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Annals of Life Sciences 4 (2019) 1–18

Research Article

Review on Antidiabetic Activity of some Medicinal Plants which are commonly used in a

Folk Herbal Compound/Medicine for Diabetes

M Khalid Iqbal1, Dr. Haseeb Anwar1,, Abdul Sami1*, Muhammad Abid1*, Imtiaz Mustafa1, Sadaqat

Ali2 Sheza Jhangir2, Aks Noor2

1. Department of Physiology, Government Collage University Faisalabad, Pakistan

1*. Department of Eastern Medicine, The Islamia University Bahawalpur, Pakistan

2. Government Collage University Faisalabad, Pakistan

*Corresponding Author’s e-mail: [email protected]

ABSTRACT

Diabetes mellitus is the most common non-communicable metabolic disorder of endocrine system. Increasing incidence of diabetes mellitus is

becoming serious problem to human health throughout the world. It is the most important cause of death in the world. There are different synthetic

compounds used to treat the diabetes mellitus were discovered directly or indirectly from plant source. Since ancient time plants have been used as

main source of medicine to treat different diseases. There are many medicinal plants have antidiabetic property. Many studies have shown that

medicinal plants with hypoglycemic activity are used to treat diabetes mellitus.

Keywords: Diabetes mellitus, Medicinal plants, Hypoglycemia, Hyperglycemia, Fat and Protein

Introduction:

Diabetes mellitus (DM) defines a group of

metabolic disorders characterized by high

blood glucose levels. People with diabetes

have high risk of developing several serious

life-threatening health complications

resulting in higher medical care costs, lower

quality of life and increased mortality [1].

Diabetes mellitus According to WHO, the

term diabetes mellitus is defined as a

metabolic disorder of multiple cause

characterized by chronic defects in insulin

secretion, insulin action, or both. The effects

of diabetes mellitus include long-term

destruction, dysfunction and failure of

various organs. Diabetes mellitus may have

the specific symptoms such as thirst,

polyuria, blurred vision and loss of weight

[5]. Diabetes mellitus is not a single disorder.

From a medical point of view, it represents a

chain of metabolic disorders associated with

hyperglycemia and caused by partial or

complete insulin insufficiency. Contact to

chronic hyperglycemia can result in micro

vascular problems in the retina, kidney or

peripheral nerves [2]. The global prevalence

of diabetes and impaired glucose tolerance in

adults has been increasing over recent years

[3-4]. A definition of diabetes from a social

perspective includes the load that the disease

places on economies, in terms of both its

expensive treatment and linked with

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premature morbidity and mortality [2]. Many

plants have been found to be beneficial in

treatment of diabetes mellitus. Plants are the

major source of drug and are available in the

bazaar as extracts directly or indirectly from

the plant sources [6]. For the purpose of

protective and curative reasons plants were

used as medicine in several parts of the

world. Medicinal herbs were used to cure

diabetes in large proportion all over the

World because of the easy accessibility and

affordability [7]. The herbal drugs with

antidiabetic activity are yet to be

commercially prepared as modern medicines,

even though they have been acclaimed for

their therapeutic characteristics in the

traditional systems of medicine [8].

Prevalence:

In 1980, the World Health Organization

(WHO) estimated that there were 108 million

people living with diabetes and this count

increased fourfold in 2014 estimates [26].

The International Diabetes Federation (IDF)

estimated the worldwide prevalence to be

151 million in 2000 [27], 194 million in 2003

[28], 246 million in 2006 [29], 285 million in

2009 [30], 366 million in 2011 [31], 382

million in 2013 [32] and 415 million in 2015

[33]. Each estimate was established on the

latest data available. It was estimated that in

2017 there are 451 million (age 18–99 years)

people with diabetes in world [34].

Types of diabetes mellitus:

Insulin Dependent Diabetes Mellitus

(IDDM, Type 1) :

Type 1 Diabetes leads to incapability to

release insulin results in low rates of glucose

acceptance into muscles and adipose tissue

[9]. Pancreatic b-cells are damaged, usually

by autoimmune inflammatory mechanisms.

Serum autoimmune markers contain islet cell

autoantibodies and autoantibodies to

glutamic acid decarboxylase (GAD); insulin,

tyrosine phosphatases IA-2 and IA-2b, and

zinc transporter ZnT8. This damaging

process typically leads to absolute insulin

deficiency with undetectable levels of plasma

C-peptide, but the rate of development can be

variable[35].

Non-Insulin Dependent Diabetes Mellitus

(Niddm Type 2) :

Type 2 diabetes usually occurs in fat

individuals and is linked with hypertension

and dyslipidemia. Thus, the treatment

purposes to reduce insulin resistance and to

motivate insulin secretion. Diabetes is a

metabolic disorder where in human body

does not yield or properly use insulin, a

hormone that is necessary to convert sugar,

starches, and other food into energy. Diabetes

mellitus is described by constant high levels

of blood glucose (sugar). Human body must

maintain the blood glucose levels at a very

narrow range which is completed with insulin

and glucagon. The function of glucagon is

triggering the liver to discharge glucose from

its cells into the blood to produce energy [9].

Gestational diabetes (Type 3):

Gestational diabetes is high blood glucose

that usually develop during the period of

pregnancy and usually disappear after giving

birth of baby. It can occur at any stage of

pregnancy but is more common in the second

half of pregnancy.

Treatment of diabetes mellitus:

Insulin and oral hypoglycemic drugs:

Insulin therapy should aim to mimic nature,

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which is remarkably successful both in

limiting postprandial hyperglycemia and

inhibiting hypoglycemia between meals.

Different products of insulin are available for

example human insulin, beef insulin, pork

insulin. Insulin therapy is not free from

problems and adverse effects. The most

significant adverse effect are weight gain and

hypoglycemia when inappropriate dose of

insulin is taken and when there is mismatch

between meals and insulin injection. They

bind to sulfonylurea receptors on the ß-cell

plasma membrane, triggering closure to ATP

sensitive potassium channels, leads to

depolarize the cell membrane.

Administration of sulfonylureas to type 2

DM patient’s rises insulin release from the

pancreas and may be further increase insulin

levels by reduce hepatic clearance of the

hormones. It has been shown to increase

peripheral acceptance of glucose, and to

decrease hepatic glucose output almost 20-

30% when given orally but not intravenously.

Impaired absorption of glucose from the gut

has also been recommended as a mechanism

of action [10].

Herbal treatment of diabetes:

WHO are listed 21,000 plants, which are used

for curative purposes throughout world.

Among these 2500 species are in India, out of

which 150 species are used commercially on

a properly large scale. India is the biggest

producer of medicinal herbs and is called the

botanical garden of the world [10]. Among

these listed medicinal plants, many plants are

used to cure diabetes throughout the world.

Active anti-diabetic ingredients

extraction techniques:

Most of the extractions used in plants extract

research are linked with the conventional

techniques. In conventional extraction, the

release of the preferred compounds

traditionally required soaking and maceration

in mild solvents. In traditional Chinese

medicine practices, decoction in water is

mostly employed and is an effective method

to be considered in cases where the existence

of a chemical solvent is undesired [11-12]. In

addition to the soaking/maceration technique,

percolations using methanol and ethanol on

the stem were also useful [13-14]. Other

solvents for example acetone, petroleum

ether and hexane have also been used as

solvents in the conventional extraction [15-

16]. Additionally, extraction by liquid

nitrogen was also observed in some research

works [17]. The Soxhlet technique for

extracting anti-diabetic ingredient was not

famous until 2005, after which the extraction

technique was incorporated with ethanol and

light petroleum [18-19]. Other than solvent

extraction techniques such as lyophilization

[20-21] and sonification [22-23] have also

been used. Furthermore, supercritical fluid

extraction and microwave assisted

techniques have also been used in recent

decades. Supercritical fluid extraction on

lotus gem were carried out by Taiwanese

research teams to investigate the antioxidant

activity of the extract [24] and microwave-

assisted extraction was used to investigate the

bioactivity of tea flower polysaccharides

[25]. These two advanced, non-conventional

techniques offer attractive benefits of short

extraction time and solvent free active

compounds, respectively. The techniques

used in the extraction are tabulated in Table

1. The extraction techniques generally used

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in plant research are lacking in the

involvement of the engineering aspect as

well, and hence the processes are not

optimized. As a result, the therapeutic

effectiveness of the plants under

investigation might be affected.

Table 1: Various techniques used in plant extraction

Conventional extraction Non-conventional extraction

Water Soaking

Maceration by water, ethanol,

methanol

Solvent extraction (ethanol,

methanol, petroleum ether,

hexane, acetone, etc.)

Percolation by water

Soxhlet extraction involved

solvents

Lyophilization

Sonification

Supercritical fluid extraction

(carbon dioxide)

Microwave assisted Extraction

Antidiabetic effect of medicinal plants:

Momordica charantia (Cucurbitaceae):

Scientific name: Momordica charantia,

Kingdom: Plantae, Division: Magnoliophyta,

Family: Cucurbitaceae, Genus: Momordica,

Species: Charantia, Duration: Annual [37].

Some common names of M.charantia

include bitter melon, ampalaya, papilla, bitter

gourd, kho gua, salsamino, corrila or karela,

hanzal, assorossie, nigauri or goya, sora,

balsam apple, pear, pear or balsa mina, and

numerous other common names (see Taylor,

2002 [36] for extensive review and technical

data). M. Charantia is a flowering vine. It is

a tropical plant that is broadly cultivated in

Asia, India, East Africa, and South America

for its intensely bitter fruits that are

commonly used in cooking and as a natural

medication for treating diabetes [44]. It is a

climbing perennial that commonly grows up

to 5m and contain elongated fruits with a

knobby surface. It is a useful medicinal and

vegetable plant for human healthiness and

one of the most gifted plants for diabetes

[45]. Various animal studies have frequently

shown hypoglycaemic effects of the seeds,

leaves, fruit pulp and whole plant of MC in

normal animals [42-43]. Numerous

phytochemicals containing hypoglycemic

properties have been isolated from M.

charantia fruit. These phytochemicals

include glycosides (momordin, charantin),

alkaloids (momordicin), and polypeptide p

[39]. Ingredients of Momordica charantia

such as momocharin and momordicin which

is believed to have insulin-like chemical

structure and properties [37]. Charantin,

vicine and p-insulin (polypeptide) are also

reported as the active ingredients. It is a

famous herbal resource to treat diabetes. It

rises the mitosis of pancreatic cells and

partially recovers the ruined cells [38]. M.

charantia decrease plasma and hepatic

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triglyceride content and tissue fat

accumulation [40-41]. Various medicinal

properties are claimed for Momordica

charantia namely anti diabetic, anthelmintic,

abortifacient, antimalarial and laxative and in

galactogogue, jaundice, contraceptive,

pneumonia, leprosy and rheumatism [38].

Cinamomum zeylanicum (Laurceae) :

Cinamomum zeylanicum commonly known

as Dalchini, Darchini, Family: Laurceae.

Commonly part used is Bark. Main

mechanism of action is elevation in plasma

insulin that decrease the glucose level [48].

Cinnamon is a native of tropical Asia and Sri

Lanka. The tree occurs in South India up to

heights of 500 m but is common at lower

heights. The tree occurs in month of January

and fruits ripen from month of May to

August. Cinnamon has been used as a spice

for thousands of years in different recipes. In

Ayurvedic medicine, cinnamon bark has

been used as an antiemetic, antiflatulent,

antidiarrheal and general stimulant [46-47].

Interest in cinnamon as a theoretically useful

treatment for type 2 diabetes began almost 20

years ago. There was isolate an unidentified

factor from cinnamon and named it as insulin

potentiating factor (IPF). They demonstrated

that IPF may be involved in the lessening of

the signs and symptoms of diabetes, and

other diseases related to insulin resistance

[49]. Active chemical constituents are

volatile oil, mannitol, tannin, ca+.oxalate

[48].

Citrullus colocynthis (Cucurbitaceae) :

Citrullus colocynthis also known as bitter

apple, is a desert plant of the family

Cucurbitaceae naturally modified to

dehydrate environments. It is a non-hardy,

herbaceous perennial vine, branched from the

base. Originally from tropical Asia and

Africa, it is now broadly distributed in the

Saharo-Arabian phyto geographic region in

Africa and the Mediterranean region [53].

Each plant yields 15-30 round fruits, about 3-

4 inches in diameter, green with undulate

yellow stripes and becoming yellow all over

when fruits dry. Seeds are small (1-4 inch or

less in length) smooth and brownish when

seeds ripe. The fruits are widely used

medically, especially for stomach pains the

pulp, due to its content of glycosides such as

colocynthin, it is an effective cathartic and

laxative. Several plant secondary metabolites

including cucurbitacins, flavonoids, caffeic

acid derivatives and terpenoids have earlier

been reported from this plant [54-55-56].

Citrullus colocynthis (CCT) is traditionally

used as an antidiabetic treatment in tropical

and subtropical countries [50]. This plant can

induce insulinotropic [51] and mild

immunostimulating effects [52]. The present

study was planned to test the acute and sub-

acute antihyperglycemic effect petroleum

ether extract of Citrullus colocynthis fruits on

Streptozotocin induced Diabetic rats. Oral

administration of two changed doses

(300&500 mg/kg P.O) of Citrullus

colocynthis fruit extract showed a significant

reduction in blood glucose level in diabetic

rats. [57].

Eugenia jambolana (Myrtaceae) :

Eugenia jambolana (EJ) usually known as

Jamun which belongs to the family

Myrtaceae, is a large evergreen tree growing

up to 30 m height, found widely in India and

the Asian subcontinent. The seeds of this

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plant have been reported to have many

medicinal properties in the Ayurveda system

of medicine. The fresh seeds are most

effective in diabetes as they quickly lessen

sugar in urine [58-59-60]. This study was

undertaken to study the effects of changed

doses (100, 200 and 400 mg per day) of

alcoholic and aqueous extracts of EJ on the

metabolic parameters (body weight and

serum glucose, insulin and triglycerides

levels) of fructose fed rats. Fructose feeding

for 15 days increased serum glucose and

insulin levels significantly and triglycerides

levels slightly vs. control (75.46 2.41 vs.

55.59 2.89 mg /dl, 6.26 1.27 vs. 15.04 2.43

mg /dl and 50.93 3.30 vs.41.1 3.33 mg /dl,

respectively). Treatment with 400mg per day

of aqueous extracts of EJ for 15 days

substantially prevented hyperglycemia and

hyperinsulinemia induced by a diet high in

fructose [61].

Gymnema sylvestre (Asclepiadaceae) :

Gymnema sylvestre (Family:

Asclepiadaceae) is a large, woody and

branched climber, distributed in the tropical

and sub-tropical areas of the world. It is

widely used in traditional systems of

medicine and mentioned in the traditional

literatures of Japan, Australia and Vietnam.

In India, it has been used in Ayurveda, the

traditional health care system, for several

centuries [62–63]. Many chemical

constituents are separated and characterized

from the plant. Gymnemic acids are

described to be the main class of chemical

constituents of Gymnema sylvestre.

Gymnemic acids I–IV were the constituents

considered to be of major importance, first

reported from the leaves of the plant followed

by gymnemic acids V and VI [66–67]. All

these constituents were isolated and

characterized from the aqueous extract of

leaves. Further investigations shown the

presence of gymnemic acids VIII and IX in

addition to gymnemic acids X–XII, which

were explained as glucosideuronic acid

derivatives of gymnemagenin acylated with

acetyl, tigloyl and/or 2-methylbutyroyl

moieties [67–68] Gymnemic acids III, IV, V,

VII and gymnemosides b were recognized as

the anti-hyperglycemic active constituents

[69]. Gymnema sylvestre is primarily used in

the treatment of diabetes and related

disorders. Separated compounds from the

leaves on oral and parenteral administration

were found to be useful in the treatment of

diabetes, impaired glucose tolerance, and

various situations associated with diabetes.

Moreover, these compounds decrease

polyuria, polydipsia and polyphagia,

regenerate the pancreatic cells, increase

endogenous insulin, lipase and amylase

levels, increase production of proinsulin and

c-peptide, and lesser blood lipids and

triglycerides and free fatty acids. A hydro

alcoholic extract without water-soluble

fraction significantly lower fasting blood

glucose levels, elevate pancreatic amylase

and lipase levels and number of pancreatic

islets and beta cells [64]. Separated

compounds in the form of pharmaceutically

acceptable salts can also be used in the

prevention or treatment of ailments related to

high blood sugar, high blood lipids, or blood

clotting [65].

Holarrhenaantidysenterica

(Apocyanaceae) :

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Holarrhena antidysenterica, Family:

Apocyanaceae, commonly known as Kurchi

[73]. Flowering and Fruiting Time from

February to June. Holarrhena

antidysenterica bark is collected from 8-10

years old plant. The bark of Kurchi is free

from attached wood and is peeled into small

parts. Kurchi is native to India and is found at

higher altitudes of 1000 meters. It is found in

Himalayan region and in the Assam, Uttar

Pradesh, states of Orissa and Maharashtra

[71]. About 30 alkaloids have been separated

from the plant, commonly from the bark.

These include conessine, kurchine, conimine,

kurchicine, conarrhimine, conessimine, iso-

conessimine, conaine, holacetin,

holarrhimine, and conkurchin [72]. The

ethanolic extract of H.antidysenterica seed

has antihyperglycemic activity as it drops

serum glucose level in diabetic albino rats

and significantly increases glucose tolerance.

It stops weight loss in diabetic rats and

corrects changed biochemical para meters

e.g. serum cholesterol, urea, triglyceride,

alanine transaminase, alkaline transferase,

total protein, aspartate transaminase,

creatinine and uric acid to near normal

physiological range. This is a signal of its

better metabolic control and powerful

antidiabetic property. Hence, further studies

are necessary to know the exact mechanism

of action and constituent responsible for

antidiabetic effect [70].

Nigella sativa (Ranunculaceae) :

Nigella sativa Linn. (family Ranunculaceae),

commonly known as black seed or black

cumin, is an annual plant that has been

frequently used in the Indian subcontinent

[75], Arabian countries [76] and Europe [77]

for cooking and medicinal purposes as a

natural medicine for a number of illnesses

and conditions that include asthma, diabetes,

bronchitis, inflammation, cough, headache,

eczema, fever, hypertension, dizziness and

influenza [78]. N. sativa seeds contain 36%–

38% fixed oils, alkaloids, proteins and

saponin and 0.4%–2.5% essential oil [74].

The effect of N. sativa on certain of the

complications of experimental (alloxan-

induced) diabetes mellitus in rabbits has been

investigated by several workers [79-80-81].

It was described that intraperitoneal

administration of the volatile oil of N. sativa

seeds (50 mg/kg) significantly reduced (by

about 15%–23%) the fasting blood glucose

concentration in normal and hyperglycemic

rabbits, 4–6 h after administration. Insulin

concentration was not affected by the

treatments, possibly indicating that the

hypoglycaemic effect was facilitated by an

(yet unidentified) mechanism that does not

involve insulin [79].

Swertia chirata (Gentianaceae) :

Swertia chirayata commonly known as

Chirayata, Family: Gentianaceae, Whole

plant is used. Main mechanism of action is to

stimulate insulin release from islets [82]. A

methanol extract of S. chirata plant (CT)

possessed antidiabetic activity and contains

mangiferin (MG), amaroswerin (AM),

sweroside (SW), amarogentin (AG) and

swertiamarin (SM) as major active

constituents [88]. These active constituents

are known to have antidiabetic, antitumor,

antiviral, chemo preventive, anticholinergic,

antioxidant and immunomodulatory activity

[83-84-85-86]. The hexane fraction of the

alcoholic extract of S.chirayita is reported to

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indicate significant hypoglycaemic activity

in albino rats [88]. Single oral administration

at a dose of 250 mg/kg body weight induced

at once a drop-in blood sugar and an increase

in plasma immune reactive insulin (IRI)

without inducing liver glycogen

concentration. Interestingly, daily

administration of the crude fraction at the

same dose for 28 days resulted in a significant

rise in liver glycogen level. It is suggested

that the hexane fraction may not be capable

of inhibiting intestinal absorption of glucose

and probably acts through its insulin-

releasing effect [89].

Terminalia chebula (Combretaceae) :

Terminalia chebula (T. chebula) is a

flowering evergreen tree of the family

Combretaceae. It has numerous common

names such as black myrobalan, ink tree, or

chebulic myrobalan (English), haritaki

(Sanskrit and Bengali), harada (Marathi and

Gujrati), harad (Hindi), Karkchettu (Telgu)

and Kadukkaya (Tamil). In Tibet, T. chebula

is known as the “King of Medicine” [90]. T.

chebula has been reported to exhibit a range

of biological activity, including antidiabetic

[96], anticancer [95], antimutagenic [97-98],

antibacterial [99], antifungal [100], and

antiviral [101-102] activities, etc. Oral

administration of 75% methanolic extract of

T. chebula (100mg/kg body weight) decrease

the blood sugar level in normal and alloxan

diabetic rats significantly within 4 h.

Continued daily administration of the drug

created a sustained effect [91]. The

chloroform extract of T. chebula seeds (100,

200 and 300 mg/kg body weight) created

dose-dependent reduction in blood glucose of

diabetic rats in both short term and long-term

study (300mg/kg body weight for 8 weeks).

Further, notable renoprotective activity was

also observed in T. chebula treated rats [92].

Oral administration of ethanolic extract of

fruits of T. chebula (200 mg/kg body weight

for 30 days) reduced the levels of blood

glucose and glycosylated hemoglobin in

streptozotocin (STZ)-induced investigational

diabetic rats [93]. In a similar study, aqueous

extract of T. chebula (200 mg/kg body weight

for two months) decrease the raised blood

glucose and increase in glycosylated

hemoglobin [94].

Tinospora cordifolia (Menispermaceae) :

Tinospora cordifolia (Willd.) Miers ex Hook.

F. & Thoms is a large, glabrous, deciduous

climbing shrub belonging to the family

Menispermaceae [103-104]. The stems of

Tinospora cordifolia are juicy with long

filiform fleshy aerial roots from the branches.

It is extensively used in folk and ayurvedic

system of medicine as general tonic,

hepatoprotective, antiperiodic, anti-

spasmodic, anti-inflammatory, antiarthritic,

anti-allergic and antidiabetic [104-105-106-

107-108-109-110-111]. A variety of

constituents are present in TC plant

belonging to different classes such as

alkaloids, diterpenoid lactones,

sesquiterpenoid, glycosides, steroids,

aliphatic compounds, phenolics and

polysaccharides. Water soluble isoquinoline

alkaloids viz., jatrorrhizine, palmatine,

berberine, tembetarine, magnoflorine,

choline, tinosporine, isocolumbine and

hydrastine are also existing (112-113-114-

115-116-117-118-119]. The oral

administration of several extracts (hexane,

ethyl acetate and methanol) of T. cordifolia

stem was found to have powerful antidiabetic

property by reducing blood sugar level in

9

streptozotocin induced diabetic rats at a dose

of 250 mg/ kg [120]. Saponarin separated

from leaf extract of T. cordifolia presented

hypoglycemic activity at doses of 20-80

mg/kg [121]. The hydro alcoholic and

chloroform extracts of T. cordifolia stem

reveals significant antidiabetic property at

250 and 500mg/kg dose dependently in

alloxan induced diabetic rats [122-123].

Conclusion:

Diabetes mellitus is a metabolic disorder

characterized by defects in insulin action and

secretion. According to the World Health

Organization diabetes mellitus increasing

day by day throughout the world. Many

synthetic drugs that are available in markets,

used to treat diabetes mellitus but have many

side effects. Many antidiabetic plants

traditionally used in the treatment of diabetes

mellitus. These medicinal plants have less

toxic effect and have no side effect. There

are many bioactive chemicals that are

responsible for antidiabetic property of these

antidiabetic plants. Further investigations

should be carried out to find the mechanism

of action of these antidiabetic plants.

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