historically , the   sweetness of urine 
 and other body fluids in diabetic patients suggested that glucose had an 
 important role in the physiopathology of this common disease .
thus , glucose 
 metabolism and the insulin - glucose axis were the leading fields for scientific 
 investigations . to emphasize this concept ,
not 
 only hyperglycaemia is crucial for the diagnosis of diabetes and the development 
 of clinical complications , but also increasing evidence demonstrated the 
 involvement of insulin in the physiopathology of this disease .
in fact , 
 diabetes is a metabolic disease characterized by hyperglycaemia resulting from either 
 defects in insulin secretion or insulin properties , or both . in the present 
 review ,
we focus on defects of insulin properties , with particular regard to 
 insulin resistance , which can be defined as a state of reduced responsiveness 
 to normal circulating levels of insulin .
this condition is a feature of various 
 disorders , such as type 2 diabetes , which may range from predominantly insulin 
 resistance with relative insulin deficiency to a predominatly secretory defect 
 of insulin .
insulin resistance is also implicated in impaired glucose 
 tolerance ( igt ) or impaired fasting glucose ( ifg ) , both considered as 
  prediabetes  by the expert committee on the diagnosis and classification of 
 diabetes mellitus [ 24 ] , as well as in obesity , hypertension , dyslipidaemia 
 ( all disorders clustering in the so - called metabolic syndrome ) , other endocrinopathies 
 , but also in different diseases , such as cancer , infections or rheumatic , and 
 autoimmune diseases [ 711 ] .
therefore , given the association between insulin 
 resistance and different diseases , no epidemiological data are available , 
 specifically focused on insulin resistance syndrome prevalence or incidence . furthermore , 
 only recently ( in 1997 )
the who have accepted obesity as an epidemic public 
 health burden in adults , without evaluating a well - defined method to monitoring 
 the problem in children [ 1215 ] .
finally , still few clinical studies on asian 
 and african cohorts focused on insulin resistance and related diseases have 
 been published [ 1619 ] .
for all these reasons , to better define insulin 
 resistance epidemiology syndrome requires more investigations
insulin resistance was initially 
 recognized as an  allergy  to insulin , with the production of antibodies 
 anti - insulin [ 20 , 21 ] .
further investigations showed that metabolism of both nonesterified 
  fatty acids ( nefa ) and free fatty acids ( ffas ) was a crucial step in the 
 development of insulin resistance [ 22 , 23 ] .
on the basis of these new evidences , 
 shafrir and raz suggested in 2003 that diabetes should be now called  lipidus  
 instead of  mellitus  . given the importance of physiological effects of insulin 
 during atherogenesis [ 2527 ] ,
there is a need to better clarify the complexity 
 of mechanisms underlying insulin resistance .
insulin is an anabolic essential hormone 
 for the maintenance of glucose omeostasis , tissue growth , and development .
it is well known that insulin is secreted by the pancreatic  cells mainly in response to 
 increased blood levels of glucose and aminoacids after the meals ( extrinsic 
 rhythm ) .
in addition , the concentration of insulin in the blood displays 
 regular variations independently from the food intake .
in fact , two 
 rhythms with periods of 510 minutes and 60120 minutes have 
 been documented ( intrinsic rhythm ) [ 3133 ] .
the extrinsic rhythm was found 
 altered in a lot of diseases including gestational diabetes , maturity onset 
 diabetes of the young ( mody ) 1 [ 35 , 36 ] , mody 3 , and 
 chagas disease .
furthermore , an altered plasma insulin secretory response 
 has been also observed as an effect of aging processes . on the contrary
, 
 the intrinsic rhythm has been found altered in various diseases , such as type 2 
 diabetes ( i.e. , mody 2 as well as maternally inherited 
 diabetes and deafness ( midd ) ) 
 [ 40 , 41 ] , obesity , and hypertension . several genetic and molecular 
 studies have been performed to investigate the causes of the dysregulated 
 plasma insulin pattern .
although genetic mutations account for a minor role in 
 the large part of insulin resistance , an alteration of insulin signal 
 transduction , which may be due to genetic mutations , could contribute to the 
 impairment of insulin secretory profile and insulin resistance .
thus , mutations 
 of glucokinase phosphorylated glucose , hepatic nuclear factor-4 alpha , hepatic 
 nuclear factor-1 alpha , mitochondrial trnaleu(uur ) , and also insulin receptor 
 genes have been found [ 35 , 37 , 4446 ] .
for instance , a mutation in the insulin 
 receptor gene of the pancreatic  cells has been correlated with a 
 defective insulin - mediated intracellular signal transduction . on the other 
 hand , obesity and
increased ffa levels mediate insulin resistance by inducing a 
 decreased irs-1-associated phosphatidylinositol 3-kinase ( pi3-k ) activity . 
 in line with these findings
, it has been shown that insulin resistance was 
 reversed when obese persons lose weight . however
, this weight loss did not 
 restore normal insulin pulsatiliy in type 2 diabetes patients .
these data 
 suggest that the defective insulin - mediated intracellular signal transduction is 
 not the only cause responsible for insulin resistance , and that the molecular 
 mechanisms of insulin resistance are not completely understood
. we will discuss 
 in the following the potential mechanisms contributing to insulin resistance 
 which are currently under investigation .
it is a member of the receptor 
 tyrosine kinase family , composed of two -subunits and two -subunits linked together by disulphide bonds .
two isoforms of insulin 
 receptors are known , exhibiting different affinity for insulin and distribution 
 within tissues .
although it is tempting to suggest that differences in binding 
 activity could contribute to insulin resistance , experimental evidence for the involvement 
 of receptor isoforms or receptor hybrids remains controversial .
apart from 
 the insulin binding step to its receptor , the receptor intracellular tyrosine 
 kinase domains ( capable of intrinsic kinase activity ) have been investigated in 
 view of their possible implication in insulin resistance .
a variety of 
 scaffolding proteins , including insulin receptor substrate ( irs ) proteins , casitas 
 b lineage lymphoma ( cbl ) , or cbl associated protein ( cap ) , bind to 
 intracellular receptor sites and become phosphorylated [ 5153 ] .
irs-1 and -2 
 are considered the most important proteins in regulation of glucose metabolism 
 .
as shown in knockout mouse models , irs-1 or irs-2 inactivation causes 
 insulin resistance [ 55 , 56 ] .
in addition , in vitro experiments showed an 
 increased serine phosphorylation of irs by tumor necrosis factor - alpha ( tnf- ) or ffa stimulation , thereby causing impaired insulin signal 
 transduction [ 54 , 57 ] .
finally , a prolonged exposure to insulin ( a typical condition 
 in hyperinsulinemic patients ) may result in a degradation of irs protein . 
 all together ,
these data support irs-1 and irs-2 as crucial players in the 
 development of insulin resistance .
furthermore , numerous studies aimed to 
 identify downstream elements of irs proteins in the insulin - mediated signal 
 transduction pathway .
three different isoforms of this kinase have been identified : ia , 
 pi3-k / akt , capable of generating phosphatidylinositol 4,5-bisphosphate ( pip2 ) 
 and phosphatidylinositol 3,4,5-trisphosphate ( pip3 ) ; ib , g protein regulated 
 kinase ; ii , incapable of generating pip2 and pip3 .
as shown in figure 1(a ) , 
 activated pi3-k is responsible for the beginning of a complex phosphorylation 
 cascade , involving the phospholipids pip2 , pip3 , the phosphoinositide - dependent 
 kinase 1 ( pdk1 ) , the protein kinase b ( pkb , also called akt ) , as well as the 
 protein kinase c ( pkc ) .
akt mediates the effects of insulin on glucose 
 transport ( glut ) , glycogen synthesis , protein synthesis , lipogenesis , and 
 suppression of hepatic gluconeogenesis .
once activated , akt detaches from 
 the plasma membrane and translocates into the nucleus through a still unknown mechanism 
 , or activates different substrates , such as glycogen synthase kinase-3 
 ( gsk-3 ) and transcription factors of the foxo - family .
all these proteins 
 and phospholipids are likely to be implicated in insulin resistance . for 
 instance
, a reduced pi3-k activity has been reported in skeletal muscle and 
 adipocytes of patients with insulin resistance [ 6264 ] .
in addition , akt 
 activation has been found reduced in several diseases associated with insulin 
 resistance [ 65 , 66 ] . however , akt involvement in insulin resistance is 
 controversial , since other studies did not show any alteration of akt 
 activation in insulin resistance associated syndromes [ 67 , 68 ] . on the other 
 hand ,
insulin - induced pkc activation has been found altered in type 2 diabetic 
  or obese   patients .
therefore , although other studies are needed , all 
 these observations suggest that a reduction of insulin - mediated intracellular 
 signaling is crucial for the establishment of insulin resistance .
another possible mechanism leading 
 to insulin resistance might be an upregulation of protein - tyrosine phosphatases 
 ( ptpases ) , capable of functioning as negative regulators of the insulin - triggered 
 pathway . among various proteins ,
ptp 1b has been shown as a key regulator of 
 insulin signaling [ 7173 ] .
other phosphatases , such as ectonucleotide 
 pyrophosphatase phosphodiesterase 1 ( enpp1 , also known as pc-1 ) , sh-2-containing 
 inositol 5-phosphatase 2 ( ship2 ) , and phosphatase and tensin homolog deleted 
 on chromosome 10 ( pten ) have been shown to interfere with insulin sensitivity 
 [ 7476 ] .
although further investigations are warranted to very verify these 
 hypotheses , these proteins may represent future potential targets for the 
 treatment of insulin resistance .
glucose uptake into muscle and fat 
 tissue depends on glucose transporter 4 ( glut4 ) expression on the cell 
 membrane .
insulin reduces glycaemia , mainly by inducing the secretion of this 
 molecule by muscle and fat cells .
however , glut4 polymorphisms or mutations 
 inactivating glut4 gene were not associated with insulin resistance . in 
 addition , glut4 concentrations in skeletal muscle of insulin resistant patients 
 were not reduced .
this suggests that alterations in glut4 expression are 
 not a primary cause for the development of insulin resistance . in this context
in fact , glut4 upregulation represents the final event of insulin 
 signaling cascade [ 8082 ] . among various kinases ( figure 1(a ) )
, akt has been shown to play an essential role . recently , in vitro and in 
 vivo studies suggested that pkb alterations   or disruption   are responsible for the reduction 
 of insulin - induced glucose uptake .
consistent with these data , recent studies 
 in humans detected a missense mutation in the kinase domain of pkb ( akt 2 ) associated with severe insulin resistance .
these data 
 suggest that insulin signaling also plays crucial role in the regulation 
 glucose homeostasis .
recent evidence suggests that 
 inflammation might be crucial for the development of insulin resistance .
proinflammatory 
 cytokines and acute - phase reactants are positively correlated with insulin 
 resistance in metabolic syndrome patients . among these soluble mediators ,
interleukin 
 ( il)-1 and il-1 receptor antagonist ( ra ) have been implicated in the 
 development of insulin resistance in humans [ 88 , 89 ] and in rodents [ 90 , 91 ] .
il-1ra 
 is anaturally occurring cytokine and a member of the il-1 family 
 whose only function is to prevent a biologic response to il-1 . in 
 humans ,
the blockade of il-1 with il-1 ra improves glycaemia and beta - cell 
 secretory function and reduces markers of systemic inflammation . 

accordingly , il-1 has been shown to induce insulin resistance mainly by 
 inhibiting insulin - mediated signaling [ 94 , 95 ] .
thus , il-1 has to be considered 
 as an important factor involved in insulin resistance . tnf- and il-6 are also of particular interest , because of their increased 
 expression in adipose tissue and their capacity to induce insulin resistance . 

further evidence for the link between tnf- and insulin resistance was provided by a study using blocking anti - tnf- antibodies in obese rodents or tnf- knockout obese mice . in these animals ,
a reduced insulin 
 resistance was obtained by the suppression of tnf-. the possible molecular mechanism of tnf--induced insulin resistance may involve irs-1 . surprisingly , the 
 infusion of anti - tnf- antibody in humans did not affect insulin resistance .
further 
 investigations are needed to better understand these opposite results obtained in 
 human and mice . on the other hand , the role of il-6 in insulin resistance
il-6 interferes with the metabolism of both adipose and 
 skeletal muscle tissues [ 99 , 100 ] , but has also a positive effect on skeletal 
 muscle cell insulin sensitivity .
in addition , il-15 has been shown to 
 play a possible role in myocyte - adipocyte crosstalk , but only few studies are 
 published at present to better clarify its role in insulin resistance . moreover
, 
 it is now established that hormones from adipose tissue hormones contribute to insulin 
 resistance .
for instance , leptin has been shown to reverse insulin resistance 
 in mice with congenital lipodystrophy .
administration of leptin to 
 patients with lipodystrophy can increase the body fat content and reverse 
 insulin resistance .
resistin , a new adipocyte hormone , may be another 
 important link between increased fat mass and insulin resistance .
resistin 
 decreases insulin - dependent glucose transport in vitro and increases fasting 
 blood glucose concentrations and hepatic glucose production in vivo [ 106109 ] . 

very recently , adiponectin has been showed as an anti - inflammatory and 
 immunomodulatory molecule [ 110 , 111 ] . in humans ,
mice deficient in adiponectin are insulin resistant 
  and the administration of adiponectine to obese and insulin resistant 
 mice has been shown to improve insulin sensitivity [ 113115 ] .
in addition , 
 inflammatory mediators such as the proinflammatory chemokine monocyte 
 chemotactic protein-1 ( mcp-1 ) are believed to play a role in the pathogenesis 
 of insulin resistance .
recent in vitro evidence suggests that mcp-1 induces 
 insulin resistance in both adipocytes and skeletal muscle cells .
finally , 
 retinol - binding protein ( rbp)-4 and tissue inhibitors of metalloproteinases ( timp)-1 
 were recently described to contribute to insulin resistance in vivo , but the 
 underlying mechanism remains unclear [ 117119 ] . in conclusion , at the present 
 state of knowledge , insulin resistance has to be defined as a complex syndrome 
 involving not only glucose and lipids , but also several proinflammatory 
 molecules .
lipid abnormalities , such as 
 increased circulating free fatty acids , are frequently associated with insulin 
 resistance .
the excessive fat intake causes an increased influx of 
 triglycerides into the blood and an excess of plasma levels of ffas , which 
 induce insulin resistance , with consequent hyperglycaemia .
the increased levels 
 of glucose stimulate pancreatic  cells to secrete more and more insulin , 
 generating hyperinsulinemia , which further triggers the elevation of triglycerides 
 and closes the vicious circle .
when insulin secretion is not sufficient 
 and elevated glucose levels prevail , 
 diabetes becomes overt .
defective 
 insulin secretion is a result of chronic exposure to elevated levels of fatty 
 acids , which inhibits insulin gene expression by functioning as true toxic 
 agents for pancreatic  cells .
 lipotoxicity  depends 
 on the interference with insulin - mediated intracellular signaling in various 
 cell types ( figure 1 ) . in particular ,
ffas have been shown to activate pkc  ( figure 1(a ) ) , which not only 
 interferes with insulin signaling ( by inducing insulin resistance ) , but also is 
 implicated in promoting proatherogenic mechanisms , such as endothelial 
 dysfunction , growth , migration , and apoptosis of   vascular smooth muscle cells , 
 induction of adhesion molecules and oxidized low - density lipoprotein uptake of oxidized low - density lipoprotein by monocyte - derived macrophages .
furthermore , it was recently 
 shown that ffas induce insulin resistance in muscle through the activation of inhibitor 
 b kinase ( ikk ) and c - jun n - terminal kinase ( jnk ) ( figure 1(a ) ) .
therefore , 
 ffas induce insulin resistance in hepatocytes and skeletal muscle cells through 
 the activation of different kinases ( figures 1(a ) and 1(b ) ) . both ffas from 
 plasma and those released from stored triglycerides
ffas are also involved in modulating 
 insulin production by pancreatic -cells and cytokine secretion by hepatocytes , adipocyte , muscle cells , 
 and inflammatory cells ( figure 1(c ) ) .
the development of atherosclerotic 
 plaques is dependent on the interaction of multistep biochemical processes that 
 lead to the plaque formation , maturation , and complication .
plaque 
 instability , rupture , and thrombosis are crucial events in the acute artery 
 occlusion , which causes dramatic ischemic consequences in the heart , brain , and 
 also peripheral tissues .
insulin resistance is considered to be a pivotal event 
 in the increased risk of plaque instability through different pathways [ 127 , 128 ] . 

high concentrations of insulin directly increase proinflammatory activities of 
 leukocytes , which are involved in atherosclerotic plaque instability .
in 
 particular , insulin directly increases neutrophil and monocyte in vitro migration in response to 
 chemokines secreted in atherosclerotic plaques [ 129 , 130 ] .
furthermore , insulin induces in vivo production of matrix metalloproteinase-9 ( mmp-9 ) , 
 which is responsible for plaque instability and rupture [ 132134 ] .
the 
 pharmacologic or behavioral treatments to reduce insulin resistance have been 
 shown to inhibit mmp-9 secretion [ 126 , 135 , 136 ] .
on the other hand , insulin 
 could also induce a serious atherothrombotic state , by increasing platelet 
 resistance to antiaggregating agents   and production of procoagulatory 
 factors , such as plasminogen activator inhibitor-1 ( pai-1 ) , factor vii , factor 
 xii , fibrinogen , and tissue plasminogen activator .
these evidences 
 strongly support an emerging role of insulin in plaque instability and rupture . 

further investigations are needed to better clarify the specific roles and the 
 interactions of insulin and lipids on inflammatory cells .
in the last years , the standard definition of insulin resistance has been shifted 
 from a traditional  glucocentric  to a new  lipocentric  view .
several 
 soluble mediators are involved in the development of insulin resistance , 
 through generating insulin signaling dysfunction . among these
, ffas have to be 
 considered as proatherosclerotic agents , capable of interfering with insulin signaling 
 and provoking insulin resistance .
new and selective therapies contrasting ffa 
 effects may be promising targets for the treatment of insulin resistance .
a 
 possible promising strategy capable of reducing the consequences of excessive 
 lipolysis and reorient ffa flux toward adipose tissue might be represented by 
 peroxisome proliferator - activated receptor ( ppar)- and - agonists .
ppar- agonists have been recently shown to regulate trygliceride lipase in 
 adipocytes in vitro and in vivo .
furthermore , ppar- has been shown as crucial in the control of differentiation of human 
 monocytes in m2 macrophages , the subset of macrophages resident in 
 atherosclerotic plaques with anti - inflammatory activity . in vivo studies
have also demonstrated that ppar- agonists treatment in patients with type 2 diabetes 
 mellitus is associated with a reduction in plasma nefa levels [ 142145 ] .
however , two recent important 
 clinical studies have shown an increase of acute cardiovascular outcomes 
 induced by treatment with thiazolidinediones ( ppar- agonists ) [ 146 , 147 ] . on the other hand , although ppar- has been shown to have vascular and metabolic beneficial effects , the 
 activity of ppar- agonists on lipid metabolism is still controversial   [ 148 , 149 ] . therefore , further trials are 
 needed to recommend the use of these pharmacological agents for reducing lipid - mediated 
 insulin resistance .
 the dysregulation of the insulin - glucose axis represents the crucial event in insulin resistance syndrome . 
 insulin resistance increases atherogenesis and atherosclerotic plaque instability by inducing proinflammatory activities on vascular and immune cells . 
 this condition characterizes several diseases , such as type 2 diabetes , impaired glucose tolerance ( igt ) , impaired fasting glucose ( ifg ) , obesity , hypertension , dyslipidemia , and other endocrinopathies , but also cancer . 
 recent studies suggest that the pathophysiology of insulin resistance is closely related to interferences with insulin - mediated intracellular signaling on skeletal muscle cells , hepatocytes , and adipocytes . 
 strong evidence supports the role of free fatty acids ( ffas ) in promoting insulin resistance . 
 the ffa - induced activation of protein kinase c ( pkc ) delta , inhibitor kappab kinase ( ikk ) , or c - jun n - terminal kinase ( jnk ) modulates insulin - triggered intracellular pathway ( classically known as pi3-k - dependent ) . 
 therefore , reduction of ffa levels represents a selective target for modulating insulin resistance . 
1. EPIDEMIOLOGY OF INSULIN RESISTANCE
2. MECHANISMS OF INSULIN RESISTANCE
3. ROLE OF INSULIN RESISTANCE IN ATHEROSCLEROTIC PLAQUE INSTABILITY
4. CONCLUSION REMARKS