the huge capacity of ms for phagocytosis renders them effective at microbial killing and the clearance of apoptotic and necrotic cells , and through their expression of mhc - ii molecules and secretion of pro- and anti - inflammatory cytokines , they can also trigger cd4 + t - cell activation and differentiation into th1 , th2 , th17 , and treg subsets [ 13 ] . importantly , ms have diverse roles in the regulation of glucose and lipid metabolism , as well as in the inflammation of adipose tissue . in recent years , it has been clearly demonstrated that macrophages display high plasticity depending on the microenvironment in which they are found . two major macrophage phenotypes have been described , specifically , classically activated macrophages ( cams ) and alternatively activated macrophages ( aams ) . cams are induced by stimulation with th1-cell - derived ifn- and microbial products , such as bacterial lipopolysaccharide ( lps ) , and respond to microbial infection with an enhanced phagocytic microbicidal capability through the expression of the cams marker , inducible nitric oxide synthase ( inos ) , which catalyzes the conversion of l - arginine into ros , such as no . these macrophages produce several proinflammatory cytokines , such as tumor necrosis factor - alpha ( tnf- ) , interleukin-12 ( il-12 ) , il-1 , and il-23 , as well as toxic mediators , such as reactive oxygen species ( ros ) and nitric oxide ( no ) , through the expression of inducible nitric oxide synthase ( inos ) . in contrast , aams are induced during th2-type responses , such as those elicited by helminthic infection and during allergic responses . the activation of these macrophages is dependent upon stimulation with il-4/il-13   through the il-4r receptor   and signal transducer and activator of transcription factor 6 ( stat6 ) , as well as with several helminth antigens [ 1922 ] . aams produce moderate levels of il-10 and tgf- and low or null levels of the proinflammatory cytokines secreted by cams . additionally , aams produce urea , polyamines , and l - ornithine , due to the high expression of the enzyme arginase-1 ( arg-1 ) , which competes for its common substrate , l - arginine , with inos , thereby lowering the levels of no secretion [ 6 , 23 ] . aams have enhanced expression of ym-1 , which induces eosinophil recruitment ; these cells , in turn , can potentiate the th2 response and the alternative activation of macrophages by the secretion of the anti - inflammatory cytokines il-4/il-13 . further , aams can express high levels of pd-1 ligands ( program - death 1 ) , pdl-1 and pdl-2 , thereby inhibiting the proliferative response of activated t - cells . aam populations have been identified as an essential part of the immune response against almost any helminth parasite , such as taenia crassiceps [ 25 , 26 ] , brugia malayi [ 27 , 28 ] , schistosoma mansoni [ 29 , 30 ] , litomosoides sigmodontis , nippostrongylus brasiliensis , heligmosomoides polygyrus , fasciola hepatica , hymenolepis diminuta , and echinococcus granulosus .   of importance for this paper , helminth - induced aams have been linked with decreased t1d - triggering inflammation , as well as glucose tolerance induction during obesity , by which these macrophages may participate in inhibiting the initiation and development of both td1   and td2 . this paper focuses on the different roles that cams and aams display in both types of diabetes , emphasizing the role of aams as essential players in diabetes regulation . diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia as a result of the impairment of insulin secretion , its action , or both . the chronic hyperglycemia of diabetes is associated with dysfunction and failure of various organs , such as the eyes , kidneys , heart , and blood vessels . it has been estimated that the number of deaths caused by diabetes worldwide is 4.6 million per year . thus , diabetes remains a major cause of death and is considered to be an epidemic . diabetes mellitus is divided into two categories : type 1 diabetes ( t1d ) and type 2 diabetes ( t2d ) , and at least 90% of all cases belong to the latter . t1d is an autoimmune disease that has increased in prevalence over the last 30 years in developed countries . it is known that more than 5.3 million people in the world have t1d , and more than 218,000 may develop the disease each year . t1d is caused by the selective destruction of the insulin - producing  cells located in pancreatic langerhans ' islets by autoantigen - specific inflammatory t cells . insulin , glutamic acid decarboxylase ( gada / gaa ) , and protein tyrosine phosphatase ( ia-2aa ) are the most common autoantigens involved in this process . when the majority of  cells are destroyed , the pancreas 's ability to secrete insulin in response to blood glucose levels is impaired , resulting in the disruption of glucose homeostasis . cams and cd4 + and cd8 + autoreactive lymphocytes are the first cells that infiltrate the langerhans islets , and the levels of cytokines , such as tnf- , il-1 , and il-6 , as well as no , are increased in the pancreas during inflammation ( figure 1 ) , where they activate different signaling pathways . il-1 and tnf- induce the nf-b ( nuclear factor b ) signaling pathway , which promotes apoptosis of  cells by increasing the expression of fas . tnf- and ifn- act synergistically to activate the transcription factor signal transducer and activator of transcription-1 ( stat-1 ) signaling , thus inducing inos overexpression and secretion of no and thereby promoting apoptosis of  cells by the p53 pathway [ 38 , 39 ] . free radicals , in turn , can induce apoptosis and necrosis of  cells by activating the caspase pathway and inducing excessive cell stress , respectively . during this process , chemokines , such as mcp-1 ( or ccl2 ) , are also secreted ; this chemokine is important in the recruitment of cams , inflammatory monocytes , dendritic cells , and t cells into the pancreatic islets [ 40 , 41 ] . another cytokine that has been involved in t1d is the macrophage migration inhibitory factor ( mif ) . mif is associated with mcp-1 , which facilitates monocyte transmigration . in a mouse model with mld - stz , the levels of mif were elevated in diabetic mice , and the use of mif inhibitors reduced the inflammatory response and insulitis .   a study performed in diabetic patients showed increased numbers of monocytes , as well as higher levels of il-1 , il-6 , and tnf- , in the pancreas of sick patients compared with healthy people . the enhanced expression of cd80 and pdl1 in the infiltrating monocytes suggests a proinflammatory profile for these cells . several studies have attempted to verify the role of cams as important cells in the initiation and development of t1d . in experimental models , martin et al .   demonstrated that the increased expression of ccl2 ( using ripccl2 transgenic mice ) promotes the recruitment of inflammatory monocytes to the pancreatic islets , thereby initiating inflammation and destruction of  cells . these data suggest that monocytes are needed for the development of diabetes . also , the experimental depletion of cams in nod mice by the intraperitoneal injection of clodronate liposomes resulted in a decrease in insulitis and inflammation [ 45 , 46 ] . recently , a new subpopulation of cd4 + t lymphocytes , known as th17 cells , have been described , which are characterized by their ability to secrete high levels of il-17 , thereby promoting an inflammatory profile . the differentiation of th17 cells is dependent upon il-6 and transforming - growth factor- ( tgf- ) stimulation , and the presence of this subpopulation of cd4 + cells has been correlated with the onset and progression of autoimmune diseases , such as t1d . il-23 is an inflammatory cytokine involved in the expansion and commitment of th17 cell populations , and one of its main sources is cams . in diabetic mice induced by streptozotocin ( stz ) , it has been shown that the administration of il-23 increases il-17 , tnf- , and ifn- secretion , which is associated with the onset of extremely severe t1d , implicating cams in the recruitment , differentiation , and expansion of pathogenic th17 lymphocytes , contributing to  cell death and t1d induction . therefore , cams and th17 cells , together with cd8 + cytotoxic t cells , are considered to be the main cell populations favoring the development of t1d . however , certain pathogens ( mainly viruses ) can induce the development of t1d , including rubella , enterovirus , rotavirus , cytomegalovirus , and mumps , by diverse mechanisms . several viruses may break self - tolerance by the expression of viral antigens ; additionally , certain viral proteins show homology with autoantigens of  cells ( known as molecular mimicry ) . furthermore , several viruses can express superantigens , which results in an increase in the autoreactive t - cell populations , or induce the cytolysis of  cells , including coxsackievirus   and encephalomyocarditis ( emc ) virus . in the case of humans , rubella virus infection correlates with an increased incidence of t1d , and one possible mechanism of induction is molecular mimicry . other examples are rotavirus and reovirus , which have been shown to induce lysis of  cells and release of autoantigens , suggesting the first mechanism of induction of t1d [ 49 , 51 ] . epidemiological observations have pointed out an increase in the incidence and prevalence of t1d and other autoimmune diseases , mainly in developed countries , which have been correlated with a decrease in the incidence of bacterial and parasitic infections , particularly helminth infections . these observations prompted the proposal of the hygiene hypothesis , which states that the lack of intense infections that actively modulate the balance of the immune response toward th2 or anti - inflammatory profiles ( such as those that can be found in helminth infections ) favors the induction of strong th1 immune responses against autoantigens , thereby favoring the development of autoimmune responses [ 40 , 52 ] . helminths share a unique ability to exert profound regulatory effects on the immune system of their hosts by inducing strong th2-type responses and increasing the numbers of regulatory cell populations , such as tregs and aams . the results of several experiments in murine models of autoimmunity and its regulation by helminth infections support the protective role of helminth - induced th2 responses proposed by the hygiene hypothesis [ 3 , 53 , 54 ] . for example , it has been shown that the infection of nonobese diabetic ( nod ) mice with heligmosomoides polygyrus has a protective effect in t1d , resulting in the regulation of hyperglycemia and reduced incidence of diabetes ; these effects were accompanied by reduced numbers of macrophages , dendritic cells , and cd4 + and cd8 + t cells in the inflammatory infiltrate in the pancreas , as well as a reduction on  cell damage . importantly , higher numbers of aams were found in the pancreatic and peripheral lymph nodes of nod mice compared to noninfected mice . interestingly , in other studies , the experimental infection of mice with schistosoma mansoni or their treatment with either helminth or soluble worm extracts ( swa ) or soluble egg antigen ( sea ) could prevent diabetes in nod mice , with a direct relationship being observed between the lower incidence of t1d and reduced insulitis and higher numbers of aams [ 810 ] . other regulatory cell populations , such as treg cells , which can inhibit inflammation and suppress several autoimmune diseases , including t1d , also increased in number during schistosoma mansoni infection and antigen administration . other parasites , such as litomosoides sigmodontis , have also been shown to reduce t1d . we have shown that previous taenia crassiceps infection of diabetic mice , which were induced by multiple low doses of streptozotocin ( mld - stz ) , significantly decreased the incidence of t1d , hyperglycemia , and the inflammatory infiltration of islets of langerhans . these effects were accompanied by a significant increase in the secretion of il-4 and the expansion of the aams population compared with noninfected , diabetic mice , suggesting that aams induced by t. crassiceps infection can be important in the protection against t1d . in a recent study , the adoptive transfer of aams , which were induced in vitro by il-4 and il-13 , into diabetic mice reduced kidney injury , hyperglycemia , and insulitis in the pancreas , clearly suggesting that aams may have a protective role against t1d . in another recent study , the adoptive transfer of aams , which expressed pdl-2 , fcriib , il-10 , and tgf- prevented 80% of nod mice from developing this disease . collectively , these data suggest that aams may have important roles in the inhibition and prevention of t1d ( table 1 and figure 1 ) . t2d is a metabolic disease , and its incidence has increased significantly in recent years . it is estimated that in 2000 , there were approximately 171 million people with this disease , and it has been predicted that by 2030 , the prevalence of t2d will increase to 366 million people . t2d is characterized by a peripheral resistance to the action of insulin and a rise in insulin production by  cells in a process called  compensatory hyperinsulinemia  to force glucose uptake in peripheral tissues . regardless , during t2d , there is a chronic deficiency of glucose uptake and insulin action , mainly in the liver , skeletal muscle , and adipose tissue ( at ) , causing hyperglycemia , hypercholesterolemia , and hyperlipidemia [ 58 , 59 ] .   at is composed of adipocytes , preadipocytes ( which are immature adipocytes that have not yet loaded any lipids ) , endothelial cells , leukocytes , fibroblasts , and macrophages . during obesity , lipid accumulation causes a high degree of stress on adipocytes , activating them and promoting the production and subsequent release of free fatty acids ( ffa ) , proinflammatory adipocytokines ( such as leptin and resistin ) , and cytokines , such as il-1 , il-6 , tnf- , mcp-1 , and mif , as well as ros [ 6163 ] , ensuring that in addition to its well - known capacity to store energy , at has the capability to function as an endocrine organ . in fact , this endocrine ability of at triggers inflammation , leading to insulin resistance and the development of t2d . several data show that macrophages are recruited into at and classically activated due to adipocytokine secretion , contributing to the establishment of an inflammatory profile and insulin resistance in this tissue . a deficiency of mcp-1 ( ccl2 ) or ccr2 ( ccl2 receptor ) in mice during obesity results in the impairment of cam recruitment to adipose tissue , thus impeding the induction of insulin resistance by a high - fat diet ( hfd ) [ 64 , 65 ] and suggesting an important role for cams in t2d initiation and development ( see figure 2 ) . additionally , the stressed at secreted the adipocytokines leptin and resistin , which have been implicated in the recruitment and activation of monocytes and cams in adipose tissue , inducing these cells to produce higher levels of tnf- , il-12 , and il-6 . besides the production of resistin by stressed at , stressed at also induces the expression of mcp-1 and cellular adhesion molecules , such as v - cam and icam , in adipose tissue and its vascularization . furthermore , ffa can be recognized by toll - like receptors ( tlrs ) with low affinity , leading to the activation of macrophages , which release more tnf- [ 67 , 68 ] . tnf- ( one of the cytokines most abundantly secreted by cams ) has the ability to reduce the expression of important genes in the glucose regulation process , such as the glucose transporter glut-4 ; in fact , tnf- receptor knock out mice are resistant to diabetes induction , suggesting that the endocrine function of at is important in the recruitment and activation of cams and the induction of insulin resistance . consistent with these observations , a recent report on a model of t2d ( induced with a single high dose of streptozotocin ) in mif ko mice showed that these mice had a reduced inflammatory response , such as reduced tnf- production , and failed to develop t2d , demonstrating that mif is also important in promoting the disease . secretion of il-1 , tnf- , and ros by at cams induces the activation of jnk and nf-b signaling in various leukocytes . nf-b is a transcription factor with an important role in the induction of inflammatory responses and the activation of cams , whereas jnk ( c - jun amino - terminal kinase ) , also known as the protein kinase activated by stress ( sapk ) , is activated by oxidative stress . therefore , the activation of these signaling pathways induces the production of more il-1 , tnf- , and mcp-1 and high levels of inos expression , contributing to insulin resistance in different tissues [ 7173 ] . when insulin binds to its receptor , irs-1 and irs-2 ( insulin - receptor substrates 1 and 2 ) are recruited to its cytoplasmic region , which permits the binding and activation of two important kinases , the first of which is pi3k ( phosphatidylinositol 3-kinase ) , and the second of which is akt ( a protein kinase b ) . however , activated jnk can induce the phosphorylation of serine residues on irs-1/2 , inhibiting their ability to couple to pi3k and thereby promoting insulin resistance . in fact , the expression of jnk and nf-b is increased in diabetic patients , suggesting an important role for these molecules in diabetes . in myeloid - specific i- ( an activator of nf-b)-deficient mice , a decrease in proinflammatory cytokine production ( il-1 , il-6 , tnf- , and mcp-1 ) and the inhibition of nf-b activation has been reported , avoiding , in this way , the development of insulin resistance . cams have been confirmed to be directly involved in diabetes because it has been found that 30% of the transcripts expressed in the adipose tissue of hfd - treated mice encode characteristic macrophage proteins associated with this subpopulation . also , the expression of transcripts for mip-1 , mcp-1 , mac-1 , f4/80 , and cd68 was associated with insulin subproduction and tnf- release . in addition , macrophage polarization to cams had a direct relationship with the development of lipid droplets . these characteristics relate the activation of cams to the promotion of at accumulation and insulin resistance . interestingly , a macrophage phenotypic switch has been reported in the at of hfd - treated mice compared with normal diet - treated mice . lumeng et al . , 2007 , reported the presence of a natural aam population within the at of lean mice , and interestingly , the phenotype of these cells shift to cams when the mice were hfd - treated . the authors also showed that the il-10 produced by aams had the ability to block the pathological effects of tnf- in adipose tissue during insulin sensitivity [ 4 , 78 , 79 ] , suggesting that while cams have insulin resistance - inducing effects , aams have a protector role within at . recently , another inflammatory chemokine has been shown to be involved in the resistance to insulin and t2d . a - zip transgenic mice ( these animals are insulin - resistant and hyperlipidemic ) , which have a deficiency in mcp-1 , displayed decreased hyperglycemia , hyperinsulinemia , and hepatomegaly ; moreover , these mice had increased levels of markers for aams , such as arg1 and chi313 .   also of note , ppars are ligand - dependent transcription factors that have important functions in fa transport , synthesis , storage , mobilization , activation , and oxidation . three distinct types of ppars have been characterized : ppar , ppar , and ppar. ppar and ppar are involved in the oxidation of ffa , while ppar contributes to adipogenesis and the storage of fa . recent reports have shown that ppar is required for aams induction and maturation , and the absence of this molecule enhances obesity and insulin resistance in hfd mice . moreover , ppar-deficient kupffer cells can not be alternatively activated , predisposing mice to develop hepatic steatosis and insulin resistance . as mentioned above , aam development is dependent on il-4/il-13 stimulation , which activates the transcription factor stat-6 . stat-6-deficient mice are more prone to obesity , and oxidative stress in their at makes them more susceptible to t2d development , which , in turn , is associated with the absence of aams . the role of other cells in the regulation of insulin sensitivity is recognized principally because of evidence in experimental models . eosinophil - deficient mice have a smaller at - aam population and gain more weight , which indicates that eosinophils are an important source of il-4 in adipose tissue . likewise , nippostrongylus brasiliensis infection induced the recruitment of eosinophils and aams , which promoted a strong th2 response and decreased obesity and insulin resistance , suggesting that eosinophils contribute to aam induction and prevent t2d .   collectively , these findings suggest that adipose tissue is an important source of inflammatory molecules during obesity and can induce insulin resistance due to the increased recruitment of cams , which , in turn , can amplify the inflammatory response , promoting development of t2d , while high numbers of aams in the adipose tissue have been involved in glucose tolerance and diabetes prevention ( figure 2 ) . there is no doubt that the incidence of diabetes has increased in recent years , perhaps reflecting changes in lifestyle with regard to diet and/or hygiene . one explanation for the increased incidence of t1d is the hygiene hypothesis , which suggests that low or null exposure to parasites , especially helminths or their antigens , promotes the development of autoreactive leukocytes that attack  cells , initiating the disease . helminth infections in mice with t1d have proved to prevent the inflammatory cascade through a mechanism associated with aam induction . aams have been implicated in the regulation of other autoimmune diseases , such as experimental autoimmune encephalomyelitis   and autoimmune colitis , suggesting that aams have a strong immunoregulatory role in the induction of autoantigen tolerance . therefore , it is likely that these cells are the main players in the regulation of t1d . the importance of aams extends beyond the regulation of autoimmunity , which we reviewed in this paper . aams can also inhibit the development of t2d , mainly by reducing obesity and insulin resistance , two major etiological factors in the induction of this disease , while cams are associated with increasing inflammation , obesity , and insulin resistance . interestingly , the use of helminth parasites to induce aams has proved to be effective in disease treatment by reducing hyperglycemia , obesity , and the incidence of t2d . finally , while cams have a major role in the injury and inflammatory response in diabetes , aams appear to reduce inflammation during type 1 and type 2 diabetes , suggesting that these macrophage populations may be therapeutic targets . thus , based on the results of the various reports reviewed in this paper , we can highlight the possible therapeutic use of diverse immune - modulatory molecules to counteract or negatively influence specific inflammatory and cytotoxic t - cell - activating properties of macrophages .
macrophages are innate immune cells derived from monocytes , which , in turn , arise from myeloid precursor cells in the bone marrow . 
 macrophages have many important roles in the innate and adaptive immune response , as well as in tissue homeostasis . 
 two major populations have been defined : the classically activated macrophages that respond to intracellular pathogens by secreting proinflammatory cytokines and reactive oxygen species and alternatively activated macrophages which are induced during th2 responses displaying anti - inflammatory activities . 
 both macrophage populations are central players in diabetes , the first one triggering inflammatory responses which initiates insulitis and pancreatic  cell death during type 1 diabetes , whereas the second population decreases hyperglycemia , insulitis , and inflammation in the pancreas , thereby negatively regulate type 1 diabetes . 
 obesity is an important factor in the development of type 2 diabetes ; classically activated macrophages are a dominant cell population involved in the establishment of the inflammatory profile , insulin resistance , and activation of inflammatory signals during the development and progression of this disease . in contrast , 
 alternatively activated macrophages regulate the release of proinflammatory cytokines , attenuating adipose tissue inflammation . here 
 , we review the advantages and disadvantages of these two macrophage populations with regard to their roles in types 1 and 2 diabetes .