review article current advances in the biochemical and...

Review ArticleCurrent Advances in the Biochemical andPhysiological Aspects of the Treatment of Type 2Diabetes Mellitus with Thiazolidinediones

D Alemaacuten-Gonzaacutelez-Duhart1 F Tamay-Cach2

S Aacutelvarez-Almazaacuten1 and J E Mendieta-Wejebe1

1Laboratorio de Biofısica y Biocatalisis Seccion de Estudios de Posgrado e Investigacion Escuela Superior de MedicinaInstituto Politecnico Nacional Plan de San Luis y Salvador Dıaz Miron Casco de Santo Tomas 11340 Ciudad de Mexico DF Mexico2Laboratorio de Investigacion en Bioquımica Departamento de Formacion Basica Disciplinaria y Seccion de Estudiosde Posgrado e Investigacion Escuela Superior de Medicina Instituto Politecnico Nacional Plan de San Luis y Salvador Dıaz MironCasco de Santo Tomas 11340 Ciudad de Mexico DF Mexico

Correspondence should be addressed to J E Mendieta-Wejebe jesmenwejyahoocom

Received 18 March 2016 Accepted 24 April 2016

Academic Editor Yue Zhang

Copyright copy 2016 D Aleman-Gonzalez-Duhart et al This 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

Thepresent review summarizes the current advances in the biochemical and physiological aspects in the treatment of type 2 diabetesmellitus (DM2) with thiazolidinediones (TZDs) DM2 is a metabolic disorder characterized by hyperglycemia triggering theabnormal activation of physiological pathways such as glucose autooxidation polyolrsquos pathway formation of advance glycation end(AGE) products and glycolysis leading to the overproduction of reactive oxygen species (ROS) and proinflammatory cytokineswhich are responsible for the micro- and macrovascular complications of the disease The treatment of DM2 has been directedtoward the reduction of hyperglycemia using different drugs such as insulin sensitizers as the case of TZDs which are able tolower blood glucose levels and circulating triglycerides by binding to the nuclear peroxisome proliferator-activated receptor gamma(PPAR120574) as full agonists When TZDs interact with PPAR120574 the receptor regulates the transcription of different genes involved inglucose homeostasis insulin resistance and adipogenesis However TZDs exhibit some adverse effects such as fluid retentionweight gain hepatotoxicity plasma-volume expansion hemodilution edema bone fractures and congestive heart failure whichlimits their use in DM2 patients

1 Introduction

The treatment of type 2 diabetes mellitus (DM2) has beendirected toward the reduction of hyperglycemia and gly-cosylated hemoglobin (HbA1c le7) in order to preventcardiovascular and other long term risks [1 2] specially by theusage of insulin sensitizers such as thiazolidinediones (TZDs)[1ndash5] an effective type of drugs for lowering blood glucoselevels as circulating triglycerides [4 6ndash9] with adverse effectssuch as adipocyte differentiation fluid retention weight gainbone loss and congestive heart failure [6ndash8 10ndash13]

Clinically pioglitazone is the only available TZD eventhough its commercialization has been restricted to a fewcountries by the US Food and Drug Administration (FDA)

since it may cause urinary bladder cancer The other TZDsrosiglitazone and troglitazone show adverse profiles so theyare no longer available in the worldwide market for examplerosiglitazone was associated with a significant increase inmyocardial infarction heart failure and death from car-diovascular diseases so the European Medicines Agencywithdrew the approval for this medication in 2010 and theFDA restricted its prescription in the United States [3 14ndash17]

In the present review we summarize the current advanceson the biochemical and physiological aspects involved in thetreatment of DM2 with TZDs

Type 2 Diabetes Mellitus (DM2) DM2 is a metabolic disordercharacterized by hyperglycemia whichmay be due to a defect

Hindawi Publishing CorporationPPAR ResearchVolume 2016 Article ID 7614270 10 pageshttpdxdoiorg10115520167614270

2 PPAR Research

Glucose autooxidation

120572-D-glucose Glucose enediol

Enediol radical

Ketoaldehyde Oxidative stress

Polyolsrsquo pathway

Glucose Sorbitol Fructose

NADPH depletion

GSH depletion

Advanceglycation end

products (AGEs) Glycolysis

Protein modification

Tissueaccumulation

NF-120581B activation

Proinflammatoryenvironment

VEGF expression

Glycerol-3-phosphate

diacylglycerolincrease

PKC activation O2

Fe3+

Hyperglycemia

Complications

O2∙minus

Figure 1 The main pathways triggered by hyperglycemia include glucose autooxidation and constant activation of polyolsrsquo pathway andformation of advance glycation end products (AGEs) and excessive glycolysis With the constant activation of these pathways living cellsand tissues are damaged mainly by impairment of target protein function increase in oxidative stress and activation of signal transductionpathways leading to the imbalance of normal physiological functions and therefore the development of diabetic complications

in insulin secretion of pancreatic 120573 cells insulin resistancein peripheral tissues andor an excessive accumulation oftriglycerides and fatty acid derivatives in skeletal musclesThis pathology remains a leading cause of cardiovascular dis-orders such as microvascular (retinopathy nephropathy andneuropathy) and macrovascular (coronary cerebrovascularand peripheral vascular diseases) complications mainly trig-gered by the abnormal activation of physiological pathways(Figure 1) and it is also associated with increased risk ofcancer psychiatric illness cognitive decline chronic liverdisease and development of arthritis [1ndash4 18ndash24]

The treatment of DM2 is directed toward the reductionof hyperglycemia and HbA1c (le7) in order to preventcardiovascular and other long term risks (Table 1) [1 25] there is a wide range of drugs which can be used inorder to reduce glycemia being notable mechanisms such asimproving insulin secretion and reducing insulin resistanceof peripheral tissues as the case of TZDs [1ndash5] whichare drugs targeting the peroxisome proliferator-activatedreceptor gamma (PPAR120574)

PPARs have emerged as links between lipids metabolicdiseases and innate immunity as they regulate energy home-ostasis [25 26] and specifically talking about PPAR120574 thisreceptor is capable of regulating metabolic genes which willbe further discussed and improves insulin sensitivity throughglucose and lipid uptake and storage in peripheral tissuessuch as skeletal muscle liver and adipose tissue [26]

The relationship between PPAR120574 and DM2 has beenestablished using both in vitro and in vivo experimentation

since it has been seen that the inactivation of PPAR120574 inmature adipocytes leads to insulin resistance as mice lackingthe receptor develop hyperlipidemia hyperglycemia andorhyperinsulinemia [26 27]

Thiazolidinediones (TZDs) TZDs are compounds used clin-ically as insulin sensitizers in order to lower blood glucoselevels as circulating triglycerides [4 6ndash9] but it has alsobeen shown that these also exhibit other biological activitiessuch as anti-inflammatory antimalarial antioxidant cyto-toxic antimicrobial and aldose reductase inhibitor activitieseither in vitro or in animal models [10 11] TZDs act asperoxisome proliferator-activated receptors gamma (PPAR120574)full agonists which are also involved in the increase ofadipocyte differentiation fluid retention weight gain boneloss and congestive heart failure Having such diverse rangeof pharmacological activities these molecules have a lot ofpotential uses so different strategies have been originated touse them not only for the treatment of DM2 but also for otherpathologies [2 5 6 8ndash11]

When TZDs interact with PPAR120574 the receptor reg-ulates the transcription of different genes mainly thosegenes involved in glucose homeostasis and adipogenesisspecifically within white adipose tissue (WAT) by inducingbrown adipose tissue- (BAT-) like features in it a uniquecharacteristic exclusive for PPAR120574 full agonists such asrosiglitazone [13 28]

However despite their excellent potencies the incidenceof undesirable side effects has been linked to the use of TZDs

PPAR Research 3

Table 1 Class of drugs used for the treatment of type 2 diabetes mellitus

Class Compounds Mechanism Physiological action Advantages Disadvantages

Biguanides Metformin Activates AMPkinase

darr hepatic glucoseproduction

Low cost noweight gain nohypoglycemiadarr CVD events

Gastrointestinalside effects

lactic acidosisvitamin B12deficiency

Sulfonylureas

GlyburideGlibenclamide

GlipizideGlimepiride

Closes K-ATPchannels on 120573cell plasmamembranes

uarr insulin secretionLow costdarrmicrovascular

risk

Hypoglycemiaweight gain

Meglitinides RepaglinideNateglinide


uarr insulin secretion darr postprandialglucose

High costhypoglycemiaweight gain

frequent dosing

120572-Glucosidaseinhibitors

AcarboseMiglitol

Inhibitsintestinal120572-glucosidase

Slows intestinalcarbohydrate

digestionabsorption

Moderate costno

hypoglycemiadarr postprandial

glucosedarr CVD events

Modest HbA1cefficacy

gastrointestinalside effects

frequent dosing

DPP4 inhibitors

SitagliptinVildagliptinSaxagliptinLinagliptin

Inhibits DPP4activity

increasingpostprandialincretin GLP-1concentration

uarr insulin secretiondarr glucagon secretion

Nohypoglycemia

High costmodest HbA1c

efficacyangioedemapancreatitis

GLP-1 receptoragonists

ExenatideLiraglutide

Activates GLP-1receptors

uarr insulin secretiondarr glucagon secretionuarr satiety

slows gastricemptying

Nohypoglycemiaweight loss

High costgastrointestinalside effects

acutepancreatitis

Bile acidsequestrants Colesevelam

Binds bile acidsin intestinal

tract increasinghepatic bile acidproduction

darr hepatic glucoseproductionuarr incretin levels

Nohypoglycemiadarr LDL


efficacyconstipationuarr triglycerides

Dopamine 2agonists Bromocriptine

Activatesdopaminergicreceptors

Modulateshypothalamicregulation ofmetabolismuarr insulin sensitivity

Nohypoglycemiadarr CVD events


efficacydizziness

syncope nauseafatigue

Thiazolidinediones PioglitazoneRosiglitazone

Activates thenuclear

transcriptionfactor PPAR120574

uarr insulin sensitivity

NohypoglycemiauarrHDLdarr triglyceridesdarr CVD events

High costweight gainedemaheartfailure bonefractures

bladder cancer(pioglitazone)uarr LDL

Insulin

Human NPHHuman regular

LisproAspartGlulisineGlargineDetemirPremixed

Activates insulinreceptors

uarr glucose disposaldarr hepatic glucose

production

Universallyeffectivedarrmicrovascular

risk

Variable costhypoglycemiaweight gain

4 PPAR Research

such as fluid retention weight gain hepatotoxicity (onlyfor troglitazone) plasma-volume expansion hemodilutionedema and congestive heart failure it is unknown if thetoxicity is mediated by the activation of PPAR120574 or if it isdue to some other mechanism unique to the TZD drugsince neither rosiglitazone nor pioglitazone has displayedthe increased incidence of hepatic adverse events seen withtroglitazone suggesting that hepatotoxicitymay not be a classeffect of PPAR120574 agonists [6 7 29ndash32] it has been proposedthat the fluid adverse effects may be due to the regulationof PPAR120574 through an unknown mechanism involved in theenhancement of urinary vasopressin excretion response [33ndash35]

Peroxisome Proliferator-Activated Receptors (PPARs) PPARsare nuclear receptors that belong to the thyroidretinoidnuclear family which act as ligand activated transcrip-tion factors Three isoforms for these receptors have beendescribed 120572 120573120575 and 120574 regulating tissue specific targetgenes involved in biological pathways for lipid and glucosehomeostasis PPAR120572 is expressed predominantly in the liverheart and BAT where it expresses genes involved in fattyacid oxidation its exogenous ligands are the hypolipidemicfibrate drugs PPAR 120573120575 is expressed in all kinds of tissuesand has a crucial role in fatty acid oxidation mainly inskeletal muscle liver and heart PPAR120574 is highly expressedin both WAT and BAT where it functions as a regulatorof adipogenesis and as a modulator of lipid metabolismand insulin sensitivity Activation of PPAR120574 is crucial forcontrolling gene networks involved in glucose homeostasisincluding increasing the expression of glucose transportertype 4 (GLUT4) adiponectin resistin and tumor necrosisfactor 120572 (TNF120572) which negatively influence insulin sen-sitivity All three isotypes of PPARs but mainly PPAR120574are ligand activated transcription factors implicated in thephysiopathology of various diseases including DM2 obesitydyslipidemia atherosclerosis neoplastic diseases tumorsinflammatory conditions and neurodegenerative diseases byforming obligate heterodimers with the retinoid X receptor(RXR) promoting the dissociation of corepressors recruit-ment of coactivators and the subsequent transcription oftarget genes [3 6 12 13 36ndash42]

So far three isoforms for PPAR120574 have been described 12057411205742 and 1205743 which arise as the product of different promoterusage mRNA of PPAR1205741 and PPAR1205743 code for the sameprotein while PPAR1205742 codes for a different protein con-taining 30 NH

2-terminal amino acids due to an alternative

promoter usage and mRNA splicing but no physiologicallyrelevant differences in the function of these two isoforms havebeen determined [9 29 37 38 43] PPAR120574 is organized inmain functional domains The amino terminal AB domaincontains a ligand dependent transactivation function (AF-1) while the C domain is the central DNA binding domainby containing two zinc finger-like structures and one 120572helical DNA binding motif the EF domain is the ligandbinding domain (LBD) which contains a ligand dependenttransactivation function (AF-2) which allows the receptorsrsquoconformational changes in the presence of the ligand leadingto the recruitment of coactivators such as the steroid receptor

AB C D E F

AF-

2

DNA bindingdomain

Ligand binding domain

Figure 2 Main functional domains of nuclear PPARs All threeisotypes of PPAR have 4main functional domains AB which is theactivation function 1 (AF-1) C or DNA binding domain D whichserves as a hinge between C and EF and EF which includes AF-2a ligand binding dimerization transactivation domain

H1

H2

H3

H4

H5

H6H7

H8

H9

H10

H11

H12

SRC

S1

S2

S3S4

H2998400

H3998400

Figure 3 Crystal structure of PPAR120574 (PDB 2PRG entry) cocrys-talized with rosiglitazone (ligand) and steroid receptor coactivator1 (SRC-1 coactivator) Figure constructed using Visual MolecularDynamics (VMD) software

coactivator type 1 (SRC-1) and the release of corepressors(Figure 2) [12 44ndash47]

The PPAR120574 LBD contains a large binding pocket thatallows a wide range of ligands searching for their properconformations in order to form ligand-receptor complexesNatural ligands of PPAR120574 are fatty acids while syntheticligands can be classified as either full or partial agonistssuch as TZDs L-tyrosine analogs and some nonsteroidalanti-inflammatory drugs [7 8 12 30 31 39 44 48ndash50] Thestructure of the LBD is comprised of 13 helices and 4 120573 sheetswith a total volume of approximately 1300 to 1400 A Thecavity is Y shaped consisting of an entrance which extendsfrom the surface of the protein and then it branches offinto two arms arm I which extends toward the AF-2 (helixH12) and arm II situated between helix H3 and the 120573 sheet(Figure 3) [44 45 47 51] An important step during theactivation process involves ligand-induced alteration of theconformation of H12 to an active position The main modelfor ligand dependent activation of nuclear receptors proposesthat agonists stabilize a specific conformation of the AF2(H12) helix which along with helices 3 and 4 providesa suitable interface for binding a coactivator acting as a

PPAR Research 5

PPRE

GLUT4aP2AdiponectinTNF120572CD36eNOSLPLGPxSODCATNOX4MCP-1Trx-1FGF1FGF21

aP-1NF-120581BLeptinSTATIL-1120573IL-6AT1RAldose reductaseMMP-9CRPResistin

TZDPPAR120574

SRC-1 (Coactivator)

RXR

Retinoicacid

Nucleus

Transcription

mRNA Protein

Biologicalactivity

Cytoplasm

5998400 3998400

Figure 4 Mechanism of action of PPAR120574 when it is activated by its exogenous ligands thiazolidinediones (TZDs)

molecular switch and creating a binding cleft on the receptorfor the coactivator [8 13 45]

TZDs are one of the most known PPAR120574 agonists Theyshare common features such as a hydrophilic head group acentral hydrophobic body and a flexible linker to a cyclic tailThe hydrophilic head group can have a hydroxyl carbonylor carboxyl oxygen atoms allowing it to form H bonds withthe key amino acid residues Tyr 473 (AF2 H12) His 449(H11) His323 (H5) Ser289 (H3) and Gln286 (H3) of theLBD generating an intermolecular network exclusive for fullagonists These H bond networks stabilize the receptor inthe proper conformation however the acid head group ofcommercially available TZDs is prone to racemization underphysiological conditions due to its stereogenic center at C5and it has been demonstrated that only the (S)-enantiomersbind to the receptor which suggests that approximately50 of the active substance is inactive Binding of theseligands results in conformational changes of the receptorsthat facilitate their interaction with coactivator proteins Theresulting complexes activate the transcription of specifictarget genes resulting in the induction of signaling cascadesthat mediate the physiological effects of the ligands (Figure 4)[7ndash10 12 29ndash31 39 43 44 47ndash52]

PPAR120574 and Inflammatory Diseases Both PPAR120572 and PPAR120574isotypes participate in the regulation of inflammation pro-cesses PPAR120572 regulates primarily catabolic and PPAR120574regulates primarily anabolic aspects of lipid metabolism [1329 43]

Prostaglandin J2 (PGJ2) activation of PPAR120574 has beendemonstrated to antagonize the activity of activator pro-tein type 1 (aP-1) which enhances the angiogenic responseseen in the diabetic microvascular complications [53] andthe signal transducer and activator of transcription (STAT)protein which regulates the inflammation cascade [54] andthe nuclear factor 120581B (NF-120581B) which also regulates theinflammation cascade mainly in adipocytes [51] these areknown for their positive control on cytokine gene expression[6 12 36 37 39ndash41]

Diverse theories propose the molecular mechanisms bywhich PPAR120574 exhibits anti-inflammatory effects amongthese theories it can be mentioned that the expression of thereceptor is upregulated by oxidized low density lipoproteins(LDL) in macrophages which will in turn stimulate theexpression of the cluster of differentiation 36 (CD36) scav-enger receptor gene resulting in a higher rate of oxidized LDLinternalization which besides serving as a fatty acid trans-porter is a novel biomarker for DM2 [55 56] but it is alsopostulated that the expressions of inflammatory mediatorssuch as tumor necrosis factor 120572 (TNF120572) interleukin 6 (IL-6) and matrix metallopeptidase 9 (MMP-9) are negativelycontrolled by PPAR120574 which in turn takes importance forthe development of atherosclerosis [50 57] It is also possiblethat PPAR120574 ligands act as anti-inflammatory and antioxidantagents through the inhibition of the transcription factor NF-120581Bp65 and the expression of NADPH oxidase 4 (NOX4)thus reducing the levels of IL-6 C-reactive protein (CRP)and monocyte chemoattractant protein 1 (MCP-1) but it

6 PPAR Research

has also been postulated that PPAR120574 activation directlyregulates the expression of endogenous antioxidants suchas superoxide dismutase (SOD) catalase (CAT) glutathioneperoxidase (GPx) and thioredoxin (Trx-1) therefore playinga crucial role in cardiac redox balance [58ndash61]

Since diabetic vascular complications are partly mediatedby inflammatory processes the use of TZDs may contributepositively to patientsrsquo outcomes since insulin sensitizers sup-press the inflammatory processes not only through loweringhyperglycemia but also by modulating the expression of keyinflammatory biomarkers as can be seen in Figure 1 Theseeffects may be potentiated when TZDs are used along withother drugs for example statins fibrates and inhibitorsof renin-angiotensin-aldosterone system which reduce theoverall risk for DM2 [62 63]

It also has been seen that TZDsmay exert antiatherogeniceffects on vessel wall cells possibly by downregulating NF-120581Binflammatory pathways [62 63]

PPAR120574 and Metabolic Disorders PPAR120574 is predominatelyexpressed in adipose tissue but it is also expressed in thelungs placenta heart and leukocytes where it regulates lipidglucose and insulin uptake into adipocytes as it is responsi-ble for regulating the expression of two markers of terminaladipocyte differentiation adipocyte protein type 2 (aP-2) andphosphoenolpyruvate carboxykinase PPAR120574 is also in chargeof regulating the expression of the genes which code forlipoprotein lipase (LPL) increasing triglycerides lipolysis invery low density lipoproteins (VLDLs) and increasing highdensity lipoproteins (HDLs) [62] the fatty acid transportprotein which regulates fatty acid uptake and fatty acidtranslocase which enhances fatty acid uptake in adipocytesas the repression of the expression of the ob gene for leptinwhich increases the appetite (Figure 4) and this is concordantwith the physiological effects of TZDs such as lowering bloodglucose levels and improving insulin sensitivity [3 12 1329 32 42 57] However adipogenesis caused in response totreatment with TZDs has been linked mainly to the identi-fication of two PPAR120574-responsive members of the fibroblastgrowth factor family fibroblast growth factor 1 (FGF1) andfibroblast growth factor 21 (FGF21) which act locally invisceral adipose tissue promoting insulin sensitization sothat the activation of the receptor in the brain rather than inadipose tissue has a major role in TZD-induced weight gain[13]

Obesity rates and westernization of lifestyle lead to theincrease of dysfunctional adipose tissue which constantlyactivates NF-120581B and delivers inflammatory cytokines suchas TNF120572 resistin IL-6 and IL-1120573 which along with theimpairment of reactive oxygen species (ROS) and waterretention are mainly present in a wide range of diseaseslike insulin resistance DM2 hypertension hyperlipidemiaand cardiovascular diseases (CVD) therefore maintaining achronic inflammatory environment [1 14 58 64ndash67]

Insulin resistance has been identified as a major contrib-utor to the development of DM2 and metabolic syndromesince it increases the delivery of fatty acids (FA) into thecirculation which modulate the ability of the heart to useglucose as a source of energy [59 66 68ndash71] leading to a

cellular stress characterized by an excessive ROS productionimpaired state of nitric oxide (NO) vasorelaxation produc-tion of inflammatory cytokines mitochondrial dysfunctionincreased advanced glycation end products (AGEs) anddysfunction of endothelial progenitor cells as the inhibitionof the antiatherogenic adipokine adiponectin [15 59 64 6668ndash72]

PPAR120574 is highly expressed in the vascular system whereit is involved in the repression or expression of certain genessuch as angiotensin type 1 receptor (AT1R) which can preventor ameliorate endothelial dysfunction and atherosclerosis[3 15 16 60 67 73 74] In accordance with this it hasbeen seen that in animal models repression of the expres-sion of PPAR120574 promotes cardiomyopathy lipid depositionarrhythmias hypertrophy and increased expression of car-diac inflammatory markers [61 66 70 71] It has also beenshown that adiponectin increases through PPAR-responsiveelement in the promoter of adipocytes playing an essentialrole for the vascular protective effects of PPAR120574 agonists asthe case where diabetic dbdbmice treated with rosiglitazonestimulated the release of adiponectin which activated AMPactivated protein kinase (AMPKeNOS) and protein kinase A(cAMPPKA) pathways in the aorta consequently leading tothe reduction of oxidative stress and the enhancement of NObioavailability improving endothelial function [15 58 75]It has also been seen either in clinical practice or in animalmodels that the continuous treatment with TZDs tends toattenuate the progression of carotid artery intimamediathickness reducing the onset of restenosis mainly due to theinhibition of smooth cell migration the increased apoptosisin vascular smooth cells and the prevention of insulindriven atherosclerosis by switching myocardial substratemetabolism toward glucose [14 70 73 74 76]

PPAR120574 and Cardiovascular Diseases CVD and DM2 areintimately linked as they share some pathophysiologicalfeatures [76] for example the development of atherosclerosiswhich may lead to myocardial infarction coronary heartdisease peripheral artery disease and critical limb ischemia[77]

It has been previously found that CVD increase the rate ofcardiovascular death nearly fivefold in subjects with diabetesmainly due to myocardial infarction Also the relevance ofdiabetes for the development of atherosclerosis has beenmade clear through the observation that amajority of patientswith coronary heart disease have insulin resistance or havebeen diagnosed with frank diabetes [77 78]

The use of TZDs has been controversial in terms ofprevention ofCVD since it has been shown that these types ofdrugs induce and maintain the regression of carotid intima-media thickness in patients with type 2 diabetes as theyhave been related to anti-inflammatory and antiproliferativeactivities in smoothmuscle cells inhibiting the atheromatousplaque progression [13 77] Another substantial side effect ofTZDs is the fluid retention with associated peripheral edemaby the alteration of sodium and water reabsorption in thedistal collecting ducts of the kidney which increases the riskfor adverse cardiovascular events such as congestive heartfailure [13]

PPAR Research 7

PPAR120574 and Bone Fractures The use of TZDs has beenrelated to bone fractures especially rosiglitazone whichexhibited an increased risk of fractures in comparison withpatients receiving metformin or glyburide [28] On theother hand pioglitazone exhibited an increased incidenceof distal extremity fractures on the PRO-active trial [3]These fractures may be due to the expression of PPAR120574 inbone narrow stromal cells osteoblasts and osteoclasts [28]which promotes an alteration on the mesenchymal stem cellmaturation leading to a shift from an osteoblastic lineageto the adipogenic lineage which turns into an accumulationof ROS and apoptosis of the cells in the osteogenic lineagethereby decreasing bone formation [13 28]

2 Conclusions

A great number of studies have shown that the activationof PPAR120574 is implicated in the development of undesirableadverse effects such as fluid retention weight gain hepa-totoxicity plasma-volume expansion hemodilution edemabone fractures and congestive heart failure but it is alsoinvolved in the prevention of developing atherosclerosis eventhough there are certainly another great number of studieswhich can demonstrate the opposite and also confirm thatsome agonists of the receptor specifically rosiglitazone mayincrease CVD riskWe believe that the associated risk of CVDduringTZDs therapymay be related to different transcriptionpatterns in the PPAR120574 activation due to different ligandssince troglitazone and pioglitazone do not increase CVD riskas pioglitazone may cause bladder cancer or rosiglitazoneor troglitazone or hepatotoxicity which is directly correlatedto the use of troglitazone or the other TZDs as theyinteract in different ways with the receptor and thereforeinduce different conformations and different interactionswith coactivatorscorepressors as different interactions withthe responsive element therefore triggering the transcriptionof diverse genes According to these it would be importantto investigate the different conformations of the receptor inthe presence of different ligands either endogenous or exoge-nous so that it would be possible to predict which coactivatoror corepressor is more susceptible to be recruited as thepossible biochemical and physiological effects of each one Bydoing this prediction it would be possible to design betterligands derived from TZDs with less adverse effects and itwould also be possible to use them for the treatment of otherdiseases such as cancer metabolic syndrome hypertensionobesity and even CVD

Disclosure

The authors alone are responsible for the content and writingof the paper

Competing Interests

Theauthors have no conflict of interests in the use ofmaterialsor techniques mentioned in this review

Acknowledgments

The authors are grateful to Secretarıa de Investigacion y Pos-grado IPN (SIP20161383SIP20160675) CONACyT (I01005322014) SIBE (COFFA) and EDI (SIP)IPN Mexico

References

[1] S E Inzucchi RM Bergenstal J B Buse et al ldquoManagement ofhyperglycemia in type 2 diabetes a patient-centered approachposition statement of the American Diabetes Association(ADA) and the European Association for the Study of Diabetes(EASD)rdquo Diabetes Care vol 35 no 6 pp 1364ndash1379 2012

[2] A Qaseem L L Humphrey D E Sweet M Starkey andP Shekelle ldquoOral pharmacologic treatment of type 2 diabetesmellitus a clinical practice guideline from the American collegeof physiciansrdquo Annals of Internal Medicine vol 156 no 3 pp218ndash231 2012

[3] B Grygiel-Gorniak ldquoPeroxisome proliferator-activated recep-tors and their ligands nutritional and clinical implicationsmdashareviewrdquo Nutrition Journal vol 13 article 17 10 pages 2014

[4] S Alex K Lange T Amolo et al ldquoShort-chain fatty acidsstimulate angiopoietin-like 4 synthesis in human colon adeno-carcinoma cells by activating peroxisome proliferator-activatedreceptor 120574rdquo Molecular and Cellular Biology vol 33 no 7 pp1303ndash1316 2013

[5] A A Onitilo J M Engel I Glurich R V Stankowski G MWilliams and S A Doi ldquoDiabetes and cancer II role of diabetesmedications and influence of shared risk factorsrdquoCancer Causesamp Control vol 23 no 7 pp 991ndash1008 2012

[6] R K Petersen K B Christensen A N Assimopoulou et alldquoPharmacophore-driven identification of PPAR120574 agonists fromnatural sourcesrdquo Journal of Computer-Aided Molecular Designvol 25 no 2 pp 107ndash116 2011

[7] H J Gim H Li E Lee J-H Ryu and R Jeon ldquoDesignand synthesis of alkoxyindolyl-3-acetic acid analogs as perox-isome proliferator-activated receptor-120574120575 agonistsrdquo Bioorganicamp Medicinal Chemistry Letters vol 23 no 2 pp 513ndash517 2013

[8] J C Dos Santos A Bernardes L Giampietro et al ldquoDifferentbinding and recognition modes of GL479 a dual agonist ofPeroxisome Proliferator-Activated Receptor 120572120574rdquo Journal ofStructural Biology vol 191 no 3 pp 332ndash340 2015

[9] F A Monsalve R D Pyarasani F Delgado-Lopez and RMoore-Carrasco ldquoPeroxisome proliferator-activated receptortargets for the treatment of metabolic diseasesrdquo Mediators ofInflammation vol 2013 Article ID 549627 18 pages 2013

[10] V R Avupati R P Yejella A Akula et al ldquoSynthesischaracterization and biological evaluation of some novel 24-thiazolidinediones as potential cytotoxic antimicrobial andantihyperglycemic agentsrdquo Bioorganic amp Medicinal ChemistryLetters vol 22 no 20 pp 6442ndash6450 2012

[11] SMandard andD Patsouris ldquoNuclear control of the inflamma-tory response inmammals by peroxisome proliferator-activatedreceptorsrdquo PPAR Research vol 2013 Article ID 613864 23pages 2013

[12] J A Youssef andM Z Badr ldquoPeroxisome proliferator-activatedreceptors discovery and recent advancesrdquo in PeroxisomeProliferator-Activated Receptors chapter 3 Springer 2013

[13] M Ahmadian J M Suh N Hah et al ldquoPPAR120574 signaling andmetabolism the good the bad and the futurerdquoNatureMedicinevol 19 no 5 pp 557ndash566 2013

8 PPAR Research

[14] H M Garcıa-Garcıa S Garg S Brugaletta et al ldquoEvaluation ofin-stent restenosis in the APPROACH trial (assessment on theprevention of progression by Rosiglitazone on atherosclerosisin diabetes patients with cardiovascular history)rdquo The Interna-tional Journal of Cardiovascular Imaging vol 28 no 3 pp 455ndash465 2012

[15] P Balakumar and S Kathuria ldquoSubmaximal PPAR120574 activa-tion and endothelial dysfunction new perspectives for themanagement of cardiovascular disordersrdquo British Journal ofPharmacology vol 166 no 7 pp 1981ndash1992 2012

[16] Y Atamer A Atamer A S Can et al ldquoEffects of rosiglitazoneon serum paraoxonase activity and metabolic parameters inpatients with type 2 diabetes mellitusrdquo Brazilian Journal ofMedical and Biological Research vol 46 no 6 pp 528ndash532 2013

[17] Y Lu D Ma W Xu S Shao and X Yu ldquoEffect and cardiovas-cular safety of adding rosiglitazone to insulin therapy in type 2diabetes a meta-analysisrdquo Journal of Diabetes Investigation vol6 no 1 pp 78ndash86 2015

[18] M M Elmazar H S El-Abhar M F Schaalan and N A FaragldquoPhytolphytanic acid and insulin resistance potential role ofphytanic acid proven by docking simulation and modulationof biochemical alterationsrdquo PLoS ONE vol 8 no 1 Article IDe45638 2013

[19] V A Dixit and P V Bharatam ldquoSAR and computer-aided drugdesign approaches in the discovery of peroxisome proliferator-activated receptor 120574 activators a perspectiverdquo Journal of Com-putationalMedicine vol 2013 Article ID406049 38 pages 2013

[20] M Takahashi ldquoGlycation of proteinsrdquo in Glycoscience Biologyand Medicine pp 1339ndash1345 Springer Berlin Germany 2015

[21] M A Babizhayev I A Strokov V V Nosikov et al ldquoThe roleof oxidative stress in diabetic neuropathy generation of freeradical species in the glycation reaction and gene polymor-phisms encoding antioxidant enzymes to genetic susceptibilityto diabetic neuropathy in population of type I diabetic patientsrdquoCell Biochemistry and Biophysics vol 71 no 3 pp 1425ndash14432015

[22] M Soltesova-Prnova J Ballekova A Gajdosikova A GajdosikandM Stefek ldquoAnovel carboxymethylatedmercaptotriazinoin-dole inhibitor of aldose reductase interferes with the polyolpathway in streptozotocin-induced diabetic ratsrdquo PhysiologicalResearch vol 64 no 4 pp 587ndash591 2015

[23] A K Tiwari D A Kumar P S R Sweeya et al ldquoVegetablesrsquojuice influences polyol pathway by multiple mechanisms infavour of reducing development of oxidative stress and resultantdiabetic complicationsrdquo Pharmacognosy Magazine vol 10 no38 pp 383ndash391 2014

[24] K M Juskova P M Soltesova andM Stefek ldquoA novel zwitteri-onic inhibitor of aldose reductase interfereswith polyol pathwayin an ex vivo and in vivo models of diabetic complicationsrdquoPharmazie vol 69 no 10 pp 747ndash751 2014

[25] W Wahli and L Michalik ldquoPPARs at the crossroads oflipid signaling and inflammationrdquo Trends in Endocrinology ampMetabolism vol 23 no 7 pp 351ndash363 2012

[26] S-S Choi J Park and J H Choi ldquoRevisiting PPAR120574 as a targetfor the treatment of metabolic disordersrdquo BMB Reports vol 47no 11 pp 599ndash608 2014

[27] R N Lamounier C N Coimbra PWhite et al ldquoApoptosis rateand transcriptional response of pancreatic islets exposed to thePPAR gamma agonist pioglitazonerdquo Diabetology amp MetabolicSyndrome vol 5 no 1 pp 1ndash10 2013

[28] J P Bilezikian R G Josse R Eastell et al ldquoRosiglitazonedecreases bone mineral density and increases bone turnover

in postmenopausal women with type 2 diabetes mellitusrdquo TheJournal of Clinical Endocrinology amp Metabolism vol 98 no 4pp 1519ndash1528 2013

[29] V A Verma B Halu and V R Kulkarni ldquoUnderstanding theantihyperglycemic agents of thiazolidinediones analogues usingquantitative structure activity relationship (QSAR) modelsrdquoWorld Journal of Pharmaceutical Sciences vol 3 no 3 pp 2212ndash2221 2014

[30] M-C Cho D-H Lee E J Kim et al ldquoNovel PPAR120574 partialagonists with weak activity and no cytotoxicity identified by asimple PPAR120574 ligand screening systemrdquoMolecular and CellularBiochemistry vol 358 no 1-2 pp 75ndash83 2011

[31] L Wang B Waltenberger E-M Pferschy-Wenzig et al ldquoNatu-ral product agonists of peroxisome proliferator-activated recep-tor gamma (PPAR120574) a reviewrdquo Biochemical Pharmacology vol92 no 1 pp 73ndash89 2014

[32] B FCariou R Hanf S Lambert-Porcheron et al ldquoDual per-oxisome proliferator-activated receptor 120572120575 agonist GFT505improves hepatic and peripheral insulin sensitivity in abdom-inally obese subjectsrdquo Diabetes Care vol 36 no 10 pp 2923ndash2930 2013

[33] L Zhou A Panasiuk M Downton et al ldquoSystemic PPAR120574deletion causes severe disturbance in fluid homeostasis inmicerdquoPhysiological Genomics vol 47 no 11 pp 541ndash547 2015

[34] L Zhou G Liu Z Jia et al ldquoIncreased susceptibility of dbdbmice to rosiglitazone-induced plasma volume expansion role ofdysregulation of renal water transportersrdquo American Journal ofPhysiologymdashRenal Physiology vol 305 no 10 pp F1491ndashF14972013

[35] S Horita M Nakamura N Satoh M Suzuki and G SekildquoThiazolidinediones and edema recent advances in the patho-genesis of thiazolidinediones-induced renal sodium retentionrdquoPPAR Research vol 2015 Article ID 646423 7 pages 2015

[36] S Hidalgo-Figueroa J J Ramırez-Espinosa S Estrada-Soto etal ldquoDiscovery of thiazolidine-24-dionebiphenylcarbonitrilehybrid as dual ppar 120572120574 modulator with antidiabetic effect invitro in silico and in vivo approachesrdquoChemical BiologyampDrugDesign vol 81 no 4 pp 474ndash483 2013

[37] H Zhang C Z Ding Z Lai et al ldquoSynthesis and biologicalevaluation of novel pyrrolidine acid analogs as potent dualPPAR120572120574 agonistsrdquo Bioorganic amp Medicinal Chemistry Lettersvol 25 no 6 pp 1196ndash1205 2015

[38] J Ye ldquoMechanisms of insulin resistance in obesityrdquo Frontiers ofMedicine vol 7 no 1 pp 14ndash24 2013

[39] A Carrieri M Giudici M Parente et al ldquoMolecular determi-nants for nuclear receptors selectivity chemometric analysisdockings and site-directed mutagenesis of dual peroxisomeproliferator-activated receptors 120572120574 agonistsrdquo European Journalof Medicinal Chemistry vol 63 pp 321ndash332 2013

[40] A Laghezza G Pochetti A Lavecchia et al ldquoNew 2-(aryloxy)-3-phenylpropanoic acids as peroxisome proliferator-activatedreceptor 120572120574 dual agonists able to upregulate mitochondrialcarnitine shuttle system gene expressionrdquo Journal of MedicinalChemistry vol 56 no 1 pp 60ndash72 2013

[41] P Garcıa-Rojas A Antaramian L Gonzalez-Davalos et alldquoInduction of peroxisomal proliferator-activated receptor 120574and peroxisomal proliferator-activated receptor 120574 coactivator1 by unsaturated fatty acids retinoic acid and carotenoidsin preadipocytes obtained from bovine white adipose tissuerdquoJournal of Animal Science vol 88 no 5 pp 1801ndash1808 2010

[42] I J Lodhi L Yin A P L Jensen-Urstad et al ldquoInhibiting adi-pose tissue lipogenesis reprograms thermogenesis and PPAR120574

PPAR Research 9

activation to decrease diet-induced obesityrdquo Cell Metabolismvol 16 no 2 pp 189ndash201 2012

[43] R M Evans and D J Mangelsdorf ldquoNuclear receptors RXRand the big bangrdquo Cell vol 157 no 1 pp 255ndash266 2014

[44] L Zhang X-M Ren B Wan and L-H Guo ldquoStructure-dependent binding and activation of perfluorinated compoundson human peroxisome proliferator-activated receptor 120574rdquo Toxi-cology and Applied Pharmacology vol 279 no 3 pp 275ndash2832014

[45] T S Hughes M J Chalmers S Novick et al ldquoLigand andreceptor dynamics contribute to the mechanism of gradedPPAR120574 agonismrdquo Structure vol 20 no 1 pp 139ndash150 2012

[46] J Burston and D Kendall ldquoPeroxisome proliferator-activatedreceptors and inflammationrdquo in endoCANNABINOIDS Actionsat Non-CB

1CB2Cannabinoid Receptors M E Abood R G

Sorensen and N Stella Eds vol 24 of The Receptors pp 221ndash233 2012

[47] A J Kroker and J B Bruning ldquoReview of the structuraland dynamic mechanisms of PPAR120574 partial agonismrdquo PPARResearch vol 2015 Article ID 816856 15 pages 2015

[48] B Xiao J Yin M Park et al ldquoDesign and synthesis of marinefungal phthalide derivatives as PPAR-120574 agonistsrdquo Bioorganicand Medicinal Chemistry vol 20 no 16 pp 4954ndash4961 2012

[49] A Georgiadi and S Kersten ldquoMechanisms of gene regulationby fatty acidsrdquo Advances in Nutrition vol 3 no 2 pp 127ndash1342012

[50] H J Gim Y-J Cheon J-H Ryu and R Jeon ldquoDesign and syn-thesis of benzoxazole containing indole analogs as peroxisomeproliferator-activated receptor-120574120575 dual agonistsrdquo Bioorganic ampMedicinal Chemistry Letters vol 21 no 10 pp 3057ndash3061 2011

[51] D Moras I M L Billas N Rochel and B P KlaholzldquoStructure-function relationships in nuclear receptors thefactsrdquoTrends in Biochemical Sciences vol 40 no 6 pp 287ndash2902015

[52] P Ketsawatsomkron and C D Sigmund ldquoMolecular mech-anisms regulating vascular tone by peroxisome proliferatoractivated receptor gammardquo Current Opinion in Nephrology andHypertension vol 24 no 2 pp 123ndash130 2015

[53] J Jia T Ye P Cui Q Hua H Zeng and D Zhao ldquoAP-1transcription factor mediates VEGF-induced endothelial cellmigration and proliferationrdquo Microvascular Research vol 105pp 103ndash108 2016

[54] Y Liu X Ge X Dou et al ldquoProtein Inhibitor of Activated STAT1 (PIAS1) protects against obesity-induced insulin resistance byinhibiting inflammation cascade in adipose tissuerdquo Diabetesvol 64 no 12 pp 4061ndash4074 2015

[55] M J Alkhatatbeh A K Enjeti S Acharya R F Thorne andL F Lincz ldquoThe origin of circulating CD36 in type 2 diabetesrdquoNutrition amp Diabetes vol 3 article e59 2013

[56] S Gautam A C Gupta and B Monisha ldquoCD36 gene variantsin early prediction of type 2 diabetes mellitusrdquo Genetic Testingand Molecular Biomarkers vol 19 no 3 pp 144ndash149 2015

[57] P Bozaykut B Karademir B Yazgan et al ldquoEffects of vitamine on peroxisome proliferator-activated receptor 120574 and nuclearfactor-erythroid 2-related factor 2 in hypercholesterolemia-induced atherosclerosisrdquo Free Radical Biology andMedicine vol70 pp 174ndash181 2014

[58] T Kim and Q Yang ldquoPeroxisome-proliferator-activated recep-tors regulate redox signaling in the cardiovascular systemrdquoWorld Journal of Cardiology vol 5 no 6 pp 164ndash174 2013

[59] K M Ali A Wonnerth K Huber and J Wojta ldquoCardio-vascular disease risk reduction by raising HDL cholesterolmdashcurrent therapies and future opportunitiesrdquo British Journal ofPharmacology vol 167 no 6 pp 1177ndash1194 2012

[60] M Auclair C Vigouroux F Boccara et al ldquoPeroxisomeproliferator-activated receptor-120574 mutations responsible forlipodystrophy with severe hypertension activate the cellularrenin-angiotensin systemrdquo Arteriosclerosis Thrombosis amp Vas-cular Biology vol 33 no 4 pp 829ndash838 2013

[61] H He H Tao H Xiong et al ldquoRosiglitazone causes car-diotoxicity via peroxisome proliferator-activated receptor amp-independent mitochondrial oxidative stress in mouse heartsrdquoToxicological Sciences vol 138 no 2 pp 468ndash481 2014

[62] A J Scheen N Esser and N Paquot ldquoAntidiabetic agentspotential anti-inflammatory activity beyond glucose controlrdquoDiabetes amp Metabolism vol 41 no 3 pp 183ndash194 2015

[63] N Esser N Paquot and A J Scheen ldquoAnti-inflammatoryagents to treat or prevent type 2 diabetes metabolic syndromeand cardiovascular diseaserdquo Expert Opinion on InvestigationalDrugs vol 24 no 3 pp 283ndash307 2015

[64] E Fuentes L Guzman-Jofre R Moore-Carrasco and IPalomo ldquoRole of PPARs in inflammatory processes associ-ated with metabolic syndrome (Review)rdquo Molecular MedicineReports vol 8 no 6 pp 1611ndash1616 2013

[65] H E Bays ldquoAdiposopathy is lsquosick fatrsquo a cardiovascular diseaserdquoJournal of the American College of Cardiology vol 57 no 25 pp2461ndash2473 2011

[66] E D Abel K M OrsquoShea and R Ramasamy ldquoInsulin resistancemetabolic mechanisms and consequences in the heartrdquo Arte-riosclerosis Thrombosis amp Vascular Biology vol 32 no 9 pp2068ndash2076 2012

[67] B M Y Cheung and C Li ldquoDiabetes and hypertension isthere a common metabolic pathwayrdquo Current AtherosclerosisReports vol 14 no 2 pp 160ndash166 2012

[68] U J Jung and M-S Choi ldquoObesity and its metabolic compli-cations the role of adipokines and the relationship betweenobesity inflammation insulin resistance dyslipidemia andnonalcoholic fatty liver diseaserdquo International Journal of Molec-ular Sciences vol 15 no 4 pp 6184ndash6223 2014

[69] J V Huang C R Greyson and G G Schwartz ldquoPPAR-amp asa therapeutic target in cardiovascular disease evidence anduncertaintyrdquo Journal of Lipid Research vol 53 no 9 pp 1738ndash1754 2012

[70] T H-W Huang and B D Roufogalis ldquoHealing the dia-betic heart modulation of cardiometabolic syndrome throughperoxisome proliferator activated receptors (PPARs)rdquo CurrentMolecular Pharmacology vol 5 no 2 pp 241ndash247 2012

[71] K Drosatos R S Khan C M Trent et al ldquoPeroxisomeproliferator-activated receptor-120574 activation prevents sepsis-related cardiac dysfunction and mortality in micerdquo CirculationHeart Failure vol 6 no 3 pp 550ndash562 2013

[72] P Balakumar and N Mahadevan ldquoInterplay between statinsand PPARs in improving cardiovascular outcomes a double-edged swordrdquo British Journal of Pharmacology vol 165 no 2pp 373ndash379 2012

[73] C Giaginis C Klonaris A Katsargyris G Kouraklis CSpiliopoulou and S Theocharis ldquoCorrelation of peroxisomeproliferator-activated receptor-120574 (PPAR-120574) and retinoid xreceptor-120572 (RXR-120572) expression with clinical risk factors inpatients with advanced carotid atherosclerosisrdquoMedical ScienceMonitor vol 17 no 7 pp CR381ndashCR391 2011

10 PPAR Research

[74] U J Jung C Torrejon C L Chang H Hamai T S Worgalland R J Deckelbaum ldquoFatty acids regulate endothelial lipaseand inflammatorymarkers inmacrophages and inmouse aortaa role for PPAR120574rdquo Arteriosclerosis Thrombosis amp VascularBiology vol 32 no 12 pp 2929ndash2937 2012

[75] M Hulsmans B Geeraert T Arnould C Tsatsanis andP Holvoet ldquoPPAR agonist-induced reduction of Mcp1 inatherosclerotic plaques of obese insulin-resistantmice dependson adiponectin-induced Irak3 expressionrdquo PLoS ONE vol 8no 4 Article ID e62253 2013

[76] Y Huang A Di Lorenzo W Jiang A Cantalupo W C Sessaand F J Giordano ldquoHypoxia-inducible factor-1120572 in vascularsmooth muscle regulates blood pressure homeostasis througha peroxisome proliferator-activated receptor-120574-angiotensin IIreceptor type 1 axisrdquo Hypertension vol 62 no 3 pp 634ndash6402013

[77] J A Beckman F Paneni F Cosentino and M A CreagerldquoDiabetes and vascular disease pathophysiology clinical conse-quences and medical therapy part IIrdquo European Heart Journalvol 34 no 31 pp 2444ndash2456 2013

[78] C V Araujo V Estato E Tibirica P T Bozza H C Castro-Faria-Neto and A R Silva ldquoPPAR gamma activation pro-tects the brain against microvascular dysfunction in sepsisrdquoMicrovascular Research vol 84 no 2 pp 218ndash221 2012

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

2 PPAR Research

Glucose autooxidation

120572-D-glucose Glucose enediol

Enediol radical

Ketoaldehyde Oxidative stress

Polyolsrsquo pathway

Glucose Sorbitol Fructose

NADPH depletion

GSH depletion

Advanceglycation end

products (AGEs) Glycolysis

Protein modification

Tissueaccumulation

NF-120581B activation

Proinflammatoryenvironment

VEGF expression

Glycerol-3-phosphate

diacylglycerolincrease

PKC activation O2

Fe3+

Hyperglycemia

Complications

O2∙minus

Figure 1 The main pathways triggered by hyperglycemia include glucose autooxidation and constant activation of polyolsrsquo pathway andformation of advance glycation end products (AGEs) and excessive glycolysis With the constant activation of these pathways living cellsand tissues are damaged mainly by impairment of target protein function increase in oxidative stress and activation of signal transductionpathways leading to the imbalance of normal physiological functions and therefore the development of diabetic complications

in insulin secretion of pancreatic 120573 cells insulin resistancein peripheral tissues andor an excessive accumulation oftriglycerides and fatty acid derivatives in skeletal musclesThis pathology remains a leading cause of cardiovascular dis-orders such as microvascular (retinopathy nephropathy andneuropathy) and macrovascular (coronary cerebrovascularand peripheral vascular diseases) complications mainly trig-gered by the abnormal activation of physiological pathways(Figure 1) and it is also associated with increased risk ofcancer psychiatric illness cognitive decline chronic liverdisease and development of arthritis [1ndash4 18ndash24]

The treatment of DM2 is directed toward the reductionof hyperglycemia and HbA1c (le7) in order to preventcardiovascular and other long term risks (Table 1) [1 25] there is a wide range of drugs which can be used inorder to reduce glycemia being notable mechanisms such asimproving insulin secretion and reducing insulin resistanceof peripheral tissues as the case of TZDs [1ndash5] whichare drugs targeting the peroxisome proliferator-activatedreceptor gamma (PPAR120574)

PPARs have emerged as links between lipids metabolicdiseases and innate immunity as they regulate energy home-ostasis [25 26] and specifically talking about PPAR120574 thisreceptor is capable of regulating metabolic genes which willbe further discussed and improves insulin sensitivity throughglucose and lipid uptake and storage in peripheral tissuessuch as skeletal muscle liver and adipose tissue [26]

The relationship between PPAR120574 and DM2 has beenestablished using both in vitro and in vivo experimentation

since it has been seen that the inactivation of PPAR120574 inmature adipocytes leads to insulin resistance as mice lackingthe receptor develop hyperlipidemia hyperglycemia andorhyperinsulinemia [26 27]

Thiazolidinediones (TZDs) TZDs are compounds used clin-ically as insulin sensitizers in order to lower blood glucoselevels as circulating triglycerides [4 6ndash9] but it has alsobeen shown that these also exhibit other biological activitiessuch as anti-inflammatory antimalarial antioxidant cyto-toxic antimicrobial and aldose reductase inhibitor activitieseither in vitro or in animal models [10 11] TZDs act asperoxisome proliferator-activated receptors gamma (PPAR120574)full agonists which are also involved in the increase ofadipocyte differentiation fluid retention weight gain boneloss and congestive heart failure Having such diverse rangeof pharmacological activities these molecules have a lot ofpotential uses so different strategies have been originated touse them not only for the treatment of DM2 but also for otherpathologies [2 5 6 8ndash11]

When TZDs interact with PPAR120574 the receptor reg-ulates the transcription of different genes mainly thosegenes involved in glucose homeostasis and adipogenesisspecifically within white adipose tissue (WAT) by inducingbrown adipose tissue- (BAT-) like features in it a uniquecharacteristic exclusive for PPAR120574 full agonists such asrosiglitazone [13 28]

However despite their excellent potencies the incidenceof undesirable side effects has been linked to the use of TZDs

PPAR Research 3








Sulfonylureas





risk






frequent dosing


AcarboseMiglitol



digestionabsorption

Moderate costno





frequent dosing

DPP4 inhibitors





Nohypoglycemia










acutepancreatitis













efficacydizziness









Insulin





production


risk


4 PPAR Research






AB C D E F

AF-

2

DNA bindingdomain



H1

H2

H3

H4

H5

H6H7

H8

H9

H10

H11

H12

SRC

S1

S2

S3S4

H2998400

H3998400




PPAR Research 5

PPRE



TZDPPAR120574

SRC-1 (Coactivator)

RXR

Retinoicacid

Nucleus

Transcription

mRNA Protein

Biologicalactivity

Cytoplasm

5998400 3998400







6 PPAR Research












PPAR Research 7


2 Conclusions


Disclosure


Competing Interests


Acknowledgments


References














8 PPAR Research































PPAR Research 9



































10 PPAR Research











of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















PPAR Research 3








Sulfonylureas





risk






frequent dosing


AcarboseMiglitol



digestionabsorption

Moderate costno





frequent dosing

DPP4 inhibitors





Nohypoglycemia










acutepancreatitis













efficacydizziness









Insulin





production


risk


4 PPAR Research






AB C D E F

AF-

2

DNA bindingdomain



H1

H2

H3

H4

H5

H6H7

H8

H9

H10

H11

H12

SRC

S1

S2

S3S4

H2998400

H3998400




PPAR Research 5

PPRE



TZDPPAR120574

SRC-1 (Coactivator)

RXR

Retinoicacid

Nucleus

Transcription

mRNA Protein

Biologicalactivity

Cytoplasm

5998400 3998400







6 PPAR Research












PPAR Research 7


2 Conclusions


Disclosure


Competing Interests


Acknowledgments


References














8 PPAR Research































PPAR Research 9



































10 PPAR Research











of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















4 PPAR Research






AB C D E F

AF-

2

DNA bindingdomain



H1

H2

H3

H4

H5

H6H7

H8

H9

H10

H11

H12

SRC

S1

S2

S3S4

H2998400

H3998400




PPAR Research 5

PPRE



TZDPPAR120574

SRC-1 (Coactivator)

RXR

Retinoicacid

Nucleus

Transcription

mRNA Protein

Biologicalactivity

Cytoplasm

5998400 3998400







6 PPAR Research












PPAR Research 7


2 Conclusions


Disclosure


Competing Interests


Acknowledgments


References














8 PPAR Research































PPAR Research 9



































10 PPAR Research











of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















PPAR Research 5

PPRE



TZDPPAR120574

SRC-1 (Coactivator)

RXR

Retinoicacid

Nucleus

Transcription

mRNA Protein

Biologicalactivity

Cytoplasm

5998400 3998400







6 PPAR Research












PPAR Research 7


2 Conclusions


Disclosure


Competing Interests


Acknowledgments


References














8 PPAR Research































PPAR Research 9



































10 PPAR Research











of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















6 PPAR Research












PPAR Research 7


2 Conclusions


Disclosure


Competing Interests


Acknowledgments


References














8 PPAR Research































PPAR Research 9



































10 PPAR Research











of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















PPAR Research 7


2 Conclusions


Disclosure


Competing Interests


Acknowledgments


References














8 PPAR Research































PPAR Research 9



































10 PPAR Research











of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















8 PPAR Research































PPAR Research 9



































10 PPAR Research











of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















PPAR Research 9



































10 PPAR Research











of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















10 PPAR Research











of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article current advances in the biochemical and...

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