A Mini Review: Phenolic Compounds in Diets for Managing Type II

Diabetes

Suryawati

, Firdausa Sarah

, Mulia Dewi Vera

, Vonna Azizah

, Sakdiah

Department of Pharmacology, Faculty of Medicine, Syiah Kuala University, Indonesia

Department of Internal Medicine, Faculty of Medicine, Syiah Kuala University, Indonesia

Department of Patology Anatomy, Faculty of Medicine, Syiah Kuala University, Indonesia

Department of Pharmacy, Faculty of Math and Science, Syiah Kuala University, Indonesia

Department of Biochemistry, Faculty of Medicine, Syiah Kuala University, Indonesia

Keywords: Diabetes Mellitus, Phenolic Compounds, Diet.

Abstract: Diet management help to prevent or reduce the progress of diabetes mellitus, one of metabolic disorder

potentially lead to serious complications such as retinopathy, nephropathy, heart and vascular diseases. This

mini review highlights the hypoglycemic effect of natural supplemented diets evaluated in animals and

humans. Several phenolic compounds from natural origins comprise of Mangifera indica, Peperomia

pellucida, Sesamum indicum, Passiflora edulis and Aegle marmelos are briefly described. Mode of action

observed in isolated phenolic compounds in improving diabetes are including free radical scavengers,

inhibition of glucose regulating enymes and disruptions expression of glucose transporter genes.

1 INTRODUCTION

1.1 Diabetes Mellitus

Diabetes mellitus is a metabolic disorder

characterized by chronic hyperglycemia caused by

absolute or relative insulin deficiency, and sometime

accompanied by insulin resistance (Robertson,

2004). DM drives the body to a condition in which

the cells are exposed to an increase of oxidative

stress. Conversely, it has been suggested that

oxidative stress lead to chronic complication in

which the level of oxidative stress in diabetic subject

is advance. Hyperglycemia is a widely known

etiology of enhanced free radical concentrations and

decreased antioxidant defense system (Ahmed,

2005).

Free radicals are singlet oxygen comprising

superoxide anion radical, hydroxyl, alkoxyl, peroxyl

radical, hydrogen peroxide, and lipid hydroperoxide.

These species are resulted from biochemical reaction

in the body or environmental exposure. Cells

injuries which lead to many diseases such as cancer,

diabetes mellitus, developed due to the action of free

radicals on PUFA, amino acids, or DNA (Nimse &

Pal, 2015).

Chronic hyperglycemia leads to toxic effects on

structure and function of organs, including β-cell in

pancreas. Islet cells of pancreas are among the

tissues that have the lowest level of antioxidant

defense. In chronic hyperglycemic state, reactive

oxygen species accumulate in an excess amount and

cause chronic oxidative stress in the islet cell. This

condition damages the cell progressively

(Robertson, 2004).

The pathophysiology of DM is complex and

multi factorials, including the interaction of genetic

and environmental factors. Three main

pathophysiology factors involve in development

DM, which are insulin resistance, decreased insulin

secretion and increased glucose production

(Polonsky & Burant, 2016).

Several biochemical pathways and mechanisms

on how hyperglycemia causes cell damage have

been explained in many studies which include

increased glycolysis, activation of sorbitol pathway,

glucose autoxidation, glycation (Ahmed, 2005),

hexosamine metabolism, protein kinase C activation,

and oxidative phosphorylation (Robertson, 2004).

Therapy is targeted to increase insulin production,

Suryawati, ., Sarah, F., Vera, M., Azizah, V. and Sakdiah, .

A Mini Review: Phenolic Compounds in Diets for Managing Type II Diabetes.

DOI: 10.5220/0008792600850091

In Proceedings of the 2nd Syiah Kuala International Conference on Medicine and Health Sciences (SKIC-MHS 2018), pages 85-91

ISBN: 978-989-758-438-1

decrease insulin resistance and stimulate cells

glucose uptake. Several key factors targeted for

combating diabetes are stimulator for insulin

secretion (glucagon like peptide, GLP), inhibitor for

GLP degradation (dipeptidyl peptidase), glucose

regulating enzymes (amylase, glucosidase, etc),

glucose transporter (GLUT 2, GLUT 4), and

activated receptor for gene expression (peroxisome

proliferator-activated receptor) (Tiwari, Thakur,

Kumar, Dey, & Kumar, 2014).

To achieve a controlled glucose level,

pharmacotherapy should be carried out with physical

activities and diet management. Physical activity to

reduces weight more than 5% was essential to

achieve normal HbA1c and nutrition management

was recommended strategy for type II diabetes

patients (Franz, Boucher, Rutten-Ramos, &

VanWormer, 2015)

1.2 Supplemented-diet

Enriched supplements with hypoglycemic agents

help to prevent risk of hyperglycemia and normalize

glucose level in diabetic patients. Diet for diabetic

could be modulated with fibre, vitamins and natural

antioxidants comes from plants (Radmila, Pavle,

Dean, & Ljupco, 2013). Mediteranian food consist

of fruits, leaves, oil etc show activity to neutralize

free radicals, inhibit inflammation, prevent glucose

absorption and lipid production (Alkhatib et al.,

2017). Several studies had shown efficacy of

compounding natural origin in diet to maintain

normal glucose level.

1.2.1 Mangifera indica

M. indica is tropical plants consumed for its tasteful

fruits. Leaves, stem bark and fruits are utilized for

their health benefits due to high content of vitamin A

and C, flavonoid and phenolic compounds. The

seeds of M. indica displayed an inhibitory activity

against alpha-amylase and glucosidase, two enzymes

involved in carbohydrate digestion. Additionally, it

prevented diabetes complication by interrupt alpha

reductase (Irondi, Oboh, & Akindahunsi). Leaves

extract suppress dipeptidyl peptidase- IV which

resulted in insulin secretion (Muthukumaran,

Srinivasan, Venkatesan, Ramachandran, &

Muruganathan).

Due its lowering effects on blood glucose level,

mangifera should be consumed routinely in daily life

based on scientific evidence. A study of diet

modulation using mangifera indica seeds conducted

by Irondi et al. (2016) . Seeds were dried and

grounded to produce kernell flour. The

administration of diet supplemented with 10-20% of

M. indica-kernell flour decreased fasting blood

glucose in streptozosin induced-diabetic rats, 3-fold

higher than diabetic rats received non-supplemented

food on day 21. Glycosilated haemoglobin value

was improved in treated rats at 6%, whereas diabetic

rats value was 10%. The kernell flour contained

flavonoid and phenolic acids, essential metabolites

for antihyperglycemic activity. Catechin, rutin,

quercetin, quercitrin, kaempferol, gallic acid, caffeic

acid, ellagic acid, and cholorogenic acid were

metabolites identified in mangifera seeds (Irondi et

al., 2016).

Consumption of diet containing catechin for 76

day decreased serum glucose in rats. In glucose

tolerance test, rats fed with catechin showed lowered

glucose amount after 120 minutes of glucose

feeding. Biomarkers for oxidative stress, albumin

and 8-hydroxy deoxyguanosine (8-OH dG) were less

excreted in urin showing catechin activity as

scavenger for free radicals (Igarashi, Honma,

Yoshinari, Nanjo, & Hara, 2007). Catechin was

observed to stimulated peroxisome proliferator

activated receptor (PPAR) γ, other key to treat

hyperglycemia (Shin et al., 2009).

There were numbers of studies reported that

using rutin 5-100 mg/kg in diabetic rats reduced

FBG and random glucose level. Rutin protected

neuron, kidney and liver from damage. It also

benefited on impairment of sexual function (Gullón,

Lú-Chau, Moreira, Lema, & Eibes, 2017). This

advantage might be correlated with its antioxidant

activity (Ghorbani, 2017).

Quercetin (15 mg/kg bw day) stimulated

endogenous antioxidant enzymes, superoxide

dismuthase (SOD), catalase and glutathione

peroxidase (GSP) in STZ-induceddiabetic rats

(Abdelmoaty, Ibrahim, Ahmed, & Abdelaziz, 2010).

The mechanism on how a flavonols like

quercetin works involving the formation of complex

with Cu that neutralizes hydroxyl radical, singlet

oxygen and hydrogen peroxide which cause

encountered oxidative stress in diabetes (Nimse &

Pal, 2015).

Figure 1. Quercetin

SKIC-MHS 2018 - The 2nd Syiah Kuala International Conference on Medicine and Health Sciences

Kaempferol given for 30 days at dose 5 and 10

mg/kg to STZ induced-diabetic rats benefit in

reducing glucose level and restoring neuron

conduction by neutralized oxidative stress. This

finding showed evidence that kaempferol enabled to

correct neuropathy as complication of chronic

hyperglycemia (Kishore, Kaur, & Singh, 2017)

1.2.2 Peperomia pellucida

P. pellucida in Indonesia, is known as kaca-kaca,

tumpangan air, rangu-rangu atau gofu goroho.

Leaves contained minerals, cardenolides, saponin,

alkaloid, tannin (Egwuche, Odetola, & Erukainure,

2011). A methanol extract showed the existence of

flavonoids and phenolic compounds and inhibit

oxidative reactions (Nirosa & Raman, 2012).

As nutrients in diets, a study conducted by

Hamzah et al showed the benefit of P. pellucida in

controlling diabetes. Fresh leaves were dried at room

temperature and processed to produce fine powder.

Diabetic animals induced by intraperitoneal alloxan

were fed with diet contained 10 and 20% of

Peperomia pellucida leaves. The glucose level was

measured after 28 days feeding and compared to the

negative and positive controls. The result showed

60% decrease in blood glucose level which was

close to positive control received glibenclamide. The

antioxidant activity was confirmed by the increase of

superoxide dismutase, CAT and GSH, the

endogenous antioxidants. Lipid peroxidation which

is abundant in diabetes was reduced. (Hamzah,

Odetola, Erukainure, & Oyagbemi, 2012).

Figure 2. Ellagic acid

Susilawati et al succeeded to isolated ellagic acid, an

antihyperglicemic agent from peperomia pellucida

(Susilawati et al., 2017). In different study, ellagic

acid showed antioxidant activity in DPPH assay and

inhibitory activity of lipid peroxidation. As alpha-

amylase inhibitors, ellagic acid displayed a better

potency compared to rosiglitazone, glimepiride and

metformin (Mehta et al., 2017)

Ellagic acid tightly interacted with glycogen

phosphorilase, an enzyme that stimulate breakdown

of glycogen. The interaction cause the inhibition of

glucose production in hepar (Kyriakis et al., 2015).

Administration of 10 mg/kg BW ellagic acid with 10

mg/kg BW pioglitazone showed more potent effect

as hypoglycemic agents compared to a single agent

use in diabetic rats. The combination influenced

positively on gene expression for GLUT 4 and

PPAR gamma (Nankar & Doble, 2017).

1.2.3 Sesamum Indicum

In in vitro study, butanol extract of black sesame

inhibited alpha glucosidase higher than inhibitory

against alpha amylase with activity superior

compared to acarbose, a standard drug.

Phytochemical screening identified glycosides,

tannin, terpenoids and steroids (Amutha &

Godavari).

Clinical trials revealed that sesamum seeds

stimulated the activity of enzymatic antioxidants,

such as SOD, as well as non-enzymatic antioxidants,

vitamin E (Vittori Gouveia, Cardoso, de Oliveira,

Rosa, & Moreira, 2016).

Akanya, Isa, Adeyemi, and Ossamulu (2015)

showed that 10%- 20% sesame seed in diet lowered

blood glucose about 35-37%. Zhou, Lin, Abbasi, and

Zheng (2016) found that black sesame contained

more phenolic acid compared to white sesame,

whereas flavonoid found to be more in white sesame

rather than in black sesame. The existence of

phenolic and flavonoid was correlated with the

antioxidant activity. Sesamol, sesamin and

sesamolin were lignant identified in a large amount

in black sesame which explained its superior

antioxidant activity (oxygen radical absorbance

capacity (ORAC) value :132.33 µmol TE/g).

Sesamin decreased blood glucose level and

stimulated cardiac function in STZ induced diabetes

rats after given orally 100 and 200 mg/kg for 4 week

(Thuy et al., 2017). Since hydroxyl functional group

is important to react with radicals, sesamin and

sesamolin with 4 OH showed more potent activity

against free radical compared to sesamol that only

pose 2 OH group (Jeng & Hou, 2005).

Figure 3. Sesamol

A Mini Review: Phenolic Compounds in Diets for Managing Type II Diabetes

Figure 4. Sesamolin

1.2.4 Passiflora edulis

Feeding 0.5–25 mg/kg of pectin from P. edulis to

alloxan induced-diabetic rats reduced blood glucose

(Silva et al., 2011). Extract of P. edulis peel were

given at dose 250 and 500 mg/kg to diabetic rats

induced by STZ for15 days. The result showed a

controlled blood glucose level with an increase of

SOD level which reflected its antioxidant effect.

Additionally, histophalogy evaluation revealed the

organ protective effects (Kandandapani, Balaraman,

& Ahamed, 2015)

Peel flour was also tested in 43 diabetic

respondents. Each volunteer consumed 30 g/day for

two months. The result showed a decrease in blood

blucose (de Queiroz et al., 2012). Supplemented diet

with 30% of peel-fluor of Passiflora edulis prevented

insulin resistance in mice induced by 8 week-

administration of 10% fructose. The study identified

two phenolics compounds, caffeic acid and

isoorientin (Goss et al., 2018).

Caffeic acid affected the expression of genes

including glucose transporter 2(Glut 2), insulin 1

(Ins 1) and some proteins played roles in increasing

insulin production (Bhattacharya, Oksbjerg, Young,

& Jeppesen, 2014). Caffeic acid is one of

hydroxycinnamates that scavenge free radicals by

giving its hydroxyl hydrogen to inhibit cells

destruction (Nimse & Pal, 2015).

Figure 5. Caffeicacid

Figure 6. Isoorientin

In a study using murine and human adipocyte, it was

revealed the mode of action how isorientin worked

as antidiabetic agent which affected insulin signal

transduction. Normally, insulin binds to insulin

receptor (IR) which then caused phosphorylationof

the receptor, followed by activation of

phosphatidylinositol 3 kinase (PI3K). PI3K

phosphorylate protein kinase B resulted in a

movement of glucose transporter (GLUT 4) to

membrane to start glucose absorption. Isoorientin

stimulated phosphorylation important protein IR,

PI3K and protein kinase B (Alonso-Castro, Zapata-

Bustos, Gómez-Espinoza, & Salazar-Olivo, 2012).

1.2.5 Aegle Marmelos

A. marmelos, known as maja in Indonesia, is

classified into Rutaceae. In a clinical study,

consumption of Aegle Marmelos Correa leaf 20

g/100 mL reduce fasting blood glucose and HbA1c

about 20%, observed after 4 weeks. The leaves

contained aegelin 2, scopoletin and sitosterol

(Nigam & Nambiar, 2018).

Identification using UHPLC-PDA showed the

presence of aegeline (alkaloid), umbelliferone,

scopoletin, marmesinin, 8-hydroxypsoralen,

angelicin and marmelosin (simultaneous, avula).

Phenolic compounds identified using RP-HPLC

analyses were gallic acid (GA), p-coumaric acid (p-

CA), vanillic acid (VA), p-hydroxy benzoic acid (p-

HBA), syringic acid (SA), ferulic acid (FA) and

chlorogenic acid (ChA) (Wali, Gupta, Mallick,

Guleria, & Sharma, 2015)

SKIC-MHS 2018 - The 2nd Syiah Kuala International Conference on Medicine and Health Sciences

GA and p-CA restored glucose regulation

indicated by decreased glucose level and HbA1c and

inclined insulin. Degeneration of neuron function in

brain of diabetic rats was improved by affecting

expression of protein Bax and Bcl-2 (abd moneim,

gallic acid).

In vivo study on streptozosin-induced diabetic

rats, given 100 mg/kg b.w of p-CA, showed the

suppression of stimulant enzymes in

gluconeogenesis along with improvement of serum

lipids contributed for hiperglicemia. Administration

of p-CA disrupted expression of protein GLUT 2

(Amalan, Vijayakumar, Indumathi, &

Ramakrishnan, 2016) which facilitate glucose

transportation across cell membrane and stimulate

insulin secretion (Thorens, 2015).

Diabetic rats treated with GA (20 mg/kg b.wt.

per day) and p-CA (40 mg/kg b.wt. per day) for 6

weeks displayed the hepatoprotective effects

reflected by the controlled level of alanin transferase

and aspartate aminotransferase (Moneim, El-Twab,

Ashour, & Yousef, 2016) . GA and p-CA affected

expression of tumour necrosis factor (TNFα) and

PPAR γ (Abdel-Moneim, El-Twab, Yousef, Reheim,

& Ashour, 2018). TNFα is a cytokine known to

induced insulin resistance and found overproduced

in adipocytes. Inhibition of its gene expression was

believed to induce insulin sensitivity (Moller,

2000).

In a study evaluating phenolic compounds as

antidiabetic agents showed that glucose was

maximally absorbed into cells when VA was

applied. In diabetic rats given 30 mg/kg bw of VA

for 3 weeks the glucose and insulin level were

decreased showing activity against insulin resistance

(Chang et al., 2015).

SA improved hyperglycemia by inhibiting

formation of glycoprotein, a complex of protein and

carbohydrate. In diabetic organism, the unutilized

glucose was bonded to protein. The administration

of SA 50 mg/kg bw in alloxan induced diabetic rats

for 30 days effectively normalized the amount of

glycoprotein including hexose, hexosamine, fucose

and sialic acid Muthukumaran et al. (2013).

Narasimhan, Chinnaiyan, and Karundevi (2015)

found that FA countered expression of GLUT 2 by

inhibiting the binding of GLUT 2 transcription

factors with their promotors. The transcription

factors including sterol response element–binding

protein (SREBP)-1c and Hepatocyte nuclear factor

(HNF). These molecules made complex with

promotor at specific site which then induced

expression of gene for GLUT 2. Hiperglycemia

stimulate the interaction of SREBP)-1c with

promotor (Im et al., 2005)

2 CONCLUSIONS

In diabetes mellitus treatment, supplemented diet is

essential to provide active agents which play roles in

inhibiting glucose absorption, stimulating insulin

production and increasing cells glucose uptake.

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A Mini Review: Phenolic Compounds in Diets for Managing Type II Diabetes