from a high-fat diet to a chow diet [56] or treating obese mice with thiazolidinediones [57] changed ATM polarization from M1 to M2 and subsequently improved insulin sensitivity. It has been reported that inducing the expression of peroxisome proliferator activated receptor γ (PPARγ) [58] and peroxisome proliferator activated receptor delta in response to IL-4 play a role in maintenance of M2 state [59]. Taken together, it is now clear that adipose tissue macrophages have heterogeneous inflammatory properties that are influenced by the diet and obesity. However, further in vitro and in vivo studies are needed to explore the molecular mechanisms underlying the heterogeneity and polarity of the macrophages in adipose tissue.

Section snippets

Macrophages in liver

The liver has a vital role in regulation of glucose and lipids metabolism in the body. Metabolic changes in hepatocytes including increased glucose production and enhanced lipogenesis are found in the states of obesity and insulin resistance [2], [60]. Studies in animal models suggest that these metabolic changes observed in obesity-associated morbidities such as non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome, are closely linked to hepatic inflammation. It has been proposed

Macrophages in skeletal muscle tissue

Skeletal muscle is another major site of insulin resistance in obesity and T2D. Skeletal muscle is the primary site of glucose disposal and accounts for almost 80% of insulin-stimulated glucose uptake in the body and, therefore, muscle insulin resistance has a profound effect on glucose intolerance and hyperglycemia in obesity and T2D [82], [83]. Although the exact underlying molecular mechanism of muscle insulin resistance remains to be elucidated, however, various hypotheses have been

Macrophages in pancreatic β cells

It is well-recognized that defects in β-cell function and mass are critical contributors to the pathogenesis of T2D. An inflammatory state was also demonstrated in pancreatic islets of type 2 diabetic patients as shown by the presence of amyloid deposit, fibrosis, increased β-cell death and infiltration of macrophages along with increased levels of pro-inflammatory cytokines and chemokines [100]. Of interest is the predominant role of IL-1β, which is upregulated in islets of patients with T2D

Nephropathy

Diabetic nephropathy (DN) is a chronic disease characterized by proteinuria, glomerular hypertrophy, decreased glomerular filtration and renal fibrosis [110]. DN is the leading cause of end stage renal diseases worldwide [110]. While hyperglycemia and advanced glycosylation products (AGEs) were believed to be the main cause of injury in DN, recent findings suggest that inflammation and inflammatory responses may also contribute to both the development and progression of the disease [111] .

Conclusions

Diabetes and its complications are becoming an emerging pandemic. There is now strong evidence that inflammatory processes are implicated in the pathogenesis and also the onset and the progression of the complications of diabetes. Among different immune cells, M1-polarized macrophages have an important role in tissue inflammation and the development of insulin resistance and β cell dysfunction in diabetic patients. Furthermore, tissue-resident macrophages have been suggested to be the major

Acknowledgements

This work was financially supported by grants (grant numbers 1393-04-97-1879, 94-01-30-28313) from the Endocrinology and Metabolism Research Institute and Deputy of Research of Tehran University of Medical Sciences, respectively. The author has no conflict of interest and has nothing to declare.

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      Citation Excerpt :

      Inflammation refers to a wide range of the body’s protective responses to foreign agents, and it is associated with many conditions such as infections, and exposure to chemicals and toxins (Arulselvan et al., 2016). Prolonged inflammation has negative long-term consequences, and it is now well established that its dysregulation plays a key role in the pathogenesis of chronic diseases such as type 2 diabetes mellitus (T2DM), rheumatoid arthritis, metabolic disorders, atherosclerosis, and other autoimmune diseases (Harris, 2007; Meshkani & Vakili, 2016). The presence and activation of innate and adaptive immune cells in tissues, as well as the increased local and systemic releases of inflammatory cytokines, are all signs of chronic low-grade inflammation (Khodabandehloo, Gorgani-Firuzjaee, Panahi, & Meshkani, 2016).

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