Eur J Nutr

DOI 10.1007/s00394-017-1552-6

REVIEW

Antidiabetic plant-derived nutraceuticals: a critical review

Jayapal Naveen1 · Vallikannan Baskaran1

Received: 16 August 2017 / Accepted: 28 September 2017

© Springer-Verlag GmbH Germany 2017

Abstract Diabetes mellitus (DM) is one of the major Introduction

health problems in the world, especially amongst the urban
population. Chemically synthesized drugs used to decrease Diabetes mellitus (DM), commonly referred as “Dia-
the ill effects of DM and its secondary complications cause betes”, has been defined as a non-communicable disor-
adverse side effects, viz., weight gain, gastrointestinal der, often devastating, characterized by hyperglycemia
disturbances, and heart failure. Currently, various other [blood glucose > 200 mg/dl or fasting plasma glucose
approaches, viz., diet control, physical exercise and use of (FPG) ≥ 7.0 mmol/l (126 mg/dl) or 75 g oral glucose toler-
antidiabetic plant-derived molecules/foods are advocated to ance test (OGTT) with FPG ≥ 7.0 mmol/l (126 mg/dl) and/
manage DM, as they are economical with fewer or no side or 2 h plasma glucose ≥ 11.1 mmol/l (200 mg/dl) or glycated
effects. This review mainly focuses on antidiabetic plants, haemoglobin (HbA1c) ≥ 6.5% / 48 mmol/mol or random (no
chemically characterized plant molecules and plant-based fasting) plasma glucose ≥ 11.1 mmol/l (200 mg/dl)] [1]. DM
foods in the treatment of DM. Very little science-based is a multifactorial, fast-growing chronic genetic and lifestyle
evidence is available on the mechanism of action of plant- disorder in the world, known to mankind for over 2000 years
derived food molecules on the DM targets. Critical DM [2]. In DM, impaired carbohydrate, fat and protein metabo-
targets include α-amylase, α-glucosidase, DPP-IV, aldose lism can be observed as a result of either deficient or no
reductase, PPAR-γ, AMP kinase and GLUT4. In-depth release of the hormone insulin by the pancreas [3–6]. Insulin
studies carried out on a few of those targets with specific is an important hormone in the human body and is known to
mechanisms of action are addressed in this review. This convert sugar, starch, and other foods into an energy source.
review may help future researchers in identifying a right During the deficiency/no production of insulin, the blood
plant molecule to treat DM or to develop food formulations glucose level increases leading to different forms of various
for DM management. complications in the body (Fig. 1). DM-associated patho-
physiologic changes in several organs, caused by metabolic
Keywords Antidiabetic · Diabetes mellitus · Insulin · dysregulations, cause an individual to develop extreme
Nutraceuticals health risk complications [7], such as peripheral neuropathy
and damage to optic nerve system.
DM is of two types: type-1 diabetes (insulin-dependent
DM), characterized by the failure of insulin secretion and
type-2 diabetes (non-insulin-dependent DM), associated
with defective insulin secretion or action [8]. High morbid-
ity and mortality are caused by DM due to macrovascular
* Vallikannan Baskaran (blood vessels damage) and microvascular (retinopathy,
[email protected] nephropathy, and neuropathy) complications [9]. DM asso-
1
Department of Biochemistry, CSIR–Central
ciated micro- and macrovascular complications are shown
Food Technological Research Institute, Mysore, in Fig. 2.
Karnataka 570020, India

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 Eur J Nutr

Fig. 1  An overview of impor-

tant human organs that are
affected by diabetes mellitus.
*up arrow indicates up-regu-
lation; down arrow indicates
down-regulation

Fig. 2  Diabetes mediated micro- and macrovascular complications

Currently, diabetes ranks eighth, worldwide [10, 11] Hence, diabetes is increasingly being recognized as a major
with the likely 7th leading cause of death by 2030. More public health crisis in developing countries. It is estimated
than 415 million individuals with diabetes were reported in that India homes around 69.1 million diabetics subjects in
2015 by the International Diabetes Federation (IDF), with 2015, with another 30 million people with prediabetes and
5 million deaths in 2015 due to diabetes [10]. One in 11 will have the largest group of diabetic people by 2030 [10,
adults has diabetes; every 6 s one person dies from diabe- 12]. Worldwide, the prevalence of diabetes in 2015, pre-
tes; 12% of global health expenditure is spent on diabetes dicted data on diabetes incidence in 2040 along with percent
(i.e., $673 billion). Type-2 diabetes cause 70% of deaths in increase are given in Table 1.
developing countries and three out of four people live in There is a growing debate worldwide to bring down the
low and middle-income countries with diabetes [10, 11]. rate of diabetes incidence since the existing strategies to

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Eur J Nutr

Table 1  Worldwide prevalence, predicted and percent increase data therapeutic agents is one of the important areas of inves-
on diabetes mellitus tigation. Thus, it is recommended to ascertain safe thera-
Geographical region Prevalence (n × 106) Projected pies for adequate control of blood glucose, with no side
increase effects and is also cost-effective. Diabetes can often be
2015 2040 (predicted) (%) prevented mainly through healthy dietary practices and
North America and the Carib- 44.3 60.5 36.56 regular physical exercise. Though the treatment adoptions
bean are alike, increasing complication of diabetes is primar-
South and Central America 29.6 48.8 64.86 ily attributable to the differences in the food habits of an
The Middle East and North 35.4 72.1 103.67 individual (lifestyle change). Changes in food habit that
Africa include a diet rich in whole grains, vegetables, fiber-rich
Africa 14.2 34.2 140.84 foods and usage of medicinal plants and their extracts sug-
Southeast Asia 78.3 140.2 79.05 gested being useful in the management of diabetes, as evi-
Europe 59.8 71.1 18.89 dent from traditional medical practices [21, 22].
Western Pacific 153.2 214.8 40.20 Ancient Ayurveda, Siddha (traditional medicinal prac-
Total cases worldwide 415 642 54.69 tices) and recent scientific research findings describe the
Source: International Diabetes Federation [10] use of a number of medicinal plants and their extracts
to treat diabetes and its complications [23]. Most of the
currently available drugs are derived from plant sources,
Table 2  Diabetic incidence, predicted and percent increase data in either directly or indirectly [24]. Crude extracts and pure
relation to the sex and region compounds from medicinal plants are used in the treatment
Prevalence (n × 106) Projected of several diseases. Herbal drugs show less side effects
increase and are of cost-effective. Use of plant-derived drugs for
(%) diabetes has been approved by the World Health Organiza-
2015 2040 (predicted) tion (WHO) [25]. The prime reason for such approval is
Based on sex that medicinal plants are non-toxic, lack adverse effects as
Men with diabetes 215.2 328.4 52.60 compared to synthetic drugs and traditionally proven their
Women with diabetes 199.5 313.3 57.04 safety [26]. Plant-based drugs are reported to play a major
Based on region role in controlling diabetes mellitus [27–29]. The present
Diabetes in urban areas 269.7 477.9 77.20 review mainly focuses on the plant materials and their
Diabetes in rural areas 145.1 163.9 13.00 molecules and also on plant-based foods which exhibit
anti-diabetic properties.
Source: International Diabetes Federation [10]

combat diabetes are insufficient. Based on the available

statistics (Table 2), an alarming increase in the diabe- Commitment of review
tes incidence among the urban population has been pre-
dicted. A detailed investigation on the biochemical and Available literature covered in this review mainly deal
physiological complication of DM is of prime importance. with the role of medicinal plants against DM complica-
Presently, antidiabetic synthetic drugs, viz., meglitinides, tion. The cross research of relevant articles in the subject
sulfonylureas, thiazolidinediones (TZDs), biguanides, area was also examined for additional citations. The col-
α-glucosidase inhibitors, glucagon-like peptide-1 recep- lective message from available studies till date indicates
tor agonists, dipeptidyl peptidase (DPP)-IV inhibitors, that plant-based foods are a rich source of nutrients and
dopamine D2-receptor agonists, amylin analogs, bile phytochemicals and also comprise anti-diabetic molecules.
acid sequestrants and insulin and its analogs have been On the other hand, usage of such foods minimizes the side
approved for the management of DM [13–16]. However, effects of synthetic chemical drugs [30]. The objective of
synthetic drugs offer greater and faster effects but also this review is primarily to focus on different plants which
pose a higher degree of side effects, the most common are reported as antidiabetic, second on plant-derived mol-
being weight gain (except in the case of metformin) [17]. ecules (phytomedicines) and finally on the plant-derived
The other side effects include retention of fluid in the food products and dietary constituents with antidiabetic
body, hypoglycemia and increased frequency of heart effects. The possible mechanisms of action of those dietary
failure and gastrointestinal disturbances and most impor- components responsible for their beneficial effects on dia-
tantly synthetic drugs are costlier [18–20]. Therefore, the betes complications are also reviewed.
search for safer, economically viable, effective antidiabetic

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 Eur J Nutr

Anti‑diabetic plants Earlier investigations have documented an association

between the consumption of specific plant foods and the
Plants form a vital therapeutic aid for alleviating ailments of incidence of diabetes, also on the impact of dietary patterns
humankind. Most of the plant-derived substances are precur- on the management of metabolic disorders. Intake of fruits
sors for the chemically synthesized drugs and hence could be and vegetables [155], as well as whole grains [156, 157], are
used for therapeutic purposes [31]. As per the World Health inversely associated with the incidence of diabetes. How-
Organization (WHO), till now, only 10% of plants have been ever, most of the food ingredients undergo processing such
utilized by mankind; out of estimated 2,50,000–5,00,000 as soaking, blanching and cooking, roasting or dry heating
plant species on earth, only about 21,000 plants are used before being consumed which may enhance or reduce the
for medicinal purposes around the world. Among these, levels of bioactive constituents and their biological avail-
around 2500 species are found in India alone; however, ability and activity. The literature on processed plant foods
only 150 species are being used commercially as medicinal with antidiabetic effect and probable mechanism of action
plants [32]. Earlier, ethnobotanical and other reports suggest are listed in Table 5.
that > 1000 plant species have been shown to exhibit anti-
diabetic potential [33, 34]. Medicinal plants and their parts
having antidiabetic potential, parts of plants, in particular, Scientific evidence with specific targets
used for the extraction of anti-diabetic ingredients and mode
of their action are listed in Table 3. α‑Amylase and α‑glucosidase

α-Amylase (E.C.3.2.1.1) is a key enzyme of the digestive

Anti‑diabetic plant molecules system involved in the breakdown of starch into a mixture of
maltose, maltotriose, and α-(1–6) and α-(1–4) oligoglucans.
Plants are a rich source of phytochemicals, which are used α-Glucosidase acts on these substances and further degrades
in the treatment of various diseases and disorders. Second- to glucose which enters the blood circulation. Digestion of
ary metabolites of primary molecules that are reported to carbohydrate is delayed by the inhibition of these enzymes
have anti-diabetic properties are alkaloids, glycosides, poly- that results in a decrease in the postprandial blood glu-
phenols, carotenoids, terpenoids, flavonoids, anthocyanins, cose level [171, 172]. Hence, it is, therefore, considered
tocopherols, peptidoglycans, steroids, saponins, xanthones, as important targets for the treatment of type 2 diabetes.
and polysaccharides. Among the molecules, only less than Moreover, retardation of starch digestion by the inhibition of
10% of secondary metabolites have been isolated, identified α-amylase and α-glucosidase plays a key role in the control
and studied for their antidiabetic activity [96]. The antidia- of diabetes (Fig. 3). Pharmacologically active agents from
betic activities of several parts of the plants (aerial parts, plants source can serve as potent and specific inhibitors of
bark, flower, root, seeds, leaves, bulb, tubers, and whole α-amylase [172]. However, only a few molecules derived
plant) have been reported [97]. Extracts of the entire plant from plant source being examined for their α-amylase and
and/or parts of the plant are said to exhibit antidiabetic prop- α-glucosidase inhibitory activity to augment T2D.
erties. Owing to this, nutraceuticals from plants have created Recently, Sudha et al. [173] screened nine limonoids from
vast market globally as components of medicine and health A. indica (Neem) as inhibitors of α-amylase in silico and
foods. Table 4 represents some of the important plants with in vitro and reported that these inhibitors could be better
their active biomolecules that are studied for their antidia- nutraceuticals for the treatment of diabetes. Myricetin, one
betic properties. of the seven flavonoids, isolated from guava leaves, exhibited
comparatively higher inhibition of maltase and α-amylase
activity in vitro [174]. They have reported that the inhibitory
Antidiabetic plant‑based foods activity of myricetin is due to the hydroxyl functional groups
attached to the A- and C-rings of the compound. Aqueous
Plants are a rich source of both macro- and micronutri- and ethanol extracts from five brown seaweeds (Fucus spi-
ents, and also bioactive compounds and hence plant-based ralis, Pelvetia canaliculata, Fucus vesiculosus, Ascophyl-
foods possess potential therapeutic health effects by virtue lum nodosum and Fucus serratus) showed α-amylase and
of the same [152, 153]. As earlier during ancient period, α-glucosidase inhibition and also lowered glycemic response
plant-based foods are now encouraged rather than isolated and Ascophyllum nodosum being the strongest inhibitor of
nutrients from plants, owing to additional advantages. Con- α-amylase [175].
sumption of diverse dietary supplements with ingredients The structure-based computational method was used to
from plants or whole plants reported helping in combating search for plant-derived α-glucosidase inhibitors by Hyun
diabetes, obesity, cardiovascular disease and cancer [154]. et al. [176]. Out of 40 natural compounds screened, rutin,

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 Table 3  List of important plants with confirmed antidiabetic property
Botanical and common name Plant parts Nature of extraction Findings and probable mechanism Reference
Eur J Nutr

Acacia Arabica (indian gum) Bark and seed powder Chloroform extract Decreased serum glucose level due to insu- Wadood et al. [35], Patel et al. [36]
lin release in diabetic rat and rabbits
Adansonia digitata (baobab) Leaves, bark, and fruits Methanol extract Reduced blood glucose levels in streptozo- Tanko et al. [37]
tocin-induced diabetic rats
Achyranthes rubrofusca (chaff-flower) Leaves Aqueous and ethanol extract Decrease blood glucose level and improves Geetha et al. [38]
pancreatic SOD, CAT & glutathione activ-
ity in diabetic rats
Aloe barbadensis (aloe) Leaves Exudates Hypoglycemic effect in diabetic rats Awadi & Gumaa [39]
Aegle marmelos (bel) Leaves Methanol extract Reduced blood glucose in alloxan-induced Sabu & Ramadasan [40]
diabetic rats
Andrographis paniculata (kariyat) Root Chloroform extract Reduced blood glucose levels in alloxan- Rao [41]
induced diabetic rats
Anthocephalus indicus (kadamba) Root Ethanol extract Decreased blood glucose, triglyceride, Kumar et al. [42]
cholesterol, and phospholipid. Inhibited
the generation of superoxide anions of OH
radicals in alloxan-induced diabetic rats
Artanema sesamoides (artanema) Aerial part of plant Methanol extract Reduced fasting blood glucose level and Selvan et al. [43]
increased glycogen level in the liver of
streptozotocin-induced diabetic rats
Azadirachta indica (neem) Leaves Alcohol extract Uptake of glucose and deposition of glyco- Chattopadhyay et al. [44]
gen in rats increased
Argyriea cuneata (purple morning glory) Leaves Ethanol extract Antidiabetic and lipid-lowering activities in Biradar et al. [45]
alloxan-induced diabetic rats
Boerhavia diffusa (red hogweed) Leaves Aqueous extract Decreased blood glucose and increased Pari and Satheesh, [46]
plasma insulin level in diabetic rats
Barleria prionitis (porcupine flower) Leaves and root Ethanol extract Decreased blood glucose and glycated Dheer and Bhatnagar, [47]
hemoglobin level and increased serum
insulin and liver glycogen level in alloxan-
induced diabetic albino rats
Butea monosperma (flame of the forest) Seeds and bark Methanol and aqueous extract Hypoglycemic activity in rats Deore et al. [48]
Cassia auriculata (tanners cassia) Flowers Aqueous and ethanol extracts Reduced blood glucose level in alloxan- Hakkim et al. [49]
induced diabetic rats
Capparis deciduas (bare caper) Stem Ethanol extract Decreased blood glucose level in diabetic Rathee et al. [50]
rats
Ceriops decandra (flat-leaf spurred man- Leaves Ethanol extract Modulated blood glucose, hemoglobin, Nabeel et al. [51]
grove) liver glycogen and carbohydrate metabolic
enzymes in alloxan-induced diabetic rats
Cocinia indica (ivy gourd) Leaves Aqueous extract Hypoglycemic and increased glucose toler- Kamble et al. [52]
ance. Restored the activities of lipoprotein
lipase, glucose-6-phosphatase and lactate
dehydrogenase in diabetic human

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 Table 3  (continued)
Botanical and common name Plant parts Nature of extraction Findings and probable mechanism Reference

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Eugenia jambolana (jambu) Kernels Aqueous and ethanol extract Reduced blood glucose level, stimulated Ravi et al. [53]
insulin secretion in islets of Langerhans
and increased serum insulin levels in
diabetic rats
Costus igneus (insulin plant) Leaves Ethanol extract Reduced blood glucose level in diabetic rats Vishnu et al. [54]
Eucalyptus citriodora (lemon scented gum) Leaves Aqueous extract Reduced blood glucose level in alloxan- Arjun et al. [55]
induced diabetic rats
Ficus bengalensis (fig) Bark Aqueous extract Decreased plasma glucose and serum lipid Chaturvedi and Sharma [56]
levels in both IDDM and NIDDM rats
Fruit Ethanol extract Lowered blood glucose level in rat Sharma et al. [57]
Ficus racemosa (cluster fig tree) Bark Methanol extract Lowered blood glucose level in alloxan- Rao et al. [58]
induced diabetic rats
Gymnema sylvestre (gudmar) Leaf Dried leaf powder Induced the gluconeogenesis and reversed Shanmugasundaram et al. [59]
the pathological changes in the liver of
hyperglycemic rabbits
Heinsia crinata (bush apple) Leaves Ethanol extract Reduced fasting blood glucose level in Okokon et al. [60]
infected mice and rats
Helicteres isora (marodphali) Root Butanol and aqueous ethanolic extract Decreased blood glucose, TG and urea Venkatesh et al. [61]
levels. Restored pancreatic islets, kidney
glomeruli and liver to normal condition in
alloxan-induced diabetic rats
Hemidesmus indicus (Indian sarsaparilla) Root Aqueous extract Decreased blood glucose level. Prevented Mahalingam and Krishnan [62]
the formation of liver and kidney lipid
peroxides thereby restored hepatic
cytochrome P-450-dependent enzyme in
streptozotocin-induced diabetic rats
Hibiscus rosa-sinesis (hibiscus) Flowers Ethanol extract Reduced blood glucose level in rats Venkatesh et al. [63]
Holarrhena antidysenterica (kurchi) Seed Seed powder Hypoglycaemic activity, anti-hypercholes- Pankaj et al. [64]
terolaemic, and reduction in blood urea
nitrogen in rabbits
Ipomoea reniformis (morning glory) Stem Ethanol and aqueous extract Reduced blood glucose and lipid level in Sangameswaran et al. [65]
diabetic rats
Juglans regia (walnut) Leaves Methanol extract Decreased blood glucose and TG levels. Teimoori et al. [66]
Increase GPX, SOD & cell antibody level
in alloxan-induced male rats
Lantana aculeate (lantanas) Dried roots Ethanol extract Decreased TG and TC levels. Increased Kumar et al. [67]
insulin and glycogen concentration in
alloxan-induced diabetic rats
Lawsonia inermis (henna) Dried leaves Aqueous and ethanol extract Decreased glucose, cholesterol and TG level Syamsudin and Winarno [68]
in mice
Lepidium sativum (garden cress) Seed Aqueous extract Hypoglycemic effect in diabetic rats Eddouks et al. [69]
Eur J Nutr
 Table 3  (continued)
Botanical and common name Plant parts Nature of extraction Findings and probable mechanism Reference
Eur J Nutr

Momordica charantia (bitter melon) Pulp Aqueous extract Decreased blood glucose level in alloxan- Tripathi and Chandra [70]
induced diabetic rats
Seed and leaves Ethanol extract Anti-hyperglycemic and hypoglycemic Cakici et al. [71]
effect in streptozotocin-induced diabetic
rats
Mukia maderaspatana (Madras pea pump- Root Methanol extract Decreased blood glucose, TG, LDL, SGOT, Wani et al. [72]
kin) SGPT, ALP and increased total protein in
alloxan-induced diabetic rats
Myristica fragrans (nutmeg) Seeds Petroleum ether extract Improved liver and pancreas weight, lipid Somani and Singhai [73]
profiles and hemoglobin in diabetic rats
Nymphaea pubescens (pink water lily) Whole plant Ethanol extract Decreased blood glucose and regeneration Sreenathkumar and Arcot [74]
of pancreas in diabetic rats
Ocimum gratissimum (nchanwu) Leaf Methanol extract Reduced blood glucose level in alloxan- Bihari et al. [75]
induced diabetic rats
Ocimum sanctum (holy basil) Leaf Ethanol extract Stimulated insulin secretion in rat islets and Hannan et al. [76]
a clonal rat beta-cell line
Phoenix dactylifera (date palm) Leaf Alcoholic extract Reduced blood glucose, TG, water intake Mard et al. [77]
and increased plasma insulin level in
alloxan-induced diabetic rats
Phyllanthus niruri (gale of the wind) Aerial parts of plant Methanol extract Reduced blood glucose, TG and cell Okoli et al. [78]
regenerative property in alloxan-induced
diabetic rats
Aerial parts of plant Ethanol extract Antidiabetic and lipid lowering effect in Jasmin and Narasimhacharya [79]
diabetic rats
Phyllanthus simplex (Indian gooseberry or Whole plant Petroleum ether, ethyl acetate, and Anti-hyperglycemic effect in alloxan Shabeer et al. [80]
amla) methanol extract induced diabetic rats
Pongamia pinnata (Pongam tree) Leaves Ethanol extract Anti-diabetic activity in diabetic rats Lanjhiyana et al. [81]
Rubia cordifolia (Madder) Root Aqueous extract Hyperglycemic and hypertriglyceridemia Nilambari et al. [82]
effects and normalized loss of body
weight in STZ-induced diabetic rats
Solanum nigrum (black nightshade) Leaves Aqueous extracts Reduced blood glucose level and modu- Poongothai et al. [83]
lated lipid parameters in alloxan-induced
diabetic rats
Sphenostylis stenocarpa (African yam bean) Seeds Methanol extract Reduced blood glucose level in rats Ubaka & Ukwe [84]
Tephrosia villosa (wild indigo) Leaves Ethanol extract Reduced blood glucose level and pancreas Ahmad et al. [85]
regenerative power in alloxan-induced
diabetic rats
Terminalia chebula (chebulic myrobalan) Fruits Ethanol extract Insulin stimulating action in streptozotocin- Kumar et al. [86]
induced diabetic rats

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 Table 3  (continued)
Botanical and common name Plant parts Nature of extraction Findings and probable mechanism Reference

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Tinospora cordifolia (gulbel) Root Aqueous and alcoholic extract Reduction in blood glucose, lipids in serum Stanely et al. [87]
and tissues in alloxan-treated diabetic rats Grover et al. [88]
and increases glucose tolerance in diabetic
mice
Trigonella foenum-graecum (fenugreek) Seeds Ethanol extract Lowered blood glucose in alloxan-induced Mowla et al. [89]
diabetic rats
Vaccinium arctostaphylos (Caucasian Fruit Ethanol extract Decreased blood glucose and triglycer- Feshani et al. [90]
whortleberry) ide levels and enhanced GLUT-4 and
INS gene expression in alloxan-induced
diabetic rats
Vernonia amygdalina (bitter leaf) Leaves Aqueous extract + metformin Decreased blood glucose level in rats Michael et al. [91]
Withania somnifera (ashwagandha) Root, leaves Aqueous extract Hypoglycemic effect in alloxan-induced Udayakumar et al. [92]
diabetes rats
Zizyphus mauritiana (Indian jujube) Whole plant Petroleum ether extract Restored glucose, TG, HDL, LDL, urea, Jarald et al. [93]
creatinine, hemoglobin and glycosylated
hemoglobin levels in hyperglycemic rats
Rosa rubiginosa (rose) Petals Aqueous extract Antidiabetic effect in streptozotocin-induced Ju et al. [94]
diabetic mice
Trichilia catigua (Catuaba) Powdered bark Ethyl acetate extract Improves glucose homeostasis, endocrine Gomes et al. [95]
pancreas function and inhibits diabetic
nephropathy development in STZ-induced
type 1 diabetic rats
Eur J Nutr
 Table 4  List of some of the important plants and plant molecules with confirmed antidiabetic activity
Botanical and common name Plant parts Characteristic molecule Property and probable mecha- Experimental model used Reference
Eur J Nutr

nism proposed

Alkaloids
Syzygium cumini (jamun) Seed Mycaminose Increased secretion of insulin Rat Gupta and Saxena [98]
Murray koenigii (curry leaf) Leaves Mahanimbine Inhibited α-amylase and Rats Dinesh Kumar et al. [99]
α-glucosidase activity and
increased insulin secretion
Areca catechu (betel nut) Nut Arecoline Hypoglycemic activity Myoblasts cell line of skeletal Prabhakar and Doble [100]
increased translocation of muscles
GLUT4 via PPARγ
Tecoma stans (yellow bells) Leaves Tecomine Potentiated insulin secretion Diabetic rats Aguilar-Santamaría et al. [101]
from beta cells
Tinospora cordifolia (guduchi) Whole plant Berberine Increased insulin receptor In silico docking studies Al-Masri et al. [102]
expression and inhibited
DPP-4
Aegle marmelos (bael) Leaves Aegeline Anti-hyperglycemic activity STZ-induced diabetic rat Narender et al. [103]
Catharanthus roseus (Mada- Leaves Catharanthine Lowered blood sugar levels STZ-induced diabetic rat Chattopadhyay [104]
gascar periwinkle)
Phenolics
Trigonelia foenum-graecum Seeds Trigonelline Increased insulin secretion Diabetic rabbit Puri et al. [105]
(fenugreek)
Bougainvillea spectabilis Leaves Pinitol Stimulated glucose-dependent STZ-induced type-I diabetic Purohit and Sharma [106]
(great bougainvillea) insulin secretion and inhibited rats
α-amylase activity
Hemidemus indicus (Indian Root 2-Hydroxy 4-methoxy benzoic Increased insulin secretion STZ-induced diabetic rats Gayathri and Kannabiran [107]
sarsaparilla) acid
Cecropia obtusifolia (trumpet Leaves Chlorogenic acid Stimulated 2-NBDG uptake STZ-induced diabetic rats Alonso-Castro et al. [108]
tree) in insulin-resistant 3T3-L1
adipocytes
Pandanus odorus (screwpine) Root 4-Hydroxybenzoic acid Increased serum insulin and Rat model Peungvicha et al. [109]
liver glycogen
Anacardium occidentale leaves, barks, seeds Anacardic acid Activated adenosine monophos- C2C12 muscle cells Tedong et al. [110]
(cashew nut) phate, protein kinase, and
membrane glucose transport-
ers
Pterocarpus marsupium Heart wood Marsupsin Increased insulin and proinsulin Streptozotocin-induced diabetic Manickam et al. [111]
(Malabar kin) levels, glucose utilization in rats
insulin-dependent tissues
Callistemon rigidus (bottle- Stem bark Piceatannol and Scirpusin B Inhibited α-amylase activity Mice Kobayashi et al. [112]
brush)
Morus alba (mulberry) Root Moracin M, Mullberroside A Hypoglycemic activity Alloxan-induced diabetic mice Zhang et al. [113]
Larrea tridentata (Creosote Whole plant Masoprocol Decreased plasma glucose level Mice Luo et al. [114]

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bush)
 Table 4  (continued)
Botanical and common name Plant parts Characteristic molecule Property and probable mecha- Experimental model used Reference
nism proposed

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Cuscuta reflexa (Aamr Bel) Whole plant 6,7-dimethoxy-2H-1-benzo- Inhibited α-glucosidase activity In vitro study Anis et al. [115]
pyran-2-one
Pterocarpus marsupium Wood Epicatechin Insulinogenic activity converted Non-insulin-dependent diabetes ICMR [116]
(Malabar Kino) proinsulin to insulin subjects
Terpenoids
Ficus bengalensis (banyan Root Αlpha-Amyrin Protective/inhibitory action Diabetic rats Cherian and Augusti [117]
tree) against insulin degenerative
process
Paeonia suffruticosa (Tree Leaves Palbinone Enhanced glycogen synthesis Human HepG2 cells Ha et al. [118]
peony)
Sorbus decora (Showy moun- Stem 3β-Caffeate Increased glucose uptake C2C12 cells Guerrero-Analco et al. [119]
tain ash)
Euclea undulata (Guarri) Root Betulin Inhibited α-glucosidase Rats Deutschlander et al. [120]
Lactuca indica (Indian lettuce) Leaves Sesquiterpene lactones Glucose transport stimulating In vitro bioassay Hou et al. [121]
activity
Lagerstroemia speciosa Leaves Glucosol TM Glucose transport stimulating Type II diabetic patients Judy et al. [122]
(Crape-myrtle) activity
Psacalium decompositum Whole plant Sesquiterpene 3-hydroxyca- Anti-hyperglycemic activity Diabetic ob/ob mice Inman et al. [123]
(Matariki) calolide
Senega radix (Snakeroot) Root Glycoside and Senegin II Hypoglycemic activity Rats Yoshikawa et al. [124]
Polygala senega (Seneca Rhizome Glycoside desmethoxy senegin Reduced blood glucose level Normal and KK-Ay mice Kako et al. [125]
snakeroot) II
Salacia chinensis (Lolly Vine) Stem Friedelane triterpene and nor- Inhibitory effect on aldose In vitro bioassay Morikawa et al. [126]
friedelane triterpene reductase
Centella asiatica (Gotu kola) Whole plant Centellasapogenol A Inhibit aldose reductase In vitro bioassay Matsuda et al. [127]
Tinospora cardifolia (Giloy) Stem Tinosporaside Hypoglycemic STZ-induced rat Maurya et al. [128]
Caesalpinia bonducella (Fever Seed kernels Triterpenoid glycosides Hypo-glycaemic, reverses dia- Diabetic rat Parameshwar et al. [129]
nut) betes induced lipid and liver
glycogen levels
Flavonoids
Cecropia obtusifolia (Trumpet Leaves Isoorientin Hypoglycemic, activated insulin Murine 3T3-F442A pre-adipose Castro et al. [130]
tree) signaling pathway cell line
Parinari excelsa Sab (Sougue) Bark Myricetin and quercetin Hypoglycemic effect and Alloxan-induced rats Ndiaye et al. [131]
induced insulin secretion
Origanum majorana Linn. Leaves 6-Hydroxy-flavonoid & 6- Inhibited α-glucosidase activity Rats Kawabata et al. [132]
(Sweet Marjoram) Hydroxy-apigenin
Scutellaria baicalensis (Baikal Bark 5, 6, 7-Trihydroxy-flavone Inhibited α-glucosidase activity Caco-2 cells Nishioka et al. [133]
skullcap)
Eur J Nutr
 Table 4  (continued)
Botanical and common name Plant parts Characteristic molecule Property and probable mecha- Experimental model used Reference
Eur J Nutr

nism proposed

Eucommia ulmoides (Rubber Aerial part of plant

Quercetin3-O-a-larabinopyra Anti-diabetic activity human tumor cell lines Lee et al. [134]
tree) nosyl-(1→2)-β-D-
glucopyranoside
Eysenhardia platycarpa Branches and leaves 1′′(R)-5,4′,1′′- Anti-diabetic activity STZ-induced diabetic rats Narvaez-Mastache et al. [135]
(Mexican kidney wood) trihydroxy-6,7-(3′′,3′′- dimeth-
ylchromano) flavones
Erigeron annuus (Linn.) (East- Flowers 3-Dioxygenated flavanone Inhibited advanced glycation In vitro bioassay Yoo et al. [136]
ern daisy fleabane) Erigeroflavanone
Pueraria Lobata (Kudzu) Root Flavonoids, kakonein Reduced blood glucose level Alloxan-induced diabetic mice Shen and Xie [137]
Pueraria thunbergiana Flowers Tectorigenin Strong hypoglycemic and STZ-induced diabetic rats Lee et al. [138]
(Kudzu) hypolipidemic effects
Aegle marmelos (golden apple Leaf, seed, fruit Aegeline 2, Coumarin, Flavo- Reduced glucose, glycosylated STZ-induced diabetic rats Kesari et al. [139], Narendhira-
or Bengal quince) noid, alkaloid hemoglobin kannan et al. [140], Narender
et al. [103]
Allium sativum (garlic) Root Diallyl disulphide oxide, Ajoene Decreased glucose and lipid STZ induced diabetes rat Hattori et al. [141], Liu et al.
Allyl S-allyl mercaptocyst- concentration. Increased insu- [142], Eidi et al. [143]
eine propyl disulfide, S-allyl lin secretion
cysteine
Lycium barbarum (chirchita) Fruit Polysaccharides Increased GLUT4 activity and NIDDM rats Zhao et al. [144], Wu et al. [145]
insulin secretion
Withania coagulans (vegetable Fruit Essential oil, alkaloid Antidiabetic activity STZ-induced diabetic rats Babu et al. [146]
rennet)
Psidium guajava (guava) Leaf, fruit Terpen, flavonoid, strictinin Reduced blood glucose concen- STZ-induced diabetic rat Ojewole [147]
Isostrictinin, pedunculagin tration
Barbados aloe (aloe vera) Leaf Pseudoprototinosaponin Decreased glycosylated hemo- Db/db mice Ayodhya et al. [148]
Prototinosaponin globin
Ziziphus spina-christi (Christ Leaves Christinin-A, Fatty acid Reduced blood glucose level STZ-induced rats and alloxan- Mohamed et al. [149]
thorn) induced dog
Adhato davasica (adusa) Leaves Vasicine and vascinol Inhibited sucrose-hydrolyzing In vitro bioassay Hong et al. [150]
activity of rat intestinal
α-glucosidase
Allium cepa (Onion) Fruit Allyl propyl di-sulphide (APDS) Stimulated insulin production Rabbits Augusti and Mathew [151]
in the pancreas and reduced
blood sugar levels

13
 Table 5  List of processed foods with confirmed antidiabetic activity
Scientific ­namea Plant parts Type of processing Extraction Active ingredient Probable mechanism References

13
Bucholzia coriacea (won- Seed Blanching Powdered Phyto-chemicals Antidiabetic effect in Ijarotimi et al. [158]
derful Kola) diabetic-induced rats
‎Helianthus annuus (sun- Seed Soaked + cooked and Methanol extract Phenolics α-Glucosidase inhibition— Kunyanga et al. [159]
flower) roasted in vitro bioassay
Cucurbita pepo (pumpkin) Leaves and fruit Cooked and blanched Methanol extract Phenolics α-Amylase and Kunyanga et al. [159]
α-glucosidase inhibition—
in vitro bioassay
Moringa oleifera (drum- Leaves Cooked and blanched Methanol extract Phenolics α-Amylase and Kunyanga et al. [159]
stick) α-glucosidase inhibition—
in vitro bioassay
Amaranthus spinosus Leaves Cooked and blanched Methanol extract Phenolics α-Amylase and Kunyanga et al. [159]
(amaranth) α-glucosidase inhibition—
in vitro bioassay-
Zingiber officinale (ginger) Rhizome Cooked Aqueous extract Phenolics Increased insulin secretion Adeniyi et al. [160]
and lowered hyperinsu-
linemia in high-fat and
diabetic rats
Brown rice Seeds Germination Solvent and aqueous extract GABA, γ-oryzanol, Anti-hyperglycemia, low Ito et al. [161], Imam et al.
dietary fibre, phe- insulin index in human [162]
nolics model
Morinda citrifolia (Noni) Fruit Fermentation Ethanol extract Phenolics Decreased blood glu- Lee et al. [163]
cose, insulin resistance,
enhanced insulin sensitiv-
ity in KK-Ay diabetic
mice
Vigna radiate (Mung bean) Seed Fermentation Aqueous extract GABA & Amino acids Anti-hyperglycemic effect Yeap et al. [164]
in alloxan-induced-dia-
betic mice
Glycine max (Soybean) Seed Soaked and germinated Aqueous extract Phenolics Regulated blood sugar in Pathak [165]
diabetic patients
Glycine max (Soybean) Seed Sprouted Aqueous extract Phenolics Lower glycemic index and McCue et al. [166]
anti-hyperglycemic activ-
ity—in vitro bioassay
Smallanthus sonchifolius Leaves Boiling in water Aqueous extract Phenolics Protective agent against Honore et al. [167]
(Yacon) renal damage in diabetic
nephropathy
Hordeum vulgare (barley) Seed Soaked in tea catechin Powder Phenolics α-Glucosidase maltase, and Zhou et al. [168]
and Triticum aestivum sucrase inhibitory activi-
(wheat) ties—in vitro bioassay
Eleusine coracana (finger Seed Soaked + cooked and Methanol extract Phenolics α-Amylase and Kunyanga et al. [159]
millet) roasted α-glucosidase inhibition
activity—in vitro bioassay
Eur J Nutr
 Eur J Nutr

quercetin and myricetin binding energies ranged from

Vadivel and Biesalski [169]

− 8.2 to − 7.7 kcal/mol compared to antidiabetic drug acar-
bose. Antidiabetic effect of betulin extracted from Ruellia

Kunyanga et al. [159]

Kunyanga et al. [159]

Kunyanga et al. [159]

Kunyanga et al. [159]
tuberose L. showed noncompetitive inhibitory activities

McCue et al. [166]

Bede et al. [170]
in silico, in vitro and in vivo against α-amylase [177].
Similarly, non-competitive inhibition by diosgenin from D.

Ju et al. [94]
References

bulbifera towards α-amylase and α-glucosidase has been

documented by Ghosh et al. [178]. Two labdane diterpe-
nes (compound I and II) isolated from Alpinia nigra seed
showed a promising inhibitory effect against α-amylase
activity—in vitro bioassay

activity—in vitro bioassay

α-Amylase inhibition activ-

α-Amylase inhibition activ-

α-Amylase inhibition activ-

α-glucosidase inhibition

α-glucosidase inhibition

Lowered serum ALT and

Antidiabetic activity—in
[179]. Several pharmacological actions against diabetes

AST levels in diabetic

ity—in vitro bioassay

ity—in vitro bioassay

ity—in vitro bioassay

Reduced blood glucose

by traditional medicinal plants and their extracts have
Probable mechanism

vitro bioassay been reported. Ahmed et al. [180] isolated (ethyl acetate
α-Amylase and

α-Amylase and

fraction) three flavonoids, 5-deoxy flavone (geraldone),

level in rats
luteolin and isokanin (methanolic extract) from Albizzia

mice
lebbeck Benth bark (ALD) and studied α-glucosidase and
α-amylase inhibitory activity in vitro.

Dipeptidyl peptidase‑IV (DPP‑IV) inhibitors

Active ingredient

Dipeptidyl peptidase (DPP)-4 enzyme is responsible for the

Polyphenols

Phenolics
Phenolics

Phenolics

Phenolics
Phenolics

Phenolics

Phenolics

degradation and inactivation of many glucose regulating

incretin hormones such as glucagon-like peptide-1 (GLP-
1) and glucose-dependent insulinotropic polypeptide (GIP),
which cause an increase in insulin production from the pan-
creatic β-cells (Fig. 4). GLP-1 is found in numerous sites,
including kidney, intestine, and capillary [102]. Hence, the
Methanol extract

Methanol extract
Methanol extract

Methanol extract

Methanol extract

treatment of type 2 diabetes mellitus is focused on inhibition

Aqueous extract
Aqueous extract

Aqueous extract

of DPP4, GLP-1, and GIP, respectively. GLP-1 plays a vital

Extraction

role in the regulation of blood glucose level by stimulating

the secretion of insulin, increasing β-cell mass, inhibiting
the secretion of glucagon, reducing the rate of gastric emp-
tying and inducing satiety [181]. Effects of fructooligosac-
charide (FOS) isolated from Aureobasidium pullulans in the
Pan fried and powdered
Sprouting + oil frying

Browning under 84%

T2DM-induced rat had been evaluated [182]. It was found

Soaked + cooked and

Soaked + cooked and

Soaked + cooked and

humidity at 80 °C
Type of processing

that FOS enhances the enzyme activity of catalase and glu-

Soaked + cooked

tathione reductase. Molecular docking study revealed that

three sugar moieties present in the FOS (1-kestose, nystose,
Sprouting
roasted

roasted
roasted

and 1-b-fructofuranosylnystose) are potent DPP-IV inhibi-

tors as well as PPAR-γ agonists. FOS also reduced the fast-
ing plasma triacylglycerol and low-density lipoprotein level
along with slight increase in fasting plasma insulin level.
Plant parts

Hence, the authors suggested that FOS can be a nutraceu-

Ocimum gratissimum (clove Leaves

tical product, beneficial in diabetes-associated metabolic

Petals

Seeds
Seed

Seed
Seed

Seed

Seed

abnormalities.
The essential oil obtained by steam distillation of Cym-
Cajanus cajan (pigeon pea)

Arachis hypogaea (ground-

Cucurbita pepo (pumpkin)

Rosa multiflora var. platy-

bopogon citratus leaf sheath exhibited antidiabetic property

Acacia nilotica (babool)
Vicia faba (Field bean)

in poloxamer-407-induced type 2 diabetic (T2D) rats [182].

Table 5  (continued)

phyllas (red rose)

Results showed amelioration of glycemia, insulinemia and

Scientific ­namea

lipid dysmetabolism, accompanied with increased GLP-1

content in cecum and reduction of oxidative markers in
Soybean
basil)

CCEO-treated diabetic rats and the major compounds of

nut)

essential oil were geranial (42.4%), neral (29.8%), myrcene

13
 Eur J Nutr

Fig. 3  Role of α-amylase, α-glucosidase in starch digestion and metabolism

(8.9%) and geraniol (8.5%). Phytoconstituents—myrcenol, Aldose reductase

linalool, α-elemol and β-eudesmol—showed significant
interaction with PPAR-γ and DPP-IV, while pimelyl dihy- Aldose reductase (AR; EC: 1.1.1.21) is responsible for the
drazide showed interaction with PTP-1B in silico. Geng conversion of glucose to sorbitol in glucose metabolism in
et al. [183] identified active ingredients of Inonotus obliquus, the polyol pathway. Accumulation of sorbitol and its poor
having potential inhibitory effect against DPP-4 in vitro. penetration through cellular membranes and its slow metab-
Acrylamide, cystine, phenyl acetic acid, caprylone and oleic olism by sorbitol dehydrogenase results in hyperosmotic
acid isolated from Rhizophora mucronata reported to have stress to cells, which is a primary cause for the development
DPP-IV inhibition. Among the compounds isolated, cysteine of retinopathy, cataracts, neuropathy and nephropathy [186].
found to be an active inhibitor, for DPP-IV with binding Hence, aldose reductase inhibitors (ARIs) represent a novel
energy − 5.89 kcal/mol [184]. Ethanolic extract of Urena and potentially direct pharmacotherapeutic approach for the
lobata showed potent DPP-IV inhibitor activity than water treatment of certain diabetic complications (Fig. 5).
extract with the ­IC50 values of 1654.64 and 6489.88 mg/ Wang et al. [187] investigated the mode of binding and
mL, respectively. Based on the in silico analysis, mangiferin, inhibition mechanism through molecular docking and
stigmasterol and β-sitosterol in U. lobata extract have shown dynamics studies to explore the interactions of six phenolic
a potent DPP-IV inhibitory activity [185]. inhibitors with human aldose reductase (hALR2). All the
inhibitors showed the inhibitory effect by forming stable
hydrogen bonds with the hALR2 active pocket formed

Fig. 4  Role of natural DDP-4 inhibitor and its mechanism of action on the blood glucose level

13
Eur J Nutr

by the residues TYR48, HIS110 and TRP111. The aque- the genus Scrophularia. Among the compounds, acacetin,
ous, ethanol, methanol and ether extracts of the roots of a methoxy flavonoid, displayed a stable binding to ALR2
G. lutea were subjected to in vitro bioassay [188]. Among with lesser binding energy value. Molecular interaction
the extracts, ether and methanol extracts exhibited excel- studies showed that acacetin restricts the proton donation
lent inhibitory activities against both rat lens and human mechanism by forming H-bond with Tyr48, necessary for
ALR2. Secoiridoid glycoside and amarogentin are com- the catalytic activity of ALR2.
monly presented constituents in the roots of G. lutea were
used for molecular docking studies and reported that the Peroxisome proliferator‑activated receptors‑γ (PPAR‑γ)
extracts exhibited ALR2 inhibitory activity suggesting
that Gentiana or its constituents might be suitable to treat Peroxisome proliferator-activated receptors (PPARs) are a
diabetic complications. Chemical components (4Z, 12Z)- family of nuclear receptors and ligand activated transcrip-
cyclopentadeca-4, 12-dienone isolated from Grewia hirsuta tion factors which regulate genes involved in cell differen-
(Tiliaceae) reported having a pharmacological action against tiation and other metabolic processes, especially lipid and
diabetes. In silico docking studies with molecular targets glucose homeostasis and also suppress inflammatory pro-
such as aldose reductase, glucokinase, pyruvate dehydroge- cesses [192]. PPARs are nuclear receptors, known to get
nase kinase isoform 2, PPAR-γ, glycogen synthase kinase-3, activated by natural molecules [193]. Three different sub-
11β-Hydroxysteroid dehydrogenase, and glutamine and types of PPAR exist, PPARα, PPARβ/δ, and PPARγ, which
fructose-6-phosphate amidotransferase revealed that the are expressed in various cell types [194]. PPARγ is highly
ligand is (4Z, 12Z)-cyclopentadeca-4, 12-dienone. (4Z, expressed in adipocytes, and also controls differentiation
12Z)-Cyclopentadeca-4, 12-dienone showed good inhibitory and metabolic processes in liver, macrophages, bone cells
action, enabling as a new alternative compound to existing and skeletal muscle. It is an essential regulator of adipocyte
anti-diabetic compounds [189]. differentiation and maintains energy homeostasis. PPARγ
Madeswaran et al. [190] studied in silico docking of regulates genes involved in lipid metabolism, inflammation,
selected flavonoids (Epalrestat, esculetin, biochanin, fise- and glucose homeostasis modulates metabolism and inflam-
tin, herbacetin and butein) with aldose reductase. The bind- mation in immune cells, as well as controls cell prolifera-
ing energy ranged between − 9.33 and − 7.23 kcal/mol tion. This nuclear receptor regulates insulin sensitivity and
compared to that of standard aldose inhibitor Epalrestat thereby regulates glucose metabolism [195, 196]. PPARγ1
(− 8.73 kcal/mol). Inhibition constant (144.13–4.98 μM) is profusely expressed in adipose tissue, large intestine, and
and intermolecular energy (− 11.42 to − 7.83 kcal/mol) hematopoietic cells, and to a lesser degree in kidney, liver,
of the compounds also coincided with the binding energy. muscles, pancreas and small intestine. Under physiological
Manivannan et al. [191] investigated the binding mode and conditions, PPARγ2 is restricted to white and brown adi-
pharmacokinetic properties of polyphenolic compounds with pose tissue [197]. The difference between these isoforms
human aldose reductase (ALR2) inhibitory activity from is an added stretch of 30 amino acid residues in the ligand

Fig. 5  Mechanism of aldose

reductase and its inhibitor in
diabetic and normal conditions.
ARIs aldose reductase inhibitors

13
 Eur J Nutr

independent domain at the N-terminal end resulting in a Fang et al. [205] isolated kaempferol and quercetin from
higher transcriptional activity in PPARγ2 compared to Euonymus alatus which improved the insulin-stimulated
PPARγ1. glucose uptake in mature 3T3-L1 adipocytes significantly.
Activation of PPARγ is reported to increase the expres- Besides, they have reported that kaempferol and quercetin
sion and translocation to the cell surface of the glucose are weak partial agonists to PPARγ reporter gene. As shown
transporters GLUT-1 and GLUT-4, thus enhancing glucose by competitive ligand-binding assay kaempferol and querce-
uptake into liver and skeletal muscle cells and reducing tin could compete with rosiglitazone at the same binding
plasma glucose levels [198]. PPARγ agonists may also repair site as PPARγ. Hence, it was confirmed that kaempferol and
insulin sensitivity by decreasing TNF-α [199] and increasing quercetin potentially ameliorate hyperglycemia.
adiponectin expression [200]. Hence, PPARγ represents a Weidner et al. [206] studied amorfrutins binding capac-
significant target for the treatment of diabetes [201] (Fig. 6). ity and activation of PPARγ and reported a particular gene
Catechin is the most potent green tea polyphenols which expression compared to current synthetic PPARγ drugs.
increased the mRNA levels of various adipogenic markers, The PPARγ binding affinity constants of amorfrutins 1–4
such as adiponectin, PPARγ, FABP4, and LPL, as meas- ranged from 236 to 354 nM indicating that compounds bind
ured during adipocyte differentiation and also adiponectin strongly to PPARγ as compared to synthetic drug piogl-
secretion in human bone marrow mesenchymal stem cells itazone. Further, amorfrutin treatment in murine 3T3-L1
(hBM-MSC). In reporter gene assay and competitive ligand cells and human primary adipocytes (cell line studies),
binding study, (−)-catechin significantly activated PPARγ diet-induced obese and db/db mice (animal experiments)
in a dose-dependent manner. The risk of type 2 diabetes has improved insulin resistance. Improved metabolic and inflam-
been reported to be reduced by the consumption of green matory parameters without concomitant increase of fat stor-
tea by promoting sensitivity of insulin by direct activation age or other unwanted side effects such as hepatotoxicity
of PPARγ [203]. Kim et al. [204] screened active com- were also observed. Studies by Atanasov et al. [207] on
pounds from natural marine products those able to enhance the effect of natural product honokiol from the traditional
PPARα/γ transcriptional activity. Sargahydroquinoic acid Chinese herbal drug Magnolia bark revealed its PPARγ
(SHQA) and Sargaquinoic acid (SQA) from Sargassum agonist activity. Further, in an animal model, they have
yezoense were identified as novel PPARα/γ dual agonists. investigated the anti-hyperglycemic activity of honokiol in
The binding affinity of SQA with PPARγ was higher than comparison with pioglitazone and found weight loss and
that of a synthetic drug troglitazone. Binding affinity of improved glucose tolerance. Weidner et al. [208] studied
SQA leads to an activation of PPARγ transcriptional activ- the anti-diabetic property of ethanolic extract (CFE) from
ity. SQA and SHQA increased differentiation of adipocyte chamomile flowers (Matricaria recutita). CFE administra-
and enhanced expression of adipogenic marker genes such tion (300 μg/ml) led to a specific expression of target genes
as PPARγ, C/EBPa, aP2, resistin, adiponectin, and Glut4 in of PPARγ in human primary adipocytes. CFE treatment
3T3-L1 cells. Also, it was found that SQA and SHQA were was also associated with strong synthetic PPAR-targeting
potent PPARα/γ agonists and hence were beneficial for insu- molecules, viz., weight gain, liver disorders, or bone cell
lin resistance through regulation of adipogenesis. turnover. Molecular docking studies of flavonoids, viz.,

Fig. 6  PPARγ agonist and its mechanism of action against diabetic mellitus. Source: Kim and Ahn [202]

13
Eur J Nutr

quercetin, kaempferol, nicotifloroside, narcissoside and rutin to increase the AMPKα and the downstream target acetyl-
of Noni fruit (Morinda citrifolia L.) were revealed [209]. CoA carboxylase (ACC) phosphorylation [214].
The result revealed that all the flavonoids showed higher Egawa et al. [215] reported that caffeine intensely stimu-
binding energy (ranging between − 8.1 and − 8.5 kcal/mol) lates skeletal muscle AMPK activity (isoform AMPKα1
compared to that of synthetic drug rosiglitazone (–8.9 kcal/ and α2 activity) and insulin-independent glucose transport
mol). This suggested these flavonoid compounds could be with a reduction of the intracellular energy status. In the
used as potential antidiabetic molecules. absence of insulin, acute activation of AMPK is linked with
a reduction in phosphocreatine content and an increased rate
AMP kinase of 3-O-methyl-d-glucose transport activity. Caffeine in the
combination of contraction had additive effects on AMPKa
AMPK (5′AMP-activated protein kinase) is an energy- Thr172 phosphorylation, a-isoform-specific AMPK activity,
sensing enzyme activated when cellular energy levels are and 3-O-methyl glucose (3MG) transport. Caffeine alone
low, and signals to stimulate uptake of glucose in skeletal inhibited insulin-stimulated signaling, including Akt Ser473
muscles, fatty acid oxidation in adipose tissues, and reduces phosphorylation, glycogen synthase kinase (GSK) β Ser9,
hepatic glucose production. AMP-activated protein kinase insulin-stimulated phosphorylation and 3MG transport in
(AMPK) is an evolutionarily sustained serine/threonine skeletal muscles without affecting insulin receptor tyrosine
kinase whose activation triggers insulin-sensitizing effects, phosphorylation in isolated rat epitrochlearis muscle [216].
making it a beneficial target for T2D (Fig. 7). Hence, AMPK An augmented activation of α1-AMPK and phosphoryla-
is now well-known key target and metabolic regulator tion of ACCβ in the absence of total α-AMPK, in addition
involved in the contraction of skeletal muscles that mediate to Thr172 phosphorylation and α2-AMPK activation in
metabolic changes by physical exercise. Exercise promotes response to caffeine stimulation, was documented by Jensen
muscle contraction, and activation of Glut4, which triggers et al. [217]. This suggested that SR Ca2 + release may work
the entry of glucose into the cells followed by activation of through a CaMKK–AMPK pathway which further implies
glucose-dependent insulin sensitivity and secretion. From a that α-AMPKThr172 phosphorylation alone should not be
nutrition perspective, the question arises is that, can intake used to evaluate AMPK activation in isolated muscle. They
of nutrition-rich food have some effect on the AMPK acti- proposed that an SR Ca2+-activated kinase, most likely
vation? The review of Miyamot [211] provides valuable CaMKK, signals upstream of AMPK to increase glucose
information related to the ability of food-derived molecules uptake, which may be necessary for caffeine-stimulated glu-
in activation of AMPK, the effect being similar to the ben- cose uptake in mouse soleus muscle.
eficial effects of physical exercise.
Antidiabetic effect of berberine in two animal models
(Obese and diabetic C57BLKS/J-Leprdb/Leprdb male mice)
of insulin resistance and also in insulin-responsive cell lines
(3T3-L1) was investigated by Lee et al. [212]. Berberine
reduced the body weight and triglyceride content in plasma
and activity of insulin by down-regulating the activation
of genes responsible for lipogenesis enhanced along with
upregulating those genes involved in energy expenditure
in adipose and muscle tissue respectively in high-fat-fed
rats. Berberine treatment increased GLUT4 translocation
in a phosphatidylinositol-3-kinase-independent manner
in L6 cells, while reduced the accumulation of lipids in
3T3-L1 adipocytes by enhancing the activity of AMPK.
Further, Turner et al. [213] investigated the effect of ber-
berine on activation mechanism of AMPK and examined
derivatization of the same in in vivo efficacy and found that Fig. 7  AMP kinase action on whole-body energy and glucose metab-
olism. Modified Coughlan et al. [210]. Activation of AMPK (green
berberine-activated AMPK and improved insulin sensitiv-
lines) stimulates the energy-generating pathways in several tissues
ity in high-fat-fed male C57Bl/6J mice and male Wistar rats while inhibiting the energy-consuming pathways (red lines). In skel-
models. The majority of compounds target respiratory com- etal muscle and heart, activation of AMPK increases glucose uptake
plex I that enhance whole-body insulin sensitivity through and fatty acid oxidation. In the liver, AMPK activity inhibits fatty
acid and cholesterol synthesis. Lipolysis and lipogenesis in adipose
increased AMPK activity. The effect of catechins on AMPK
tissue are also reduced by AMPK activation. Activation of AMPK in
was examined in cultured cells (Hepa 1–6, L6, and 3T3-L1 pancreatic β-cells is associated with decreased insulin secretion. In
cells) and mice. Epigallocatechin gallate (EGCG) reported the hypothalamus, activation of AMPK increases food intake

13
 Eur J Nutr

Glucose transporter type 4 (GLUT4) levels of GLUT4 translocation by 65% and glucose trans-
port by 58% compared to control cells. Induction of 90%
Glucose transporter type 4 (GLUT4) is a protein found pri- GLUT4 membrane translocation and glucose transport
marily in adipose tissue and striated muscle (skeletal and was achieved by GA at 10 µM. However, the expression of
cardiac) of humans, encoded by the GLUT4 gene. Insulin GLUT4 and glucose transport reduced as the concentration
stimulates the glucose transport in the target tissues (muscles of GA increased.
and adipocytes) by the induction of translocation of GLUT4 The effect of epigallocatechin gallate (EGCg) on glu-
to the plasma membrane [218]. Interestingly, insulin secre- cose uptake and translocation of insulin-sensitive GLUT4
tion in pancreatic beta cell is glucose induced (i.e., through in skeletal muscle of mice and rats and insulin-resistant
GLUT 2 channel) (Fig. 8). L6 myotubes was investigated by Ueda et al. [221]. Oral
Singh et al. [219] investigated the action of Cinnamo- administration of EGCg (75 mg/kg body weight) promoted
mum tamala and Aloe vera for their anti-diabetic and insu- GLUT4 translocation in rat skeletal muscle and significantly
linomimetic effect in rat and NIH/3T3 cell lines. Routine increased glucose uptake accompanying GLUT4 transloca-
administration of each individually and in combination tion in L6 myotubes at 1 nm concentration.
(at 250 mg/kg) restored normal blood sugar, HbA1C, and
liver glycogen level and also restored pathological changes
of liver and kidney in alloxan (ALX)-induced diabetic rat. Current status of research
Further, gene expression and cellular insulin signaling path-
way in NIH/3T3 cells, viz., insulin receptor substrate (IRS), DM is a devastating metabolic disease, which causes various
phosphatidylinositol 3-kinase (PI3-K), AKT, and GLUT4 organs failure. Due to this, high economic loss occurs, and it
were analyzed by western blot, ELISA, semi-quantitative poses significant challenges to the economic development of
RT-PCR, and real-time PCR. An increased expression of developing nations [222]. Despite efforts aimed at combating
pIRS1and pAKT in a time-dependent manner was observed the DM, no definite cure has been found. A simple method
with no significant difference in expression level of PI3K- to prevent DM is that a change of lifestyle along with food
85α (85 kDa) protein between challenged and unchallenged habit; diet control (i.e., use of antidiabetic-compound-rich
groups. Enhanced expression of GLUT-4 by further sug- foods in daily life) and also by physical activities. Hence,
gested that both the phytochemicals serve as useful anti- depth of research is being aimed towards plant-derived mol-
diabetic drugs either by resembling or improving insulin ecules as they are economical with no side effects. Avail-
action. Anti-diabetic property of an active constituent from able reports have confirmed the benefits of plant foods and
sea buckthorn transfected leaves (SBL) and a hydrolysis plant-derived compounds with hypoglycemic effects in the
product of the same was studied in 3T3-L1 adipocytes by management of DM. Many phytochemical preparations and
Vishnu Prasad et al. [220]. Three compounds were examined compounds have been candidates for antidiabetic drug devel-
of which one was gallic acid (GA). The hydrolysis product opment. Although the currently available therapies have
of SBL (SBL-H+) at 5 µg/ml concentration increased the yielded considerable improvements in the quality of life of

Fig. 8  a Glucose-induced insulin secretion by pancreatic beta cell; b GLUT4 translocation and its mechanism of action on glucose uptake into
the cells

13
Eur J Nutr

diabetics, several reports have indicated that such improve- with respect to the mode of action and with no pinpointing
ments are associated with side effects. However, the rate of the effect of bioactives of plants such as polysaccharides,
developing these drugs is very slow, with only one clinical phenolics, glycosides, alkaloids, flavonoids, and carotenoids.
drug being reported to have gone from plant to pharmacy Importantly, most of the active compounds derived from
[223]. This may be due to lesser knowledge about these phy- plants have not been well characterized. In this regard, a
tochemicals and mainly due to lesser scientific evidence. A separate database/library needs to be brought out for the
flowchart demonstrating stepwise methodology to prepare future benefits of the researchers. In addition, toxicity of
and assess the antidiabetic property of a plant material or phytochemicals needs to be examined along with their bio-
its bioactive is described in Fig. 9. availability and metabolomics. So, scientific investigation on
the efficacy of plant-derived molecules as alternative medi-
cines/nutraceuticals to treat diabetes has to be encouraged
as diabetes poses many health complications.
Conclusion for future prospect
Acknowledgements Author Dr. Naveen, J. (Award No. F./PDFSS-
Currently, the incidence of diabetes and its associated com- 2015-17-KAR-11600) greatly acknowledges the University Grant Com-
plications are increasing worldwide and it is estimated that mission (UGC), Government of India, for financial assistance. The
the incident will grow further in coming future. Despite sev- authors are grateful to Dr. N. S. Mahendrakar, Ex-chief editor, Journal
of Food Science and Technology, for editing the manuscript for its
eral synthetic drugs were made available to manage the dia- English language.
betes, its related complications are still increasing. Despite
the availability of antidiabetic medicines, medications from Author contributions First author NJ performed the literature search
plants, especially traditional medicinal preparations, are and prepared the manuscript. Corresponding author VB edited the
found to be successful in treating diabetes. Hence, currently manuscript. All authors read and approved the manuscript.
traditional plant-based treatments for diabetes are encour- Compliance with ethical standards
aged owing to safe and no side effects compared to synthetic
medicines. Recommendations of WHO also emphasises Conflict of interest The authors declare that they have no conflict
use of components from plant origin practised in traditional of interest.
medicine [224]. However, very little scientific information
is available on the antidiabetic property of plants, in general,

Fig. 9  Flowchart demonstrating

stepwise methodology to pre-
pare and assess the antidiabetic
property of a plant material or
its bioactives

13
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