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Not Bot Horti Agrobo 2012 40(1)314-325

Print ISSN 0255-965X Electronic 1842-4309

Notulae Botanicae Horti AgrobotaniciCluj-Napoca

Plants and Natural Compounds with Antidiabetic Action

Cristina COMAN Olivia Dumitriţa RUGINĂ Carmen SOCACIU

University o Agricultural Sciences and Veterinary Medicine Department o Chemistry and Biochemistry Mănăştur St 3-5400372 Cluj-Napoca Romania casocaciuusamvclujro socaciucarmengmailcom (corresponding author)

Abstract

Diabetes has become the most common metabolic disease worldwide In particular type 2 diabetes is the most commonlyencountered type o diabetes which is characterised by the inability o the organism to respond to normal levels o circulating insulinalso called insulin resistance Current antidiabetic therapy is based on synthetic drugs that very ofen have side effects For this reasonthere is a continuous need to develop new and better pharmaceuticals as alternatives or the management and treatment o the diseaseNatural hypoglycaemic compounds may be attractive alternatives to synthetic drugs or reinorcements to currently used treatmentsTeir huge advantage is that they can be ingested in everyday diet Recently more attention is being paid to the study o natural productsas potential antidiabetics Tis mini review o the current literature is structured into three main sections ocused on (a) plant extracts(b) plant biomolecules and (c) other natural molecules that have been used or their antidiabetic effects Potential molecular mechanismso action are also discussed

Keywords antidiabetic plants antidiabetic natural biomolecules type 2 diabetes

Introduction

Diabetes is a metabolic disease that has become a se-rious problem o modern society due to the severe long-term health complications associated with it In particular

type 2 diabetes mellitus (2DM) is the most encounteredorm o diabetes accounting or more than 80 o the to-tal cases o diabetes (Berg et al 2002 Cheţa 2010 Mlinaret al 2007) Glucose metabolism disturbances are majoractors leading to diabetes Te insulin released by the

pancreatic β-cells is the hormone responsible or glucosehomeostasis (Garrett and Grisham 1999 Sesti 2006) In-sulin stimulates hepatocytes myocytes and adipocytes touptake glucose rom the circulatory system Depending onneed glucose can either be used as an energetic source byglycolysis or alternatively stored as glycogen inside muscleor liver cells Te inappropriate utilization o insulin leadsto insulin resistance which is characterised by the inabilityo cells to respond to normal levels o circulating insulin(Berg et al 2002 Cheţa 2010) thus leading to the occur-rence o the disease

Natural compounds may be easible alternatives or thetreatment o diabetes or reinorcements to currently usedtreatments Tey may even reduce the risk o the diseaseLarge amounts can be consumed in everyday diet whichis a positive aspect Tere are a large number o plants andnatural biomolecules that have been discussed in litera-ture or their antidiabetic effects For example plants havebeen used since ancient times to prevent conditions asso-ciated with diabetes (Soumyanath 2003) Te mechanism

is most ofen not completely understood but more andmore studies are being conducted to elucidate the mecha-

nisms o action o different plants and natural compoundsTis mini review aims to discuss some key aspects relatedto the potential use o plants and natural biomolecules orthe prophylaxis and treatment o type 2 diabetes as well asthe potential mechanisms o action

A Plant Extracts with Antidiabetic ActionTere are more than 1000 plant species being used or

the treatment o 2DM worldwide (rojan-Rodrigues et al 2011) In parts o the world where the population hasrestricted access to the healthcare system the use o me-dicinal plants or the treatment o 2DM is widespreadIn many cases very little is known about the mechanism oaction o traditionally used antidiabetic plants thus pre-

venting them rom being used in standard diabetes careRecently more research is being ocused on elucidatingthe action o these plants and their active constituentsab 1 presents a number o plants that are currently usedor their antidiabetic properties together with their activebiomolecules based on recent studies

Gallega officinalis has been used since ancient timesin Europe or treating symptoms associated with 2DM(Whitters 2001) It is now well established that its hypo-glycaemic and insulin-sensitizing potential is associated

with its guanide compound galegine Tis plant is still ogreat importance today despite the act that the guanidecompounds were discovered to be toxic or the humanbody Related compounds such as the biguanide metorm-in molecule were later developed and are still widely usedin antidiabetic therapy (Goldstein and Wieland 2008)

Brazil is one country where a significant percent o thetotal population uses plants as antidiabetics In their re-



Coman C et al Not Bot Horti Agrobo 2012 40(1)314-325

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α-glucosidases leads to the retardation o their action con-sequently becoming an effective approach or the treat-ment o 2DM (Goldstein and Wieland 2008) Current-ly there is a whole class o antidiabetic drugs that unctionas α-glucosidase inhibitors

Other α-glucosidase inhibitors were also ound in Morus alba another natural antidiabetic plant Teα-glucosidase inhibitory effect o Morus alba was alsoobserved in studies on Caco-2 cell cultures (Hansawasdiand Kawabata 2006) Yang et al (2012) ound 15 bioac-tive molecules (ab 1) with α-glucosidase and tyrosinaseinhibitory effects in the lea extracts o Morus alba con-taining the ollowing compounds flavanes prenylatedstilbenes and iminosugars Katsube et al (2006) also iden-tified the presence o flavonol glycosides (see also sectionB) another class o antioxidant compounds with antidi-abetic potential

A number o culinary herbs rom Tailand (Wongsaet al 2012) were tested or total phenolic content anti-oxidant activity (by the 11-diphenyl-2-picrylhydrazyl(DPPH) radical inhibition assay) and α-amylase andα-glucosidase potential inhibition activity It was oundthat Solanum xanthocarpum Ocimum sanctum and Aca-cia pennata could be used in the dietary management o2DM due to their high contents o polyphenolics ca-eic acid and p-coumaric acid Acacia pennata had thestrongest effect on α-amylase inhibition the presence ocaffeic acid was correlated with this effect α-glucosidaseinhibition was linked to the total phenolic content Other

plants with the α-glucosidase inhibitor effect are Macaran- ga tanarius (Puteri and Kawabata 2010) Salacia oblongaSalacia chinensis (Giron et al 2009 Muraoka et al 2010)

Eleutherine americana (Ieyama et al 2011) Aquilaria sin-ensis (Feng et al 2011) and Panax japonicus (Chan et al 2010)

In a study on type 2 diabetic mice administration oCurcuma longa L rhizomes extract led to the activation othe peroxisome prolierator-activated receptor-γ (PPAR-γ)(Kuroda et al 2005) through the ligand binding activityo the extract towards the receptor PPAR-γ is a key recep-tor in lipid and glucose homeostasis because o its abilityto reduce the plasma ree atty acids (FFAs) (Bajaj et al 2007 Kasuga et al 2007 Nunn et al 2007) Te recep-tor is currently used as a target or the treatment o 2DM(Goldstein and Wieland 2008) the antidiabetic thiazo-lidinediones drugs exert their insulin sensitizing actionthrough their high affinity or the receptor PPAR-γ TusCurcuma longa is a promising therapeutic agent in the pre-

vention andor amelioration o 2DM Lee et al (2008)tested a combined hypoglycaemic mixture o Melissa o-

ficinalis L Morus alba L and Artemisia capillaris Tunbthat resulted in changes in the expression o the PPAR-αanother key receptor in lipid and lipoprotein metabolism

Urtica dioica is another example o a hypoglycaemic

plant In vivo studies on diabetic rats (Bnouham et al 2003) showed an increase in blood insulin levels and

cent review rojan-Rodrigues et al (2011) list 81 plantspecies rom 42 amilies that are being used or diabetescare in the Brazilian state o Rio Grande do Sul Te moststudied species or their effects are shown in ab 1 Alar-con-Aguilara et al (1998) perormed a screening study on28 medicinal plants used in Mexico or 2DM treatmentand ound eight o them (ab 1) to exert hypoglycaemiceffects Aslan et al (2010) tested plants used as part o thediet and as antidiabetics in urkey Tey ound that Cydo-nia oblonga Mill and Allium porrum L possessed potentantidiabetic effects

Administration o Swertia punicea extract and themethylswertianin and bellidiolin ractions o the extractto type 2 diabetic mice improved insulin sensitivity (ianet al 2010) Te mechanism involved increased expres-sion o key proteins (insulin receptor (IR) insulin recep-tor substrate-1 (IRS-1) and phosphatidylinositol 3-kinase

(PI3K)) that are involved in the insulin signalling pro-cesses Additionally methylswertianin and bellidiolin de-creased the activity o glucokinase (GK) and increased theactivity o glucose-6-phosphatase (G6Pase) enzymes thatare involved in the secretion o insulin rom pancreaticβ-cells Similar mechanisms o action leading to increased

phosphorylation o IR and IRS-1 together with increasedglucose transporter 4 (GLU4) and PI3K mRNA ex-

pression in the L6 cells were observed by Kanaujia et al (2010) afer administration o the ruit extract o Capparismoonii Te effect was attributed to the presence o twogallotannins with insulin-mimetic activity in the extract

Artemisia dracunculus L has been reported to have hypoglycaemic effects by several researchers (Ribnicky et al 2009 Wang et al 2011) Wang et al (2011) ound that

Artemisia dracunculus L improved insulin sensitivity andIR signaling in insulin-resistant KK-Ay mice models Teycould not explain the cellular mechanisms behind the e-ect One suggestion given was the modulation o skeletalmuscle protein degradation and phosphatase activity Lo-gendra et al (2006) isolated 45-di-O-caffeoylquinic acid6-demethoxycapillarisin and 2rsquo4rsquo-dihydroxy-4-methoxy-dihydrochalcone rom the ethanolic extract o Artemisiadracunculus L Te compounds showed inhibitory effectstowards the enzyme aldose reductase a key enzyme in-

volved in diabetic complications which may explain theantidiabetic effect Te bioactive compounds in Artemisiadracunculus L also include davidigenin sakuranetin and5-O-caffeoylquinic acid (Eisenman et al 2011)

Salacia reticulata has been traditionally used or thetreatment o 2DM in countries such as Sri Lanka Indiaand Tailand From this plant Muraoka et al (2008) iso-lated α-glucosidase inhibitors such as salacinol kotalanolde-O-sulphated-salacinol and de-I-sulphated-kotalanolthe inhibitory effects o which are similar to that o vo-glibose and acarbose which are widespread antidiabeticdrugs (see section C) α-glucosidase is an enzyme that

catalyses the decomposition o disaccharides to glucoseAny inhibitory effect rom an external stimulus towards



316

ab 1 Examples o some plants with confirmed antidiabetic properties

Plant Used part Active compounds ype o study Preparation Reerences

Gallega officinalis leaves seeds galegine diabetic rats aqueous extract Whitters 2001 Goldstein and

Wieland 2008 Lemus et al 1999

Syzygium cumini seeds leaves flower mycaminose diabetic rats ethanolic extract rojan-Rodrigues et al 2011 Kumar et al 2008

Bauhinia orficataleaves flowers

bark k ae mp e ro l- 3- ne ohe sp er id os ide ( in su li n m im et ic ) r at s ole us m us cl e e th an ol ic e xt ract

rojan-Rodrigueset al 2011Cazarolli et al 2009

Bidens pilosa L whole plant polyacetylenic glucosidesdiabetic mice

rat pancreatic isletsaqueous extract rojan-Rodrigues et al 2011 Hsu et al 2009

Swertia punicea whole plant methylswertianin bellidiolin diabetic mice ethanol extractethyl-acetate extract

ian et al 2010

Capparis moon ruits gallotannins (chebulinic acid derivatives) L6 cells ethanolic extract Kanaujia et al 2010

Artemisia dracunculus L whole plantdavidigenin sakuranetin 2rsquo4rsquo-dihydroxy-4-

methoxydihydrochalcone 45-di-O-caffeoylquinic acid5-O-caffeoylquinic acid 6-demethoxycapillarisin

diabetic m ice ethanolic e xtra ct Wang et al 2011 Ribnicky et al 2009

Eisenman et al 2011 Logendra et al 2006

Salacia reticulata root stemSalacinol kotalanol de-O-sulated salacinol de-O-

sulated kotalanol ponkolanol salaprinolcompound isolation

identificationaqueous extract Muraoka et al 2008

Morus alba leaves(2S)-euchrenone chalcomoracin moracin C moracin

D moracin N (2R)(2S)-euchrenone moracin N quercetin norartocarpetin several flavanes

compound isolationidentification

ethanolic extract Yang et al 2012

Morus alba leavesquercetin 3-(6-malonylglucoside) rutin (quercetin3-rutinoside) isoquercitrin (quercetin 3-glucoside)

Caco-2 cellsethanolic extractaqueous extract

Hansawasdi and Kawabata 2006Katsube et al 2006

Ocimum sanctum leaves polyphenols caffeic acid p-coumaric acid in vitro aqueous extract Wongsa et al 2012

Acacia pennata shoot tips polyphenols caffeic acid in vitro aqueous extract Wongsa et al 2012

Solanum xanthocarpum ruit polyphenols caffeic acid in vitro aqueous extract Wongsa et al 2012

Macaranga tanarius seedsellagitannins (mallotinic acid corilaginchebulagic acid macatannins A and B)


ethanolic extract Puteri and Kawabata 2010

Salacia oblonga Salacia chinensis

root stem leaves salacinol kotalanol mangierin compound isolationidentification

aqueous extract Muraoka et al 2010 Giron et al 2009

Eleutherine americana bulb eleutherinoside A compound isolation

identificationmethanolic extract Ieyama et al 2011

Aquilaria sinensis leavesmangierin iriflophenone 2-O-α-L-rhamnopyranoside iriflophenone

3-C -β-D-glucoside iriflophenone 35-C -β-D-diglucopyranosidecompound isolation

identificationethanolic extract Feng et al 2011

Panax japonicus rootpolyacetylenes phenolic compounds one

sesquiterpenoid one sterol glucosidecompound

identificationethanolic extract Chan et al 2010



317

ab 1 Examples o some plants with confirmed antidiabetic properties (cont)


Curcuma longa rhizome curcumin demethoxycurcumin bisdemethoxycurcumin ar-turmeronediabetic mice

in vitroethanolic extract Kuroda et al 2005

Rhododendron tomentosum Picea mariana

ruit quercetin Caco-2 cellsdiabetic rats

ethanolic extract Nistor Baldea et al 2010

Aronia melanocarpa ruit anthocyanins diabetic rats ruit juiceKulling and Rawel 2008 Valcheva-

Kuzmanova et al 2007

Stevia rebaudiana leaves alkaloids flavonoids diabetic rats aqueous extract Kujur et al 2010

Nigella sativa seeds

gallic acid (ndash)- p-hydroxybenzoic acid chlorogenicacid vanillic acid p-coumaric erulic acid trans-2-

hydroxycinnamic acid trans-cinnamic acid epicatechin(+)-catechin quercetin apigenin amentoflavone flavone

diabetic ratscrude aqueous extract

methanolic extractBourgou et al 2008 Meddah et al 2009

Eucalyptus globules leaves diabetic rats ethanolic extract Ahlem et al 2009

Phaseolus vulgaris L seedsalkaloids flavonoids fiber proteins tannins terpenoids

saponins quercetin anthocyanin catechindiabetic rats extract Ocho-Anin Atchibri et al 2010

Marrubium vulgare aerial part flavonoids diabetic rats methanolic extract Elberry et al 2011

Ruta graveolens leaves rutin diabetic rats aqueous extract Ahmed et al 2010

Carissa carandas ruit gallic acid flavonoids diabetic rats ethanol extract Itankar et al 2011

Pinus pinaster bark p olyphenol s p roant hoc ya nid ins catechin epic atechin

Caco-2 cellsDiabetic rats

2DM human

patients

Aqueous extractEl-Zein et al 2011 Bedekar et

al 2010 Liu et al 2004

Piper retrofactum ruits piperidine alkaloids piperine pipernonalinedehydropipernonaline33-L1 adipocytes

L6 myocytesEthanol extract Kim et al 2011




318

decrease in blood glucose levels upon administration oUrtica dioica extracts According to Nistor Baldea et al (2010) Rhododendron tomentosum and Picea mariana ex-ert inhibitory effects on the intestinal glucose absorptionboth in vitro and in vivo and decrease the expression o theNa+-dependent glucose transporter (SGL1) and glucosetransporter 2 (GLU2) proteins in CaCo-215 cell linesindicating that these plants can be useul in diabetes pre-

vention and care Aronia melanocarpa berries possess numerous biologi-

cal and medicinal effects (Kulling and Rawel 2008) Teyare rich in phenolic antioxidants especially anthocyaninsValcheva-Kuzmanova et al (2007) have investigated theinfluence o Aronia melanocarpa ruit juice on plasma glu-cose and lipid levels in diabetic streptozotocin rats Teadministration o Aronia ruit juice lowered the glucoseand triglyceride levels in diabetic rats Additionally in a

human study the daily intake o Aronia juice over a pe-riod o 3 months was effective in lowering asting glucoselevels in patients with type 2 diabetes (Kulling and Rawel2008) Aronia melanocarpa ruit juice may become use-ul in the treatment o diabetes mellitus and its associatedcomplications In vivo studies and clinical trials must beconducted to validate in vitro results related to the actiono anthocyanins and anthocyanidins

By conducting in vitro experiments on rat pancreaticβ-cells using Cornus officinalis extracts Chen et al (2008)ound that the extracts possessed insulin-mimetic activityand stimulated β-cell unction by enhancing insulin secre-

tion and protecting β-cells against toxic damage Admin-istration o Stevia rebaudiana extracts (Kujur et al 2010)led to decreased blood glucose levels in diabetic rats Withregards to the mechanism o action it is suggested that thecounteraction o glucotoxicity in the pancreatic β-cells orthe suppression o glucagon secretion by α-pancreatic cellscould be involved (glucagon normally raises glucose levelsin the blood)

Seed extracts o Nigella sativa have many therapeutic purposes relevant or antidiabetic use Meddahet al (2009)studied the effect o the crude aqueous extract o Nigella

sativa seeds on intestinal glucose absorption Nigella sativa inhibited the intestinal absorption o glucose supportingits use as an antidiabetic compound Other examples o

plants with antidiabetic properties that were studied andconfirmed by literature studies include the ollowing Eu-calyptus globules (Ahlem et al 2009) Phaseolus vulgaris L (Ocho-Anin Atchibri et al 2010) Marrubium vulgare (Elberry et al 2011) Coriandrum sativum L (Aissaoui et

al 2011) Swertia punicea (ian et al 2010) Viscum al-bum (Ohran et al 2005) Brassica juncea (Tirumalai et

al 2011) Sal983158ia officinalis L (Eidi et al 2005) Ruta gra-veolens (Ahmed et al 2010) Carissa carandas (Itankar et

al 2011) Pinus pinaster (Bedekar et al 2010 El-Zein et al 2011) Punica granatum (Bagri et al 2009) and Piper

retrofactum (Kim et al 2011)

B Natural Plant Biomolecules with Antidiabetic ActionSynthetic drugs currently in use or diabetes treat-

ment sometimes have side effects (Goldstein 2008 Stum- voll et al 2005) For this reason natural hypoglycaemiccompounds present an attractive alternative to syntheticdrugs or as reinorcements or currently used treatments(Kimura 2006 Rout et al 2009) Tis section presentssome o the literature findings related to antidiabetic plantbiomolecules with particular emphasis on large classeso compounds that are easily available rom many plantsources ab 2 shows the different classes o plant com-

pounds with antihyperglycaemic activity together withew examples rom each class

A large number o hypoglycaemic compounds haveantioxidant properties Among the trigger actors or2DM oxidative stress has a well-established role (Gold-stein and Wieland 2008) Oxidative stress leads to the

ormation o ree radical species which in turn negativelyaffect vital cellular processes Te antioxidant propertieso natural compounds may be acting synergistically withtheir hypoglycaemic activity in exerting an overall antidi-abetic action

Polyphenolic compounds especially flavonoids areamong the classes o compounds that have received themost attention (Soumyanath 2003) with regard to theirantidiabetic properties Flavonoids are natural polyphe-nolic molecules o plant origin known or their antioxi-dant anti-inflammatory and anticarcinogenic properties(Pinent et al 2008) Dietary intake o flavonoids might

prove to be important or alternative diabetes treatmentsor reduction o the risk o the disease Attempts have beenmade to determine their potential in preventing β-cellapoptosis promoting β-cell prolieration and insulin se-cretion (Pinent et al 2008) and enhancing insulin activ-ity (Ahmed et al 2010) Trough in vitro and in vivo stud-ies Ahmed et al (2010) were able to demonstrate that the

pharmacologically active compound o Ruta graveolensthe flavonoid rutin had the ability to positively influenceinsulin activity and insulin resistance in type 2 diabeticrats Teir results showed that rutin decreased glycaemialipidaemia serum insulin concentrations liver glycogencontent and hexokinase activities Rutin was also effectivein increasing the expression o the receptor PPAR-γ lead-ing to improved muscle insulin sensitivity and insulin sig-naling by increasing insulin-stimulated GLU4 receptoractivity (Petersen et al 2006) (GLU4 known as glucosereceptor 4 is the receptor that accounts or most o theinsulin-stimulated glucose uptake in muscles and adiposetissue cells (Kobayashi et al 2004)) Catechin a flavan-3-ol was also identified as a modulator o insulin secretion(Chemler et al 2007)

Isoflavones commonly known as phytoestrogens mayalso act as potential antidiabetics or example genisteiningested in soy products at dietary concentrations in-

creased glucose-stimulated insulin secretion in cell linesand mouse pancreatic islets (Fu and Liu 2009 Liu et al




319

2006) Te mechanism o their action involved the activation o the cAMPPKA (cyclic adenosine monophos- phateprotein kinase A) signaling cascade which led to anincrease in intracellular Ca2+ leading to the stimulation oinsulin secretion

As discussed above reactive oxygen species are amongthe trigger actors or insulin resistance (Guichard et al 2008 Houstis et al 2006 Rahimi et al 2005 Song et al 2006) Tis is one more reason why antioxidant therapiesare promising or the treatment o 2DM Kaemperola plant flavonol was recently tested on HI-15 by Leeet al (2010) Tey ound that kaemperol molecules pro-tected the cells against the apoptosis induced by oxidativestress

Anthocyanins another subclass o flavonoids are redor violet colored polyphenolics with high antioxidant po-tential Tey are composed o an aglycone (polyphenolicanthocyanidin) and a sugar residue Anthocyanins play a

vital role in the prevention o neuronal and cardiovasculardiseases cancer and diabetes (Castantildeeda-Ovando et al 2010) Anthocyanin-containing ruits are sometimes usedas complementary antidiabetic preparations (Castantildeeda-Ovando et al 2010 Jayaprakasam et al 2005) For exam-

ple cyanidin 3-glucoside an anthocyanin rom black riceexhibited a protective effect on insulin sensitivity in ex-

periments on insulin-resistant adipose tissue cells inducedby hydrogen peroxide (H

2O

2) or tumour necrosis actor α

(NF-α) (Guo et al 2008) It is known that both H2O2 and the inflammatory NF-α molecule inhibit the processo insulin signaling (Sesti 2006) Te exposure to H2O2 or

NF-α leads to IRS serine phosphorylation concurrent with a decrease in insulin-stimulated IRS tyrosine phos-

phorylation and a decrease o cellular glucose uptake Cya-nidin 3-glucoside exerts its protective role by reducing theintracellular production o the reactive oxygen species andattenuating the unwanted effects due to H2O2 or NF-αin a dose-dependent way by a mechanism that involves the

inhibition o c-Jun NH2-terminal kinase Te effect o ananthocyanin-rich extract rom black rice was also studiedon ructose-ed rats exhibiting high plasma insulin levelsand low insulin sensitivity (Guo et al 2007) Te effects

were compared to those o pioglitazone a prescriptiondrug or 2DM Administration o the anthocyanin-richextract prevented the development o ructose-inducedinsulin resistance Additionally the treatment with theanthocyanin-rich extract ameliorated glucose intoleranceand hyperlipidaemia as pioglitazone did but the extractailed to reverse ructose-induced hyperinsulinaemia Teunderlying mechanism may be related to inhibition o oxi-dative stress and improvement o the plasma lipid profile

Activation o the nuclear actor NF- κB is a key signal-ling mechanism or pancreatic β-cell damage that is con-nected to insulin resistance NF-κB controls the transcrip-tion process or different genes it is involved in cellularresponses to different stimuli such as stress cytokines andree radicals It is normally held in its inactive orm by be-ing bound to the inhibitory IκB molecule However it maybe activated i IκB undergoes phosphorylation by I-Kap-

pa-B kinase (IKK) leading to the release and activationo NF-κB that may induce pancreatic β-cell damage (Songet al 2010 Stumvoll et al 2005) Te activation o thenuclear actor NF-κB by stress actors (cytokine molecules

and ree radicals) is strongly connected to β-cell damageSulphuretin extracted rom Rhus verniciflua was ound to

ab 2 Classes o reported antidiabetic compounds and some examples rom each class

Classes o compounds Compounds

Flavonoids

Anthoc yanidins c yanid in delphynidin petunidin peonid in pelargonid in malvidin

Anthocyaninsanthocyanidins+sugar residue (glucose galactose arabinose rhamnose xylose)

eg cyanidin 3-glucoside cyanidin 3-galactoside pelargonidin-3-arabinoside

Flavones

Flavonols quercetin kaemperol myricetin isorhamnetin rutin(quercetin-3-O-rutinoside) kaemperol-3-neohesperidoside

isoquercitrin (quercetin 3-glucoside) apigenin

Flavanones sakuranetin

Flavanonol taxiolin (dihidroquercetin) dihidrokaemperol

Isoflavones genistein

Flavan-3-ols catechins (proanthocyanidins) epicatechins

Isoflavonoids phytoestrogens

Chalcones davidigenin 2rsquo4rsquo-dihydroxy-4-methoxydihydrochalcone

anninsgallotannins 136-tri-O-galloyl-2-chebuloyl-β-D-glucopyranoside

136-tri-O-galloyl-2-chebuloyl ester-β-D-glucopyranosideellagitannins mallotinic acid corilagin chebulagic acid macatannins A and B

Xanthones mangierin bellidiolin swerchirin methylswertianinOrganic acids kaurenoic acids p-coumaric acid vanillic acid gallic acid p-hydroxybenzoic acid

Cinamic acid derivatives caffeic acid erulic acid chlorogenic acid

Sugars salacinol kotalanol ponkolanol salaprinol

Curcuminoids curcumin demethoxycurcumin bisdemethoxycurcumin

Alkaloids conophylline piperine pipernonaline dehydropipernonaline




320

lated rom Piper retrofactum such as piperine pipernona-line and dehydropipernonaline activated AMP-activated

protein kinase (AMPK) signaling and the PPAR-γ protein(Kim et al 2011) in 33-L1 adipocytes and L6 myocytessuggesting potential antidiabetic effects

Pygnogenol the patented name o the pine bark ( Pinus pinaster ) extract possesses antidiabetic effects (Bedekar et al 2010 El-Zein et al 2011) Te extract contains bio-active compounds namely proanthocyanidins (dimersor oligomers o catechin and epicatechin and their gallicacid esters) the flavonoids catechin and epicatechin er-ulic and caffeic acids and taxiolin (Bedekar et al 2010)Te mechanism o action o pygnogenol is still not entire-ly clear El-Zein et al (2011) studied its effect on Caco-2cells it decreased intestinal glucose transport Teir worksuggested that the mechanism involves decreasing thenumber o glucose transporters (GLU2) by processes

that lead to activation o p38 mitogen-protein kinase(p38 MAPK) and PI3K thus affecting the insulin signal-ing pathway Another study (Schaumler and Houmlgger 2007)claimed that the oligomeric proanthocyanidins romthe pine bark extract have a higher α-glucosidase inhibi-tory effect than acarbose a commonly used antidiabeticα-glucosidase inhibitor

Ellagitannins are another class o plant biocomoleculesthat inhibit α-glucosidase enzymes (McDougall and Stew-art 2005 Puteri and Kawabata 2010) Sugar-like struc-tures more precisely thiosugars such as kotalanol (Xie et

al 2011a) salacinol (Muraoka et al 2010) neoponkora-

nol neosalaprinol (Xie et al 2011b) and de-O-sulphated-kotalanol (Muraoka et al 2008) also have α-glucosidaseinhibitory effects that are sometimes comparable to thato the prescription drugs acarbose and voglibose Similareffects are also reported or the alkaloids nummularine-Rnummularin-C and hemsine-A (Choudhary et al 2011)some polyacethylenes and saponins (Chan et al 2010)

polyphenolic compounds such as iriflophenone 2-O-α-L-rhamnopyranoside iriflophenone 3-C-β-D-glucosideiriflophenone-35-C-β-D-diglucopyranoside (Feng et al 2011) eleutherinoside and eleuthoside (Ieyama et al 2011) and bromophenols such as 246-tribromophenoland 24-dibromophenol (Kim et al 2011)

Te xanthone compound mangierin is another natu-ral molecule with hypoglycaemic properties (Soumyanath2006) According to Giron et al (2009) mangierin thebioactive compound o the Salacia oblonga extract in-creases the expression o GLU4 glucose transporters andtheir translocation to the cell membrane in L6-myocitesand 33-adipocytes thus stimulating glucose uptake bythe cells

In a recent study Gandhi et al (2011) ound thatmethyl caffeate administered to diabetic rats had a hy-

poglycaemic effect caused by an increased expression othe GLU4 receptor and regeneration o the pancreatic

β-cells

inhibit cytokine- or streptozotocin-induced damage in ratinsulinoma β-cells and in isolated cells that induced toxic-ity (Song et al 2010)

Anthocyanin-rich extracts obtained rom blueberriesexhibited hypoglycaemic effects in diabetic mice Te hy-

poglycaemic activity was comparable to that o the knownantidiabetic drug metormin (Grace et al 2009) Jay-aprakasam et al (2005) perormed in vitro studies on ro-dent pancreatic β-cells and ound that anthocyanins suchas cyanidin-3-glucoside delphinidin- 3-glucoside and

pelargonidin-3-galactoside as well as the anthocyanidin pelargonidin were efficient in stimulating insulin secretionrom pancreatic β-cells Te stimulation o insulin secre-tion is also the mechanism o action o oral hypoglycaemicagents used in diabetes therapy such as sulonylurea-baseddrugs that directly stimulate insulin release rom β-cellso type 2 diabetic patients Sulonylurea-based drugs have

the disadvantage o ailing to control normal blood glu-cose levels and this is the reason behind why anthocyaninsmay serve as a natural alternative treatment

Some anthocyanin-rich plant extracts have inhibitoryeffects towards α-glucosidase and α-amylase (Bedekar et

al 2010 Matsui et al 2001) Matsui et al (2001) testeddifferent extracts towards α-glucosidase inhibition andound that some o the extracts had α-glucosidase andα-amylase inhibitory effects However it was not entirelyclear whether the effect was caused by the anthocyanins orother compounds rom the extract

Because anthocyanins and anthocyanidins are not

harmul in any way to humans it is important to evaluatetheir clinical efficacy in the prevention and treatment o2DM

Apart rom the biomolecules discussed above thereare many more flavonoids mentioned in the literature ortheir hypoglycaemic effect rhamnocitrin-3-O-isorhamni-noside rhamnetin-3-O-isorhamninoside apigenin (Am-mar et al 2009) apigenin 6-neohesperidose kaemperol3-robinobioside kaemperol 3-rutinoside (Abraham et al 2008) luteolin-7-O-glucoside apigenin-7-O-glucoside(Bansal et al 2011) and quercetin (Coskun et al 2005apas et al 2008)

Kojima and Umezawa (2006) perormed experimentson pancreatic AR42J cells (a model o pancreatic progeni-tor cells) and on rats with induced diabetes Tey oundthat conophylline an alkaloid compound extracted romthe leaves o the tropical plant Ervatamia microphylla waseffective in stimulating the differentiation o progenitorcells into β-cells Conophylline also induced differentia-tion in cultured pancreatic progenitor cells obtained romoetal and neonatal rats Conophylline increased the ex-

pression o neurogenin-3 by activating p38 mitogen-activated protein kinase and thereby induced differentiationo AR42J cells Additionally conophylline was effective inreversing hyperglycaemia in neonatal streptozotocin-treat-

ed rats both the insulin content and the β-cell mass wereincreased by conophylline Other alkaloid compounds iso-




321

tors and are used in 2DM therapy especially in Centraland South Europe and Asia (Goldstein and Wieland2008) Acarbose is a pseudotetrasaccharide a secondarymetabolite produced by the bacterium species Actino-

planes sp SE50 Miglitol and voglibose both contain onlyone sugar ring Miglitol is synthesised rom D-glucoseby Glucanobactor oxydans while voglibose is synthesisedrom valilamine that is obtained rom the ermentation oStreptomyces culture broth

Teir inhibitory effects on the α-glucosidase enzymeoffer ways to control the release o glucose rom carbo-hydrates Basically the inhibition reduces the degrada-tion o carbohydrates leading to poor carbohydratemetabolisation and digestion Due to their high affinityor α-glucosidases the inhibitors block the enzyme rombinding to the carbohydrates resulting in a decreased abil-ity to metabolise the complex sugars to monosaccharides

thereore decreasing the glucose concentration Acarboseinhibits both α-glucosidases and pancreatic α-amylasesenzymes voglibose has little effect on α-amylases whilemiglitol shows no effect (Goldstein and Wieland 2008)(pancreatic α-amylases catalyse the digestion o complexstarches to oligosaccharides while α-glucosidases such assucrases maltases isomaltases hydrolise oligosaccharisdestrisaccharides and disaccharisdes into monosaccharides)Acarbose miglitol and voglibose show different inhibito-ry effects on α-glucosidases Acarbose is most effective onglucoamylase ollowed by sucrase maltase and dextranaseMiglitol is a more potent inhibitor sucrase and maltase

than acarbose it is also active on isomaltase but shows noeffect on α -amylase Voglibose has a strong α-glucosidaseinhibitory effect but little effect on α -amylase

Conclusions

Natural products such as plant extracts phytochemi-cals and microbial metabolites are attracting more andmore attention or their potential uses in the treatment and

prevention o type 2 diabetes mellitus A number o plantextracts and natural biomolecules that have been tested ortheir antidiabetic properties using both in vivo and in vitro approaches were reviewed here Some o them show very

promising effects which indicate that the dietary intake o phytochemicals could be a promising strategy or diabetes prevention Additionally therapies based on phytochemi-cals could constitute a novel pharmacological approachor treatment or an approach that would reinorce existingtreatments

AcknowledgementsTis work has benefited rom financial support

through the postdoctoral POSDRU8915S52432 andPOSDRU8915S60746 projects co-financed by theEuropean Social Fund through the Sectorial Operational

Program Human Resources Development 2007-2013

Te use o inhibitors o 11β-hydroxysteroid dehy-drogenase-1 is a novel approach in the management o2DM (ahrani et al 2011) Potential inhibitors or11β-hydroxysteroid dehydrogenase-1 were also sought outin flavonoid compounds orres-Piedra et al (2010) testedseveral flavonoids on human embryonic kidney (HEK293)cells and ound that quercetin and flavone had inhibitoryeffects on the 11β-hydroxysteroid dehydrogenase-1 en-zyme Te effect is thought to be related to the interac-tion with the catalytic active site o 11β-hydroxysteroiddehydrogenase-1 However more studies are required toelucidate the exact mechanism and to identiy novel plantcompounds that can act as 11β-hydroxysteroid dehydro-genase-1 inhibitors

C Other Natural Biomolecules with Antidiabetic Action

Compounds such as acarbose miglitol and voglib-ose (Fig 1) are a ew examples o natural compounds omicrobial origin that are currently used in the treatmento 2DM (Bedekar et al 2010 Goldstein and Wieland2008) All these compounds act as α-glucosidase inhibi-

Fig 1 Molecular structures o the (a) acarbose (b) miglitol and(c) voglibose




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α-glucosidases leads to the retardation o their action con-sequently becoming an effective approach or the treat-ment o 2DM (Goldstein and Wieland 2008) Current-ly there is a whole class o antidiabetic drugs that unctionas α-glucosidase inhibitors

Other α-glucosidase inhibitors were also ound in Morus alba another natural antidiabetic plant Teα-glucosidase inhibitory effect o Morus alba was alsoobserved in studies on Caco-2 cell cultures (Hansawasdiand Kawabata 2006) Yang et al (2012) ound 15 bioac-tive molecules (ab 1) with α-glucosidase and tyrosinaseinhibitory effects in the lea extracts o Morus alba con-taining the ollowing compounds flavanes prenylatedstilbenes and iminosugars Katsube et al (2006) also iden-tified the presence o flavonol glycosides (see also sectionB) another class o antioxidant compounds with antidi-abetic potential

A number o culinary herbs rom Tailand (Wongsaet al 2012) were tested or total phenolic content anti-oxidant activity (by the 11-diphenyl-2-picrylhydrazyl(DPPH) radical inhibition assay) and α-amylase andα-glucosidase potential inhibition activity It was oundthat Solanum xanthocarpum Ocimum sanctum and Aca-cia pennata could be used in the dietary management o2DM due to their high contents o polyphenolics ca-eic acid and p-coumaric acid Acacia pennata had thestrongest effect on α-amylase inhibition the presence ocaffeic acid was correlated with this effect α-glucosidaseinhibition was linked to the total phenolic content Other

plants with the α-glucosidase inhibitor effect are Macaran- ga tanarius (Puteri and Kawabata 2010) Salacia oblongaSalacia chinensis (Giron et al 2009 Muraoka et al 2010)

Eleutherine americana (Ieyama et al 2011) Aquilaria sin-ensis (Feng et al 2011) and Panax japonicus (Chan et al 2010)

In a study on type 2 diabetic mice administration oCurcuma longa L rhizomes extract led to the activation othe peroxisome prolierator-activated receptor-γ (PPAR-γ)(Kuroda et al 2005) through the ligand binding activityo the extract towards the receptor PPAR-γ is a key recep-tor in lipid and glucose homeostasis because o its abilityto reduce the plasma ree atty acids (FFAs) (Bajaj et al 2007 Kasuga et al 2007 Nunn et al 2007) Te recep-tor is currently used as a target or the treatment o 2DM(Goldstein and Wieland 2008) the antidiabetic thiazo-lidinediones drugs exert their insulin sensitizing actionthrough their high affinity or the receptor PPAR-γ TusCurcuma longa is a promising therapeutic agent in the pre-

vention andor amelioration o 2DM Lee et al (2008)tested a combined hypoglycaemic mixture o Melissa o-

ficinalis L Morus alba L and Artemisia capillaris Tunbthat resulted in changes in the expression o the PPAR-αanother key receptor in lipid and lipoprotein metabolism

Urtica dioica is another example o a hypoglycaemic

plant In vivo studies on diabetic rats (Bnouham et al 2003) showed an increase in blood insulin levels and

cent review rojan-Rodrigues et al (2011) list 81 plantspecies rom 42 amilies that are being used or diabetescare in the Brazilian state o Rio Grande do Sul Te moststudied species or their effects are shown in ab 1 Alar-con-Aguilara et al (1998) perormed a screening study on28 medicinal plants used in Mexico or 2DM treatmentand ound eight o them (ab 1) to exert hypoglycaemiceffects Aslan et al (2010) tested plants used as part o thediet and as antidiabetics in urkey Tey ound that Cydo-nia oblonga Mill and Allium porrum L possessed potentantidiabetic effects

Administration o Swertia punicea extract and themethylswertianin and bellidiolin ractions o the extractto type 2 diabetic mice improved insulin sensitivity (ianet al 2010) Te mechanism involved increased expres-sion o key proteins (insulin receptor (IR) insulin recep-tor substrate-1 (IRS-1) and phosphatidylinositol 3-kinase

(PI3K)) that are involved in the insulin signalling pro-cesses Additionally methylswertianin and bellidiolin de-creased the activity o glucokinase (GK) and increased theactivity o glucose-6-phosphatase (G6Pase) enzymes thatare involved in the secretion o insulin rom pancreaticβ-cells Similar mechanisms o action leading to increased

phosphorylation o IR and IRS-1 together with increasedglucose transporter 4 (GLU4) and PI3K mRNA ex-

pression in the L6 cells were observed by Kanaujia et al (2010) afer administration o the ruit extract o Capparismoonii Te effect was attributed to the presence o twogallotannins with insulin-mimetic activity in the extract

Artemisia dracunculus L has been reported to have hypoglycaemic effects by several researchers (Ribnicky et al 2009 Wang et al 2011) Wang et al (2011) ound that

Artemisia dracunculus L improved insulin sensitivity andIR signaling in insulin-resistant KK-Ay mice models Teycould not explain the cellular mechanisms behind the e-ect One suggestion given was the modulation o skeletalmuscle protein degradation and phosphatase activity Lo-gendra et al (2006) isolated 45-di-O-caffeoylquinic acid6-demethoxycapillarisin and 2rsquo4rsquo-dihydroxy-4-methoxy-dihydrochalcone rom the ethanolic extract o Artemisiadracunculus L Te compounds showed inhibitory effectstowards the enzyme aldose reductase a key enzyme in-

volved in diabetic complications which may explain theantidiabetic effect Te bioactive compounds in Artemisiadracunculus L also include davidigenin sakuranetin and5-O-caffeoylquinic acid (Eisenman et al 2011)

Salacia reticulata has been traditionally used or thetreatment o 2DM in countries such as Sri Lanka Indiaand Tailand From this plant Muraoka et al (2008) iso-lated α-glucosidase inhibitors such as salacinol kotalanolde-O-sulphated-salacinol and de-I-sulphated-kotalanolthe inhibitory effects o which are similar to that o vo-glibose and acarbose which are widespread antidiabeticdrugs (see section C) α-glucosidase is an enzyme that

catalyses the decomposition o disaccharides to glucoseAny inhibitory effect rom an external stimulus towards



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Flavonoids




Flavones



















320












β-cells

















321






Conclusions































References












































































































316












ian et al 2010



































317
























2DM human

patients








318



























319







2O












Flavonoids




Flavones



















320












β-cells

















321






Conclusions































References












































































































317
























2DM human

patients








318



























319







2O












Flavonoids




Flavones



















320












β-cells

















321






Conclusions































References













































































































318



























319







2O












Flavonoids




Flavones



















320












β-cells

















321






Conclusions































References













































































































319







2O












Flavonoids




Flavones



















320












β-cells

















321






Conclusions































References













































































































320












β-cells

















321






Conclusions































References













































































































321






Conclusions































References






























































































































References

















































































































































































































































































Documents

Aktivitas Bawang Dayak