Review Article Potential Biomarkers of Insulin Resistance ...downloads.hindawi.com/journals/ije/2013/698567.pdf · uptake in muscles and adipocytes. Ine cient glucose uptake by muscle

Hindawi Publishing CorporationInternational Journal of EndocrinologyVolume 2013 Article ID 698567 11 pageshttpdxdoiorg1011552013698567

Review ArticlePotential Biomarkers of Insulin Resistanceand Atherosclerosis in Type 2 Diabetes MellitusPatients with Coronary Artery Disease

Sharifah Intan Qhadijah Syed Ikmal1 Hasniza Zaman Huri12

Shireene Ratna Vethakkan3 and Wan Azman Wan Ahmad24

1 Department of Pharmacy Faculty of Medicine University of Malaya 50603 Kuala Lumpur Malaysia2 Clinical Investigation Centre 13th Floor Main Tower University Malaya Medical Centre 59100 Lembah PantaiKuala Lumpur Malaysia

3 Endocrinology Unit Department of Medicine Faculty of Medicine University of Malaya 50603 Kuala Lumpur Malaysia4Cardiology Unit Department of Medicine Faculty of Medicine University of Malaya 50603 Kuala Lumpur Malaysia

Correspondence should be addressed to Hasniza Zaman Huri hasnizazhumedumy

Received 27 July 2013 Accepted 10 September 2013

Academic Editor Ajit Vikram

Copyright copy 2013 Sharifah Intan Qhadijah Syed Ikmal et alThis is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

Type 2 diabetes mellitus patients with coronary artery disease have become a major public health concern The occurrence ofinsulin resistance accompaniedwith endothelial dysfunctionworsens the state of atherosclerosis in type 2 diabetesmellitus patientsThe combination of insulin resistance and endothelial dysfunction leads to coronary artery disease and ischemic heart diseasecomplications A recognized biological marker high-sensitivity C-reactive protein has been used widely to assess the progressionof atherosclerosis and inflammation Along with coronary arterial damage and inflammatory processes high-sensitivity C-reactiveprotein is considered as an essential atherosclerosis marker in patients with cardiovascular disease but not as an insulin resistancemarker in type 2 diabetes mellitus patients A new biological marker that can act as a reliable indicator of both the exact state ofinsulin resistance and atherosclerosis is required to facilitate optimal health management of diabetic patients Malfunctioning ofinsulin mechanism and endothelial dysfunction leads to innate immune activation and released several biological markers intocirculation This review examines potential biological markers YKL-40 alpha-hydroxybutyrate soluble CD36 leptin resistininterleukin-18 retinol binding protein-4 and chemerin as they may play significant roles in insulin resistance and atherosclerosisin type 2 diabetes mellitus patients with coronary artery disease

1 Review

In 2010 it was estimated that 285 million people had beendiagnosed with diabetes mellitus worldwide a prevalenceof 64 This is predicted to increase to 439 million aprevalence of 77 by 2030 [1] The number of deathsindirectly linked to diabetes mellitus is estimated to be 396million per year for all age groups a prevalence of 68[2] Type 2 diabetes mellitus (T2DM) (previously knownas non insulin-dependent diabetes mellitus) accounts forabout 90 of diabetic patients worldwide [1] T2DM isdescribed as a ldquosilent diseaserdquo and is characterized by the

combination of inadequate insulin secretion due to islet 120573-cell deterioration and insulin resistance [3] T2DM is anindependent risk factor for the development and mortalityof various complications implicate microvascular problemsincluding retinopathy neuropathy and nephropathy andmacrovascular problems including coronary artery disease(CAD) [4 5]

CAD is one of the most common causes of death amongdiabetic patients with a 2- to 3-fold higher prevalencecompared with nondiabetic people [2] CAD is definedconservatively as past myocardial infarction (MI) coronaryartery bypass graft (CABG) or percutaneous transluminal

2 International Journal of Endocrinology

coronary angioplasty through confirmation by review ofmedical records or a major Q wave on electrocardiogramexamination (ECG) in Insulin Resistance AtherosclerosisStudy (IRAS) [6] Concomitant risk factors including per-sistent hyperglycemia dyslipidemia hypertension smokinga family history of the disease and the presence of micro-andmacroalbuminuria directly increase themortality risk ofCAD among T2DM patients by approximately 2- to 4-foldcompared with nondiabetic people [4 5] CAD is definedas an accumulation of cholesterol substance build-up incoronary arteries Anatomically coronary arteries are bloodvessels supplying oxygen to cardiacmuscle Coronary arteriesbranch off from the aorta into four major arteries Theseare the right coronary artery the left main coronary arterythe left anterior descending artery and the left circumflexartery Blockage to any of these arteries due to plaqueinstability known as atherosclerosis leads to angina andischemic conditions resulting in CAD and also increasingthe potential development of ischemic heart disease and othermajor cardiovascular diseases (CVDs) [7]

Owing to recent advances in understanding circulatingmolecular actions between endothelial function and theimmune system several potential biomarkers have beenidentified that appear to be linked to T2DM and CAD interms of insulin resistance and atherosclerosis This reviewexamines these potential biomarkers as a new alternative todetermining the status of insulin resistance in T2DMpatientswith CAD

2 Mechanism of Insulin Resistance

According to the American Diabetes Association 2013 guide-lines insulin resistance and persistent hyperinsulinemia arefound in a variety of medical conditions including dys-lipidemia and hypertension [4 5] Insulin resistance hasbeen established as a precursor and acts as a strong factorlinking T2DMwith CVD Studies have reported an increasedpotential risk of diabetic patients acquiring CAD within thepast two decades [2 6] This is mainly because of insulinresistance development through genetics and environmentalfactors [8] Alterations of 120573-cell function and insulin proper-ties underlay the metabolic syndrome that includes dyslipi-demia hyperglycemia hypertension impaired fibrinolysisand atherosclerosis thus contributing to lower insulin sen-sitivity [6]

At a basic level insulin resistance occurs through theactivation of various types of macrophages Malfunctioningadipocytes and adipose tissue release greater amounts ofvarious proinflammatory cytokines Subclinical inflamma-tion due to insulin resistance might also correlate with thepathogenesis of all phases of atherosclerosis This involveslow-grade elevation of acute phase reactants proinflamma-tory cytokine secretion and cell adhesion molecules andleads to myocardial infarction stroke and other majorperipheral vascular diseasesThese factors therefore increasecardiovascular mortality Activation of the innate immunesystem greatly contributes to the occurrence of T2DM andCAD (Figure 1) [9]

Endothelial dysfunction triggered by persistent inflam-mation due to increased levels of triglycerides (TRYL)free fatty acids (FFA) and low-density lipoprotein (LDL)and decreased levels of high-density lipoprotein (HDL) thateventually leads to alteration of insulin signaling and glucoseuptake in muscles and adipocytes

Inefficient glucose uptake by muscle and adipose tissueleads to insulin resistance or a medical condition knownas compensatory hyperinsulinemia 120573 cells of the pancreaticislets release excessive amounts of insulin in an attempt tocompensate for high plasma glucose levels in the blood [910] Persistent hyperinsulinemia increases serum levels oftriglycerides free fatty acids (FFA) and low-density lipopro-tein and decreases serum levels of high-density lipoproteinIncreased levels of circulating FFA in the blood activate theinnate immune system to release pr-inflammatory cytokinesincluding tumor necrosis factor-120572 interleukin (IL)-6 and IL-1120573 [11] The presence of these cytokines leads to an alterationin insulin sensitivity and disruption of glucose homeostasis[11] The process involves cytokines first mediating insulinsignaling mechanisms in adipocytes muscles and the liverto increase the occurrence of insulin resistance [11] beforedisabling liver X receptors (LXRs) causing an increase in theaccumulation of cholesterol thus stimulating hepatic produc-tion and secretion of inflammatory markers including C-reactive protein plasminogen inhibitor-1 serum amyloid-A1205721-acid glycoprotein and haptoglobin [12] Cytokines thenstimulate fibrinogen which acts as an atherosclerotic riskfactor and leads to CAD [11] Finally cytokines increaseproduction of very low-density lipoprotein and FFA whichleads to the characteristics of diabetic dyslipidemia and thesubsequent increase in plaque accumulation [9 11 12]

3 Correlation between InsulinResistance Endothelial Dysfunctionand Atherosclerosis

The endothelium is located at the interior surface of bloodand lymphatic vessels The endothelium consists of a thinlayer of cells defined as being either vascular endothelial cells(cells in direct contact with blood) or lymphatic endothelialcells (cells in direct contact with lymph) The function ofthe endothelium is to sense mechanical stimuli such ashigh pressure and stretching and hormonal stimuli such asvasoactive substances The endothelium plays a role in theregulation of vasomotor functions stimulates inflammatoryprocesses and influences hemostasis [13]

Studies suggest that persistent hyperinsulinemia mighttrigger endothelial dysfunction In diabetes the occur-rence of insulin resistance is due to an alteration ininsulin signaling Once this alteration happens phospho-rylation of major pathways (eg phosphatidylinositol 3-kinase phosphoinositide-dependent kinase-1 and AKTpro-tein kinase B pathways) which activate endothelial nitric-oxide synthase (eNOS) is downregulated drastically Dueto this downregulation the role of eNOS changes froman antiatherogenic effect to a proatherogenic effect whichfurther contributes to the development of atherosclerosis

International Journal of Endocrinology 3

Persistent hyperglycemia

Persistent hyperinsulinemia

Activation of innate immunity

(endothelial dysfunction)

Alteration of insulin

sensitivity (insulin resistance)

CD36

RBP4

Leptin

ResistinChemerin

YKL-40

120572-HB

IL-18

Release of pro-inflammatory

cytokines

Alteration of glucose

homeostasis

uarr TRYL levels uarr FFA levels uarr LDL levels darr HDL levels

Figure 1 Mechanism of insulin resistance endothelial dysfunction and proinflammatory secretion

One of the insulin receptor pathways mitogen-activated pro-tein kinase which stimulates mitogenic effects and growthremains unaffected [13 14]

A commonmechanismof endotheliumdysfunction is thedepletion of eNOS According to Willa and Manuel 2003prolonged decreases of eNOS lead to decreased bioavailabilityof nitric oxide (NO) which acts as vascular protection byinhibiting inflammation oxidation vascular smooth musclecell proliferation and migration [14] Decreased bioavailabil-ity of NO along with low levels of high-density lipoproteinhigh levels of small dense low-density lipoprotein highsecretion of angiotensin II sensitivity and high releasesof FFA in the blood worsen is the status of endothelialdysfunction and promotes further atherogenic processes[14] In addition the effects of inflammation and reactiveoxygen species contribute to decreasing NO bioavailabilityand stimulate secretion of proinflammatory cytokines which

are termed as possible biomarkers Identification of thesebiomarkers might serve as tools for predicting insulin resis-tance and endothelial dysfunction in T2DM patients withCAD (Figure 2) [14]

The persistent events of hyperinsulinemia lead to insulinresistance and results to T2DM Frequent hyperinsulinemiadue to increased level of triglycerides FFAs and LDL anddecreased HDL contributes to endothelial dysfunction andinterrupts nitric oxide (NO) secretion increases reactiveoxygen species (ROS) and free radicals formation and inter-ruptions of adhesion molecule expression of chemokine andcytokine release All themechanisms contribute to inflamma-tion atherosclerosis and CAD Several cytokines had beendiscovered and used as biomarkers strongly supporting theidea that the occurrence of hyperinsulinemia correlates withendothelial dysfunction leading to major diseases T2DMand CAD


Endothelial dysfunction

Insulin resistance

T2DM

Nitric oxide

(NO)

reduction

Increased ROS

production from

endothelium

Increased adhesion

molecule

expression of

chemokine and

other cytokine

release

Atherosclerosis

CAD

Inflammation

Possible cytokines

as biological

marker between

T2DM and CAD

Hyperinsulinemia

Figure 2 Insulin resistance in T2DM and endothelial dysfunction in CAD development

4 Potential Biomarkers for InsulinResistance in T2DM Patients withCoronary Artery Disease

41 YKL-40 YKL-40 or alternatively termed as BPR-39 orhuman cartilage glycoprotein-39 produced by the geneChitinase 3-like 1 (CH3L1) [15] is a heparin- and chitin-binding lectin without chitinase activity and a member ofthe mammalian chitinase-like protein cluster [16] YKL-40belongs to the glycosyl hydrolase family 18 which consists ofenzymes and proteins includes hydrolytic enzymes named aschitinases from various species includingmammalian bacte-ria fungi nematodes insects and plants [16] YKL-40 basedon its three NH

2-terminal amino acids tyrosine (Y) lysine

(K) and leucine (L) and its molecular weight of 40 kDa [16]is located at chromosome 1q31-q32 [15] consists of 10 exonsand spans about 8 kb of genomic DNA [16] and has a crystalstructure [17] YKL-40 is produced at the site of inflammation[18] secreted by activated macrophages including activatedneutrophils arthritic chondrocytes fibroblast-like synovialcells osteoblasts and differentiated vascular smooth musclecells [15]

Even though minor research has been conducted on theexact functions of YKL-40 several studies have reportedthat YKL-40 is an essential factor in extracellular tissueremodeling involving type 1 collagen fibril formation agrowth factor for fibroblasts and chondrocytes and alsocontrols mitogenesis by modulating MAP kinase and PI-3 K

signaling cascades in fibroblasts [16 19] YKL-401015840

s associa-tion withmigration reorganization and adhesion of vascularendothelial cells and vascular smooth muscle cells suggeststhat it may also play a role in angiogenesis [16 19]

YKL-40 serum levels increase in patients with acuteinfections [18] and chronic inflammation [15] Recent stud-ies have reported that elevated levels of plasma YKL-40are proportional with the HOMA-IR in T2DM subjectsThis indicates that YKL-40 shows some correlation withinsulin resistance and dyslipidemia High levels of YKL-40 also appeared in adult subjects who did not reporta medical history of T2DM and CVD comorbidities [2021] even at the childhood stage [22] Other studies havereported elevated levels of plasma YKL-40 and albumin-uria detected in both type 1 and type 2 diabetes melli-tus patients [21] The results of these studies suggest thatYKL-40 might act as a potential biomarker for endothelialdysfunction atherosclerosis insulin resistance and T2DM[20]

42 Alpha-Hydroxybutyrate Alpha-hydroxybutyrate (120572-HB) has been found to be the most significant biomarkerassociated with insulin sensitivity diabetes mellitus andCVD According to Walter et al 2010 the underlyingbiochemical mechanisms of alpha-hydroxybutyrate involvelipid oxidation and oxidative stress [23] Alpha-hydro-xybutyrate acts as an earlier marker of dysglycemia whencompared to other biomarkers in the same research such


as alpha-ketobutyrate (120572-KB) creatine acylcarnitines andlysoglycerophospholipids [23] The study showed that theexpression of alpha-ketobutyrate served as early indicatorin insulin resistance by differentiating the group of normalglucose tolerance-insulin sensitivity (NGT-IS) from normalglucose tolerance-insulin resistance (NGT-IR) amongnondiabetic population [23]

Alpha-hydroxybutyrate is an organic acid that is formedas a by-product during production of alpha-ketobutyratethrough a reaction catalyzed by lactate dehydrogenase (LDH)or by an LDH isoform in the heart known as alpha-hydro-xybutyrate dehydrogenase (120572-HBDH) [23 24] Elevated lev-els of alpha-hydroxybutyrate occur due to an increased rate ofalpha-ketobutyrate catabolism or inhibition of the productsof dehydrogenase that catalyze the conversion of alpha-ketobutyrate to propionyl-CoA [25]

Walter et al 2010 also reported that elevated levelsof alpha-hydroxybutyrate might be associated with insulinresistance by two possible mechanisms [23] First the incre-ment of hepatic glutathione stress causes increased pro-duction of glutathione which contributes to the supply ofmore alpha-ketobutyrate substrate and subsequently resultsin increased formation of alpha-hydroxybutyrate Secondincreased levels of lipid oxidation lead to increased levelsof nicotinamide adenine dinucleotide (NADH or NAD+)are parallel to the concentration of insulin-inhibited freefatty acid (FFA) [25] Previous study showed positive cor-relation between steady states of FFA and plasma alpha-hydroxybutyrate in the diabetic cohorts This supports theidea that increasing amounts of NADH or NAD+ cor-relate with the reduction of alpha-ketobutyrate to alpha-hydroxybutyrate [23]

43 Soluble CD36 CD36 also known as Fatty Acid Translo-case (FAT) is a complex multifunctional protein that presentasmononuclear phagocytes serves as a scavenger receptor foroxidized low-density lipoprotein (LDL) cellular transporterof long chain fatty acids in muscles and adipocytes andapoptotic cells on macrophages [26 27] CD36 has been alsoshowed to be involved in several processes including long-chain fatty acids advanced glycosylation products oxidizedphosphocholines collagen growth-hormone releasing hor-mone (GNRH) peptides hexarelin and thrombospondin-1(TSP-1) [28]

In 2008 Handberg et al studiesrsquo has identified theexistence and availability of soluble CD36 in cell-free plasmafor further research discovery [29] CD36 has been proposedas a biomarker of macrophage activation and inflammation[30] and atherosclerosis [31] Several studies report thatthe expression of this 88 kDa transmembrane glycoproteinCD36 is strongly associated with atherosclerosis angiogen-esis inflammation lipid metabolism platelet activation [31ndash33] hyperglycemia and insulin resistance [34] OxidizedLDL stimulates membrane CD36 expression on the surfaceof monocytes and macrophages resulting in an increasedatherosclerotic effect and might be the underlying mecha-nism causing lipid accumulation in the subendothelial space[27 30ndash32]

Previous study discovered that CD36 has the abilityto bind and modify LDL that is trapped in arterial wallcontributing to the formation of lipid-engorged macrophagefoam cells and initiate atherosclerotic lesions [26 27 31]CD36 interaction with oxidized LDL stimulates a signalingresponse that act as proinflammatory and proatherogenicwhere they differentiate intomacrophages [26]The signalingpathway involves activation of Src-family kinases and MAPkinases and Vav family guanine nucleotide exchange factorsthereby contributing to ligand internalization foam cellformation and inhibition of migration [26]

Activation mechanism of CD36 pathway started whenLDL particles cross the endothelium and become trappedin the intima connective tissue [26] Under the influenceof proinflammatory cytokines the macrophage producesreactive oxygen and nitrogen species which oxidized theunsaturated phospholipids present in LDL One oxidizedthe LDL particles lose their infinity to its specific LDLreceptor but gain affinity for scavenger receptors includingCD36 and internalized by intima macrophages [26] Duringinternalization specific oxidized lipids present in oxidizedLDL serve as ligands or precursors of ligands for the nuclearhormone receptor peroxisome proliferator-activated receptor120574-dependent (PPAR-120574) This receptor once engaged andactivated acts as a transcription factor that drives disor-derly expression of many metabolic genes including CD36[26]

Furthermore elevated FFA in monocytes and macro-phages also stimulate CD36 expression through PPAR-120574-dependent mechanism [26 31 33] Fat accumulation in thehuman liver results in elevated levels of FFA and lipolysiseventually leads to insulin resistance and diabetic dyslipi-demia Upregulation of CD36 expression in insulin-resistantsubjects which involves an impaired insulin signaling cas-cade is another pathological mechanism [30]

Increased levels of CD36 in monocytes among diabeticpatients are highly correlated with insulin resistance Severalstudies had showed that high levels of CD36 present in pre-diabetes overt diabetes polycystic ovary syndrome (PCOS)and impaired glucose tolerance strongly suggest that CD36is involved in diabetes [30] and atherosclerosis pathogenesisand acts as inflammation biomarker [31 32]

44 Leptin Plasma leptin has a strong correlation withobesity T2DM CVD insulin resistance metabolic syn-dromes and inflammatory markers [35] Leptin a 16 kDahormone component of adipokine is stimulated and secretedspecifically by white adipose cells [36] and has been pro-posed as a biomarker for atherosclerotic CVD [37] Theexpression of leptin receptors mainly in atheroscleroticlesions [38] is involved in a variety of actions includingendothelial activation [39 40] smooth muscle cell pro-liferation and calcification [41] and activation of mono-cytes and adaptive immune responses [42] Studies havereported that leptin levels are linked to inflammatory andfibrinolysis markers including C-reactive protein and plas-minogen activator inhibitor-1 and are associated with CVD[35 43]


Leptin is an adipocyte-specific ob gene product that hasbeen found to be associated with insulin resistance anddiabetes in obesity patients through insulin sensitivity andinsulin secretion alterations [44] Low insulin sensitivity has apathophysiological effect on metabolic syndromes includingcentral obesity dyslipidemia hyperglycemia hypertensionimpaired fibrinolysis and atherosclerosis [43] Leptin secre-tion by adipocytes might be stimulated by insulin whichdirectly influences islet 120573-cell action on insulin levels [45]Recent research reported a significant association betweenleptin in coronary heart disease (CHD) and insulin resistance[46]

45 Resistin Resistin and resistin-likemolecule protein orig-inates from a family of cysteine-rich secretory proteinsproduced during adipocyte catabolism in the presence of thethiazolidinediones a cluster of insulin-sensitizing drugs [36]Resistin plays a role in the regulation of energy glucose andlipid homeostasis [47] and the maintenance of fasting bloodglucose levels [48] by modulating hepatic insulin action [3749] Resistin is a macrophage-derived signaling polypeptidehormone with a molecular weight of 125 kDa and is 108amino acids long It has low circulating levels [50] but insome studies it has been reported to be upregulated in insulinresistance T2DM and CVD [51]

The expression of resistin primarily by monocytes andmacrophages is much greater compared with adipocytecatabolism [47] Resistin may increase the susceptibilityof metabolic syndrome (MS) by regulating adiponectinsecretion from adipocytes and enhancing hepatic gluconeo-genesis by inhibiting the enzymes involved in gluconeo-genesis through AMP-activated protein kinase activation[52] A recent study reported that subjects with prematureatherosclerosis have higher levels of plasma resistin comparedwith subjects with established atherosclerosis [53] Correla-tions between insulin sensitivity adiposity and T2DM [54]still remain to be fully revealed even though resistin hasbeen proposed as a potential link between obesity insulinresistance and T2DM with CVD [51 55]

46 Interleukin-18 The proinflammatory cytokine IL-18 islocated on chromosome 11q222-223 [56] and is a memberof the IL-1 cluster Originally IL-18 was described as aninterferon-120574-inducing factor because of its strong abilityto stimulate interferon-120574 release with the presence of co-stimuli such as IL-12 or lipopolysaccharide [57] Recentlystudies have suggested that IL-18 is involved in apoptosisand tissue destruction [58] as part of the host defenseagainst infections and neoplasms [57] abnormally expressedin adipose tissue through a mechanism called lipodystrophy[59] and is a predictor of cardiovascular mortality amongcoronary atherosclerosis subjects [60]

Inflammatory activity by macrophages monocytes den-dritic cells osteoblastic stroma cells and cells of the centralnervous system (CNS) stimulates activity of the precursor ofIL-18 called pro-IL-18 Pro-IL-18 is cleaved by either caspase-1-dependent conversion [61] or through the FAS ligand ina caspade-1-independent processing of IL-18 manner [62]

to release the active peptide [63] Once secreted the activepeptide of IL-18 can bind to either the IL-18 receptor or IL-18 binding protein or might be bind to the both The IL-18receptor consists of an 120572-chain and a 120573-chain The 120572-chain isresponsible for extracellular binding of IL-18 and the 120573-chainis responsible for intracellular signal transduction [64] As forcontrolling proinflammatory activity excess amounts of IL-18 secretion will bind to IL-18 binding protein which resultin a free fraction of IL-18 in a negative feedback mechanismThis free fraction of IL-18 is able to activate the 120573-chain whilecombination of free fraction of IL-18 and protein-bound IL-18is able to activate the 120572-chain [65]

The general mechanisms of IL-18 in the context of insulinresistance involve lineal effects of IL-18 on insulin signalingwith or without tumor necrosis factor-120572 (TNF-120572) stimulationin tissues and a secondary response of IL-18 to insulinresistance Previous research has reported a slight correlationbetween IL-18 and fasting plasma glucose in T2DM [66] andbetween IL-18 and fasting plasma insulin in obese women[67] Persistent circulatory levels of IL-18 have been reportedin T2DM subjects in parallel with elevated fasting glucoselevels and hyperglycemia [67] However IL-18 appears toact as an indicator for insulin resistance but not for 120573-cellmalfunction It has therefore been suggested that there is aplausible correlation between the functions of IL-18 and type 1diabetes mellitus (T1DM) [56] T2DM [68] obesity [66] andCVD [60] Recent investigation showed a strong and clearcorrelation between IL-18 and insulin resistance in T2DMsubjects and also in non-T2DM subjects [68]

47 Retinol Binding Protein-4 Retinol binding protein-4(RBP4) had been identified as the only specific transportprotein for retinol (vitamin A) that delivers retinol to tissuesfrom the blood [69] It is highly expressed in adipose tissuecompared with the liver and has a strong association withendothelial function Research has reported that the regionnear the RBP4 locus on human chromosome 10q has beenlinked to an increased risk of T2DM [69] Fischer et alreported that decreasing secretion of RBP4 serum levelsimproved insulin action and showed strong associationsbetween high RBP4 serum levels and insulin resistance[69] Previously RBP4 serum levels were found to have anassociationwith insulin sensitivity and to increase in lean andobese nondiabetic [70] and T2DM subjects [71]

Lack research had been done to discover the exact roleof RBP4 in human metabolism as most research has beenconducted using glucose transporter-4 knockout mice in anattempt to discover the mechanisms of RBP4 in adiposetissue However a recent study reported a strong correlationbetween RBP4 and insulin resistance in nondiabetic subjectswithout a medical or family history of diabetes [71]

Investigation showed that high secretion of RBP4 byadipocytes decreased the expression of glucose transporter-4 (GLUT-4) in adipose tissue which is commonly found inT2DM [71] A study reported that high circulating levels ofserum RBP4 increased the potential for insulin resistance byblocking insulin signaling in muscle thus increasing hepaticglucose output However correlations between RBP4 and


Endothelial dysfunctionAtherosclerosis Insulin resistance

Chemerin

anabolism

Acts synergistically with

and PI3K signaling

Expression through

through impaired insulin

Direct effect on insulin signaling secondary

response to IR indirect effects on insulin signaling

Lineal effects on

insulin signaling in

the transcription and translation of resistin mRNA degradation

insulin signaling pathway

Increased glutathione production due to increased hepatic glutathione stress

action on insulin levels

YKL-40 CD36 IL-18 Resistin RBP-4 Leptin 120572-HB

Stimulated by macrophages and adipocytes Glutathione

IGF-1 and intiates MAPKGLUT-4 which blocking

influence islet 120573-cell

PPAR-120574 mechanism andAttenuate IR by IRS-1

signaling cascade

phosphorylation in

via TNF- 120572 inductionmuscles

The presence directly

uarr Insulin level stimulates

Figure 3 Summary of potential biomarkers mechanism

vascular endothelium oxidative stress low-grade inflamma-tion related to insulin resistance and diabetic complicationsare still unclear [71]

48 Chemerin Chemerin (also known as retinoic acid recep-tor responder 2 and tazarotene-induced gene 2) discovered as18 kDa adipokine is secreted in the liver acts as chemotacticagents and is highly stimulated by the innate immunesystem such as plasmacytoid dendritic cells andmacrophages[72] Chemerin had been discovered as a natural ligandof the chemerin receptor termed as ChemR23 also knownas chemokine-like receptor 1 (CMKLR1) Chemerin alsoinvolves in intracellular calcium release and phosphorylationof extracellular signal-regulated kinase-1 and -2 (ERK 12)[72]

Chemerin is released as an inactive precursor Throughproteolytic cleavage chemerin is activated by serine proteasesof the coagulation fibrinolytic and inflammatory cascadesChemerin is produced as a preproprotein preprochemerinwhich requires N-terminal cleavage of a secretion signalpeptide before it is secreted as an inactive precursor proteinprochemerin This proprotein has low biological activityand requires further extracellular C-terminal processing byplasmin carboxypeptidases or serine proteases of the coagu-lation fibrinolytic and inflammatory cascades [73]

These findings showed that chemerin has multiple cleav-age sites in the C-terminal domain In order to reach itsmaximal anti-inflammatory effects bioactivity of chemerinis dependently regulated by proteolytic cleavage in the C-terminal region [74] The presence of chemerin isoforms

in hemofiltrate serum or ascites has potent chemotacticactivity indicating a proteolytic activation mechanism ofchemerin bioactivity Through mass spectrometry analysisthe isoforms of chemerin have been identified as chem21ndash154 and chem21ndash157 respectively however the proteasesrequired for the isoforms activation remain unknown [74]

Increased activity of the coagulation cascade anddecreased activity of the fibrinolytic cascade have beenreported in obesity [75] and T2DM [76 77] thus indicatingthe role of chemerin in immune responses [73] The greaterthe activity of the serine proteases involved in coagulationthe higher the levels of activated chemerin [78]

A previous study has reported that chemerin is secretedequally in normal and T2DM subjects [77] In another studychemerin levels were reported as an independent biomarkerof metabolic syndrome [79] A recent study by Johanna et alin 2010 reported that chemerin levels correlated with bodymass index and waist-to-hip ratio but not with high-densitylipoprotein cholesterol which is highly secreted in obeseand T2DM subjects In terms of a biomarker elevated levelsof chemerin positively correlated with elevated levels of C-reactive protein in overweight and T2DM subjects [78]

5 Summary

The association between the pathophysiology of T2DM andCAD and the presence of biomarkers was summarisedin Figure 3 Through endothelial dysfunction along withinsulin resistance mechanism different bioreceptors releasedbiomarkers into the blood circulation to give a signal on


the occurrence of inflammation The presence of potentialbiomarkers might reflect an underlying disease pathophysi-ology which would be essential to predict future events andtreatment response indication

6 Conclusion

Studies have reported strong evidence that suggests YKL-40 120572-HB soluble CD36 leptin resistin IL-18 RBP4 andchemerin could be new biomarkers for the pathogenesisof insulin resistance and endothelial dysfunction in T2DMpatients Components of these biological markers have beenproposed to act as predictors of cardiovascular events indiabetic patients However the exact role of these biomarkersin insulin resistance and associations between biomarkersand disease need to be further elucidated It is importantto have a detailed understanding of the involvement ofthese biomarkers to clarify the biological action of cytokinesand endothelial dysfunction and the occurrence of insulinresistance In conclusion these potential biomarkers mightprovide an alternative diagnostic tool for ensuring optimalmanagement of T2DM patients with CAD

Abbreviations

CAD Coronary artery diseaseCMKLR1 Chemokine-like receptor 1CVD Cardiovascular diseaseFAT Fatty Acid TranslocaseeNOS Endothelial nitric-oxide synthaseFFA Free fatty acidGLUT-4 Glucose Transporter 4GNRH Growth-hormone releasing hormoneHOMA-IR Homeostasis model of assessment-insulin

resistanceIGF-1 Insulin growth factor-1IL InterleukinIR Insulin resistanceIRIS Insulin Resistance Atherosclerosis StudyIRS-1 Insulin receptor substrate-1LDL Low-density lipoproteinMAPK Mitogen-activated protein kinaseMS Metabolic syndromeNADH Nicotinamide adenine dinucleotidePI-3K Phosphatidylinositol 3-kinasePPAR-120574 Peroxisome proliferator-activated receptor

120574-dependentRBP4 Retinal binding protein-4ROS Reactive oxygen speciesTNF-120572 Tumor necrosis factor-120572T1DM Type 1 diabetes mellitusT2DM Type 2 diabetes mellitusTSP-1 Thrombospondin-1

Conflict of Interests

The authors declare that there is no conflict of interests

Authorsrsquo Contributions

Sharifah IntanQhadijah Syed Ikmal wrote the paper HasnizaZaman Huri Shireene Ratna Vethakkan and Wan AzmanWan Ahmad revised the manuscript critically for importantintellectual content All authors read and approved the finalmanuscript

Acknowledgments

The authors would like to thank the Ministry of ScienceTechnology and Innovation Malaysia (Sciencefund 12-02-03-2097) and University of Malaya Malaysia (University ofMalaya Research Grant RG42812HTM) for financial andtechnical support

References

[1] J E Shaw R A Sicree and P Z Zimmet ldquoGlobal estimates ofthe prevalence of diabetes for 2010 and 2030rdquoDiabetes Researchand Clinical Practice vol 87 no 1 pp 4ndash14 2010

[2] G Roglic and N Unwin ldquoMortality attributable to diabetesestimates for the year 2010rdquo Diabetes Research and ClinicalPractice vol 87 no 1 pp 15ndash19 2010

[3] M Stumvoll B J Goldstein and T W van Haeften ldquoType 2diabetes principles of pathogenesis and therapyrdquo The Lancetvol 365 no 9467 pp 1333ndash1346 2005

[4] American Diabetes Association Prevention and Managementof Diabetes Complications American Diabetes AssociationAlexandria Va USA 2013


[6] R Marian Z Daniel D Ralph et al ldquoInsulin sensitivityinsulinemia and coronary artery disease the Insulin ResistanceAtherosclerosis studyrdquo Diabetes Care vol 27 no 3 pp 781ndash7872004

[7] American Heart Association httpwwwheartorgHEARTO-RGConditionsMoreMyHeartandStrokeNewsCoronary-Ar-tery-Disease-The-ABCs-ofCAD UCM 436416 Articlejsp

[8] H E Lebovitz ldquoType 2 diabetes anoverviewrdquo Clinical Chem-istry vol 45 no 8 pp 1339ndash1345 1999

[9] P Libby ldquoInflammation in atherosclerosisrdquoNature vol 420 no6917 pp 868ndash874 2002

[10] G Reaven ldquoThe metabolic syndrome or the insulin resistancesyndrome Different names different concepts and differentgoalsrdquo Endocrinology and Metabolism Clinics of North Americavol 33 supplement 2 pp 283ndash303 2004

[11] B Alaa K Amira H Pierre et al ldquoType 2 diabetes mellitus andinflammation prospects for biomarkers of risk nd nutritionalinterventionrdquoDiabetes Metabolic Syndrome and Obesity vol 3pp 173ndash186 2010

[12] A Sjoholm and T Nystrom ldquoInflammation and the etiology oftype 2 diabetesrdquoDiabetesMetabolismResearch andReviews vol22 pp 4ndash10 2006

[13] D H Endemann and E L Schiffrin ldquoEndothelial dysfunctionrdquoJournal of the American Society of Nephrology vol 15 no 8 pp1983ndash1992 2004

[14] A H Willa and J Q Manuel ldquoRole of endothelial dysfunctionin insulin resistancerdquo The American Journal of Cardiology vol92 pp 10ndash17 2003


[15] M Rehli H Niller C Ammon et al ldquoTranscriptional regula-tion of CHI3L1 a marker gene for late stages of macrophagedifferentiationrdquo Journal of Biological Chemistry vol 278 no 45pp 44058ndash44067 2003

[16] J S Johansen B V Jensen A Roslind D Nielsen and P APrice ldquoSerum YKL-40 a new prognostic biomarker in cancerpatientsrdquoCancer Epidemiology Biomarkers and Prevention vol15 no 2 pp 194ndash202 2006

[17] A Roslind and J S Johansen ldquoYKL-40 a novel marker sharedby chronic inflammation and oncogenic transformationrdquoMeth-ods in Molecular Biology vol 511 pp 159ndash184 2009

[18] C Oslashstergaard J S Johansen T Benfield P A Price andJ D Lundgren ldquoYKL-40 is elevated in cerebrospinal fluidfrompatients with purulentmeningitisrdquoClinical andDiagnosticLaboratory Immunology vol 9 no 3 pp 598ndash604 2002

[19] K C Nishikawa and A J T Millis ldquogp38k (CHI3L1) is a noveladhesion and migration factor for vascular cellsrdquo ExperimentalCell Research vol 287 no 1 pp 79ndash87 2003

[20] C N Rathcke J S Johansen and H Vestergaard ldquoYKL-40 abiomarker of inflammation is elevated in patients with type2 diabetes and is related to insulin resistancerdquo InflammationResearch vol 55 no 2 pp 53ndash59 2006

[21] C N Rathcke F Persson L Tarnow P Rossing and H Vester-gaard ldquoYKL-40 a marker of inflammation and endothelialdysfunction is elevated in patients with type 1 diabetes andincreases with levels of albuminuriardquo Diabetes Care vol 32 no2 pp 323ndash328 2009

[22] I Kyrgios A Galli-Tsinopoulou C Stylianou E Papakon-stantinou M Arvanitidou and A Haidich ldquoElevated circulat-ing levels of the serum acute-phase protein YKL-40 (chitinase3-like protein 1) are a marker of obesity and insulin resistancein prepubertal childrenrdquoMetabolism vol 61 no 4 pp 562ndash5682012

[23] E G Walter B Kirk A L Kay et al ldquo120572-hydroxybutyrate is anearly biomarker of insulin resistance and glucose intolerancein a nondiabetic populationrdquo PLoS ONE vol 5 supplement 5Article ID e10883 11 pages 2010

[24] S B Rosalki and J HWilkinson ldquoReduction of 120572-ketobutyrateby human serumrdquoNature vol 188 no 4756 pp 1110ndash1111 1960

[25] S Landaas ldquoThe formation of 2 hydroxybutyric acid in experi-mental animalsrdquo Clinica Chimica Acta vol 58 no 1 pp 23ndash321975

[26] R L Silverstein W Li Y M Park and S O RahamanldquoMechanisms of cell signaling by the scavenger receptor CD36implications in atherosclerosis and thrombosisrdquo Transactions ofthe American Clinical and Climatological Association vol 121pp 206ndash220 2010

[27] A Handberg K Levin K Hoslashjlund and H Beck-NielsenldquoIdentification of the oxidized low-density lipoprotein scav-enger receptor CD36 in plasma a novel marker of insulinresistancerdquo Circulation vol 114 no 11 pp 1169ndash1176 2006

[28] J J D Maximilliano X Nengming L C Adam et al ldquoSolubleCD36 ectodomain binds negatively charged diacylglycerol lig-ands and acts as a co-receptor for TLR2rdquo PLoS ONE vol 4 no10 Article ID e7411 2009

[29] A Handberg M Skjelland E M Annika et al ldquoSoluble CD36in plasma is increased in patients with symptomatic atheroscle-rotic carotid plaques and is related to plaque instabilityrdquo Strokevol 39 no 11 pp 3092ndash3095 2008

[30] C Liang S Han H Okamoto et al ldquoIncreased CD36 proteinas a response to defective insulin signaling in macrophagesrdquo

Journal of Clinical Investigation vol 113 no 5 pp 764ndash7732004

[31] S Collot-Teixeira J Martin CMcDermott-Roe R Poston andJ L McGregor ldquoCD36 and macrophages in atherosclerosisrdquoCardiovascular Research vol 75 no 3 pp 468ndash477 2007

[32] M Febbraio and R L Silverstein ldquoCD36 implications incardiovascular diseaserdquo International Journal of Biochemistryand Cell Biology vol 39 no 11 pp 2012ndash2030 2007

[33] E A Podrez T V Byzova M Febbraio et al ldquoPlatelet CD36links hyperlipidemia oxidant stress and a prothrombotic phe-notyperdquo Nature Medicine vol 13 no 9 pp 1086ndash1095 2007

[34] A Handberg M Norberg H Stenlund G Hallmans J Atter-mann and J W Eriksson ldquoSoluble CD36 (sCD36) clusters withmarkers of insulin resistance and high sCD36 is associatedwithincreased type 2 diabetes riskrdquo Journal of Clinical Endocrinologyand Metabolism vol 95 no 4 pp 1939ndash1946 2010

[35] F M H van Dielen C Vanrsquot Veer AM Schols P B SoetersWA Buurman and J W M Greve ldquoIncreased leptin concentra-tions correlate with increased concentrations of inflammatorymarkers in morbidly obese individualsrdquo International Journalof Obesity vol 25 no 12 pp 1759ndash1766 2001

[36] CM Steppan andMA Lazar ldquoResistin and obesity-associatedinsulin resistancerdquo Trends in Endocrinology and Metabolismvol 13 no 1 pp 18ndash23 2002

[37] M W Rajala and P E Scherer ldquoMinireview the adipocytemdashat the crossroads of energy homeostasis inflammation andatherosclerosisrdquo Endocrinology vol 144 no 9 pp 3765ndash37732003

[38] S M Kang HM Kwon B K Hong et al ldquoExpression of leptinreceptor (Ob-R) in human atherosclerotic lesions potential rolein intimal neovascularizationrdquo Yonsei Medical Journal vol 41no 1 pp 68ndash75 2000

[39] S Yamagishi D Edelstein X Du Y Kaneda M Guzmanand M Brownlee ldquoLeptin induces mitochondrial superoxideproduction andmonocyte chemoattractantprotein-1 expressionin aortic endothelial cells by increasing fatty acid oxidation viaprotein kinase Ardquo Journal of Biological Chemistry vol 276 no27 pp 25096ndash25100 2001

[40] H Park H M Kwon H J Lim et al ldquoPotential role of leptin inangiogenesis leptin induces endothelial cell proliferation andexpression of matrix metalloproteinases in vivo and in vitrordquoExperimental andMolecular Medicine vol 33 no 2 pp 95ndash1022001

[41] F Parhami Y Tintut A Ballard A M Fogelman and LL Demer ldquoLeptin enhances the calcification of vascular cellsartery wall as a target of leptinrdquo Circulation Research vol 88no 9 pp 954ndash960 2001

[42] R Faggioni K R Feingold and C Grunfeld ldquoLeptin regulationof the immune response and the immunodeficiency of malnu-tritionrdquoThe FASEB Journal vol 15 no 14 pp 2565ndash2571 2001

[43] AMWallace A DMcMahon C J Packard et al ldquoPlasma lep-tin and the risk of cardiovascular disease in theWest of ScotlandCoronary Prevention Study (WOSCOPS)rdquoCirculation vol 104no 25 pp 3052ndash3056 2001

[44] C S Mantzoros ldquoThe role of leptin in human obesity anddisease a review of current evidencerdquo Annals of InternalMedicine vol 130 no 8 pp 671ndash680 1999

[45] S Margetic C Gazzola G G Pegg and R A Hill ldquoLeptin areview of its peripheral actions and interactionsrdquo InternationalJournal of Obesity vol 26 no 11 pp 1407ndash1433 2002


[46] R A Karatela andG S Sainani ldquoInterrelationships of factorVIIactivity and plasma leptin with insulin resistance in coronaryheart diseaserdquo Atherosclerosis vol 209 no 1 pp 235ndash240 2010

[47] L Patel A C Buckels I J Kinghorn et al ldquoResistin is expressedin human macrophages and directly regulated by PPAR120574 acti-vatorsrdquo Biochemical and Biophysical Research Communicationsvol 300 no 2 pp 472ndash476 2003

[48] R R Banerjee S M Rangwala J S Shapiro et al ldquoRegulationof fasted blood glucose by resistinrdquo Science vol 303 no 5661pp 1195ndash1198 2004

[49] E D Muse S Obici S Bhanot et al ldquoRole of resistin indiet-induced hepatic insulin resistancerdquo Journal of ClinicalInvestigation vol 114 no 2 pp 232ndash239 2004

[50] S Galic J S Oakhill and G R Steinberg ldquoAdipose tissue asan endocrine organrdquoMolecular and Cellular Endocrinology vol316 no 2 pp 129ndash139 2010

[51] M H Zhang B Na N B Schiller and M A WhooleyldquoAssociation of resistin with heart failure and mortality inpatients with stable coronary heart disease data from the heartand soul studyrdquo Journal of Cardiac Failure vol 17 no 1 pp 24ndash30 2011

[52] Y Miyamoto H Morisaki Y Kokubo et al ldquoResistin genevariations are associated with the metabolic syndrome inJapanese menrdquoObesity Research and Clinical Practice vol 3 no2 pp 65ndash74 2009

[53] M S Burnett J M Devaney R J Adenika R Lindsay andB V Howard ldquoCross-sectional associations of resistin coro-nary heart disease and insulin resistancerdquo Journal of ClinicalEndocrinology and Metabolism vol 91 supplement 1 pp 64ndash68 2006

[54] B Youn K Yu H J Park et al ldquoPlasma resistin concen-trations measured by enzyme- linked immunosorbent assayusing a newly developed monoclonal antibody are elevated inindividuals with type 2 diabetes mellitusrdquo Journal of ClinicalEndocrinology and Metabolism vol 89 no 1 pp 150ndash156 2004

[55] B H Chen Y Song E L Ding et al ldquoCirculating levels ofresistin and risk of type 2 diabetes in men and women resultsfrom two prospective cohortsrdquo Diabetes Care vol 32 no 2 pp329ndash334 2009

[56] K F Nolan D R Greaves and H Waldmann ldquoThe humaninterleukin 18 gene IL18 maps to 11q222-q223 closely linkedto the DRD2 gene locus and distinct frommapped IDDM locirdquoGenomics vol 51 no 1 pp 161ndash163 1998

[57] C A Dinarello D Novick A J Puren et al ldquoOverviewof interleukin-18 more than an interferon-120574 inducing factorrdquoJournal of Leukocyte Biology vol 63 no 6 pp 658ndash664 1998

[58] S Kashiwamura H Ueda and H Okamura ldquoRoles ofinterleukin-18 in tissue destruction and compensatory reac-tionsrdquo Journal of Immunotherapy vol 25 supplement 1 pp S4ndashS11 2002

[59] B Lindegaard A E Hansen H Pilegaard P Keller J Gerstoftand B K Pedersen ldquoAdipose tissue expression of IL-18 andHIV-associated lipodystrophyrdquo AIDS vol 18 no 14 pp 1956ndash1958 2004

[60] S Blankenberg G Luc P Ducimetiere et al ldquoInterleukin-18and the risk of coronary heart disease in European men theProspective Epidemiological Study of Myocardial Infarction(PRIME)rdquo Circulation vol 108 no 20 pp 2453ndash2459 2003

[61] Y Gu K Kuida H Tsutsui et al ldquoActivation of interferon-120574 inducing factor mediated by interleukin-1120573 convertingenzymerdquo Science vol 275 no 5297 pp 206ndash209 1997

[62] H Tsutsui N Kayagaki K Kuida et al ldquoCaspase-1-independ-ent FasFas ligand-mediated IL-18 secretion frommacrophagescauses acute liver injury in micerdquo Immunity vol 11 no 3 pp359ndash367 1999

[63] G Fantuzzi and C A Dinarello ldquoInterleukin-18 and interleu-kin-1120573 two cytokine substrates for ICE (caspase-1)rdquo Journal ofClinical Immunology vol 19 no 1 pp 1ndash11 1999

[64] Z Kato J Jee H Shikano et al ldquoThe structure and bindingmode of interleukin-18rdquo Nature Structural Biology vol 10 no11 pp 966ndash971 2003

[65] D Novick B Schwartsburd R Pinkus et al ldquoA novel IL-18BPELISA shows elevated serum IL-18BP in sepsis and extensivedecrease of free IL-18rdquoCytokine vol 14 no 6 pp 334ndash342 2001

[66] Y Oikawa A Shimada A Kasuga et al ldquoSystemic adminis-tration of IL-18 promotes diabetes development in young non-obese diabetic micerdquo Journal of Immunology vol 171 no 11 pp5865ndash5875 2003

[67] K Esposito A Pontillo M Ciotola et al ldquoWeight loss reducesinterleukin-18 levels in obese womenrdquo Journal of ClinicalEndocrinology and Metabolism vol 87 no 8 pp 3864ndash38662002

[68] C P Fischer L B Perstrup A Berntsen P Eskildsen and BK Pedersen ldquoElevated plasma interleukin-18 is a marker ofinsulin-resistance in type 2 diabetic and non-diabetic humansrdquoClinical Immunology vol 117 no 2 pp 152ndash160 2005

[69] Q Yang T E Graham N Mody et al ldquoSerum retinol bindingprotein 4 contributes to insulin resistance in obesity and type 2diabetesrdquo Nature vol 436 no 7049 pp 356ndash362 2005

[70] M C Young B Youn H Lee et al ldquoPlasma retinol-bindingprotein-4 concentrations are elevated in human subjects withimpaired glucose tolerance and type 2 diabetesrdquo Diabetes Carevol 29 no 11 pp 2457ndash2461 2006

[71] S Gavi L M Stuart P Kelly et al ldquoRetinol-binding protein 4is associated with insulin resistance and body fat distribution innonobese subjects without type 2 diabetesrdquo Journal of ClinicalEndocrinology andMetabolism vol 92 supplement 5 pp 1886ndash1890 2007

[72] S Roh S Song K Choi et al ldquoChemerinmdasha new adipokinethat modulates adipogenesis via its own receptorrdquo Biochemicaland Biophysical Research Communications vol 362 no 4 pp1013ndash1018 2007

[73] M C Ernst and C J Sinal ldquoChemerin at the crossroadsof inflammation and obesityrdquo Trends in Endocrinology andMetabolism vol 21 no 11 pp 660ndash667 2010

[74] X Du and L L K Leung ldquoProteolytic regulatory mechanism ofchemerin bioactivityrdquo Acta Biochimica et Biophysica Sinica vol41 no 12 pp 973ndash979 2009

[75] B A Zabel S J Allen P Kulig et al ldquoChemerin activation byserine proteases of the coagulation fibrinolytic and inflamma-tory cascadesrdquo Journal of Biological Chemistry vol 280 no 41pp 34661ndash34666 2005

[76] Y Aso S Matsumoto Y Fujiwara K Tayama T Inukai and YTakemura ldquoImpaired fibrinolytic compensation for hypercoag-ulability in obese patients with type 2 diabetes association withincreased plasminogen activator inhibitor-1rdquo Metabolism vol51 no 4 pp 471ndash476 2002

[77] K Bozaoglu K Bolton J McMillan et al ldquoChemerin is a noveladipokine associated with obesity and metabolic syndromerdquoEndocrinology vol 148 no 10 pp 4687ndash4694 2007

[78] W Johanna N Markus W Josef et al ldquoSystemic chemerin isrelated to inflammation rather than obesity in type 2 diabetesrdquoClinical Endocrinology vol 72 no 3 pp 342ndash348 2010


[79] D Stejskal M Karpisek Z Hanulova and M SvestakldquoChemerin is an independent marker of the metabolic syn-drome in a Caucasian populationmdasha pilot studyrdquo Biomedicalpapers of the Medical Faculty of the University Palacky vol 152no 2 pp 217ndash221 2008

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


coronary angioplasty through confirmation by review ofmedical records or a major Q wave on electrocardiogramexamination (ECG) in Insulin Resistance AtherosclerosisStudy (IRAS) [6] Concomitant risk factors including per-sistent hyperglycemia dyslipidemia hypertension smokinga family history of the disease and the presence of micro-andmacroalbuminuria directly increase themortality risk ofCAD among T2DM patients by approximately 2- to 4-foldcompared with nondiabetic people [4 5] CAD is definedas an accumulation of cholesterol substance build-up incoronary arteries Anatomically coronary arteries are bloodvessels supplying oxygen to cardiacmuscle Coronary arteriesbranch off from the aorta into four major arteries Theseare the right coronary artery the left main coronary arterythe left anterior descending artery and the left circumflexartery Blockage to any of these arteries due to plaqueinstability known as atherosclerosis leads to angina andischemic conditions resulting in CAD and also increasingthe potential development of ischemic heart disease and othermajor cardiovascular diseases (CVDs) [7]

Owing to recent advances in understanding circulatingmolecular actions between endothelial function and theimmune system several potential biomarkers have beenidentified that appear to be linked to T2DM and CAD interms of insulin resistance and atherosclerosis This reviewexamines these potential biomarkers as a new alternative todetermining the status of insulin resistance in T2DMpatientswith CAD

2 Mechanism of Insulin Resistance

According to the American Diabetes Association 2013 guide-lines insulin resistance and persistent hyperinsulinemia arefound in a variety of medical conditions including dys-lipidemia and hypertension [4 5] Insulin resistance hasbeen established as a precursor and acts as a strong factorlinking T2DMwith CVD Studies have reported an increasedpotential risk of diabetic patients acquiring CAD within thepast two decades [2 6] This is mainly because of insulinresistance development through genetics and environmentalfactors [8] Alterations of 120573-cell function and insulin proper-ties underlay the metabolic syndrome that includes dyslipi-demia hyperglycemia hypertension impaired fibrinolysisand atherosclerosis thus contributing to lower insulin sen-sitivity [6]

At a basic level insulin resistance occurs through theactivation of various types of macrophages Malfunctioningadipocytes and adipose tissue release greater amounts ofvarious proinflammatory cytokines Subclinical inflamma-tion due to insulin resistance might also correlate with thepathogenesis of all phases of atherosclerosis This involveslow-grade elevation of acute phase reactants proinflamma-tory cytokine secretion and cell adhesion molecules andleads to myocardial infarction stroke and other majorperipheral vascular diseasesThese factors therefore increasecardiovascular mortality Activation of the innate immunesystem greatly contributes to the occurrence of T2DM andCAD (Figure 1) [9]

Endothelial dysfunction triggered by persistent inflam-mation due to increased levels of triglycerides (TRYL)free fatty acids (FFA) and low-density lipoprotein (LDL)and decreased levels of high-density lipoprotein (HDL) thateventually leads to alteration of insulin signaling and glucoseuptake in muscles and adipocytes

Inefficient glucose uptake by muscle and adipose tissueleads to insulin resistance or a medical condition knownas compensatory hyperinsulinemia 120573 cells of the pancreaticislets release excessive amounts of insulin in an attempt tocompensate for high plasma glucose levels in the blood [910] Persistent hyperinsulinemia increases serum levels oftriglycerides free fatty acids (FFA) and low-density lipopro-tein and decreases serum levels of high-density lipoproteinIncreased levels of circulating FFA in the blood activate theinnate immune system to release pr-inflammatory cytokinesincluding tumor necrosis factor-120572 interleukin (IL)-6 and IL-1120573 [11] The presence of these cytokines leads to an alterationin insulin sensitivity and disruption of glucose homeostasis[11] The process involves cytokines first mediating insulinsignaling mechanisms in adipocytes muscles and the liverto increase the occurrence of insulin resistance [11] beforedisabling liver X receptors (LXRs) causing an increase in theaccumulation of cholesterol thus stimulating hepatic produc-tion and secretion of inflammatory markers including C-reactive protein plasminogen inhibitor-1 serum amyloid-A1205721-acid glycoprotein and haptoglobin [12] Cytokines thenstimulate fibrinogen which acts as an atherosclerotic riskfactor and leads to CAD [11] Finally cytokines increaseproduction of very low-density lipoprotein and FFA whichleads to the characteristics of diabetic dyslipidemia and thesubsequent increase in plaque accumulation [9 11 12]

3 Correlation between InsulinResistance Endothelial Dysfunctionand Atherosclerosis

The endothelium is located at the interior surface of bloodand lymphatic vessels The endothelium consists of a thinlayer of cells defined as being either vascular endothelial cells(cells in direct contact with blood) or lymphatic endothelialcells (cells in direct contact with lymph) The function ofthe endothelium is to sense mechanical stimuli such ashigh pressure and stretching and hormonal stimuli such asvasoactive substances The endothelium plays a role in theregulation of vasomotor functions stimulates inflammatoryprocesses and influences hemostasis [13]

Studies suggest that persistent hyperinsulinemia mighttrigger endothelial dysfunction In diabetes the occur-rence of insulin resistance is due to an alteration ininsulin signaling Once this alteration happens phospho-rylation of major pathways (eg phosphatidylinositol 3-kinase phosphoinositide-dependent kinase-1 and AKTpro-tein kinase B pathways) which activate endothelial nitric-oxide synthase (eNOS) is downregulated drastically Dueto this downregulation the role of eNOS changes froman antiatherogenic effect to a proatherogenic effect whichfurther contributes to the development of atherosclerosis








CD36

RBP4

Leptin

ResistinChemerin

YKL-40

120572-HB

IL-18


cytokines


homeostasis









Insulin resistance

T2DM

Nitric oxide

(NO)

reduction

Increased ROS

production from

endothelium

Increased adhesion

molecule

expression of

chemokine and

other cytokine

release

Atherosclerosis

CAD

Inflammation

Possible cytokines

as biological

marker between

T2DM and CAD

Hyperinsulinemia



































Chemerin

anabolism


and PI3K signaling

Expression through




Lineal effects on











signaling cascade

phosphorylation in












5 Summary




6 Conclusion


Abbreviations








Acknowledgments


References

























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























CD36

RBP4

Leptin

ResistinChemerin

YKL-40

120572-HB

IL-18


cytokines


homeostasis









Insulin resistance

T2DM

Nitric oxide

(NO)

reduction

Increased ROS

production from

endothelium

Increased adhesion

molecule

expression of

chemokine and

other cytokine

release

Atherosclerosis

CAD

Inflammation

Possible cytokines

as biological

marker between

T2DM and CAD

Hyperinsulinemia



































Chemerin

anabolism


and PI3K signaling

Expression through




Lineal effects on











signaling cascade

phosphorylation in












5 Summary




6 Conclusion


Abbreviations








Acknowledgments


References

























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















Insulin resistance

T2DM

Nitric oxide

(NO)

reduction

Increased ROS

production from

endothelium

Increased adhesion

molecule

expression of

chemokine and

other cytokine

release

Atherosclerosis

CAD

Inflammation

Possible cytokines

as biological

marker between

T2DM and CAD

Hyperinsulinemia



































Chemerin

anabolism


and PI3K signaling

Expression through




Lineal effects on











signaling cascade

phosphorylation in












5 Summary




6 Conclusion


Abbreviations








Acknowledgments


References

























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of








































Chemerin

anabolism


and PI3K signaling

Expression through




Lineal effects on











signaling cascade

phosphorylation in












5 Summary




6 Conclusion


Abbreviations








Acknowledgments


References

























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























Chemerin

anabolism


and PI3K signaling

Expression through




Lineal effects on











signaling cascade

phosphorylation in












5 Summary




6 Conclusion


Abbreviations








Acknowledgments


References

























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















Chemerin

anabolism


and PI3K signaling

Expression through




Lineal effects on











signaling cascade

phosphorylation in












5 Summary




6 Conclusion


Abbreviations








Acknowledgments


References

























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















6 Conclusion


Abbreviations








Acknowledgments


References

























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Review Article Potential Biomarkers of Insulin Resistance ...downloads.hindawi.com/journals/ije/2013/698567.pdf · uptake in muscles and adipocytes. Ine cient glucose uptake by muscle