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Current Status of Commercial Anticancer Phytochemicals and Their Derivatives
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Chapter 9
Medicinal Plants for the
Treatment of Type 2 Diabetes
Bui Thanh Tung
VNU University of Medicine and Pharmacy, Vietnam National University, Hanoi, Vietnam
Nguyen Thi Ngoc Huyen
VNU University of Medicine and Pharmacy, Vietnam National University, Hanoi, Vietnam
163
ABSTRACT
Type 2 diabetes (T2D) is a metabolic disorder related to persistent hyperglycemia. It is characterized by
lack of secretion and/or reduce activity of insulin, which causes many chronic complications. Medicinal
plants offer a passel of remedies that resolve symptomatology and mitigate the progression of T2D.
Although several pre-clinical and clinical investigations indicate the success of conventional medicine
in the prevention and treatment of diabetes, still there are several side effects. Consequently, this necessitates the exploration of complementary and alternative treatment programs that may include natural
products as safe and effective anti-diabetic candidates. This chapter reviews the medicinal plants and
their bioactive compounds utilized in diabetes therapy and molecular targets of Type 2 diabetes treatment. The authors elucidate present findings and contribute to ongoing investigations into potential
alternative therapies for T2D.
INTRODUCTION
Diabetes mellitus, a chronic state of metabolic diseases, is caused by deficiency of insulin secretion and
insulin activity. There are three primary types of the disease: Type 1 diabetes (T1D), Type 2 diabetes
(T2D) and Gestational diabetes (GD). Of the three, Type 2 diabetes or non-insulin dependent diabetes
(NIDDM) is the most prevalent form of this disorder in the world (Jin et al., 2019). The preponderance
of this pathology is projected to significantly increase from 285 million (9.3%) in 2019 to 578 million
(10.2%) in 2030 and 700 million (10.9%) in 2045 (Federation, 2019). Although the main risk factors for
T2D are obesity, age, family history, hypercaloric diets and inactive lifestyle, the effect of this disease on
non-obese and physically active people is fundamental in determining an onset mechanism (Ferhati et
DOI: 10.4018/978-1-6684-5129-8.ch009
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Medicinal Plants for the Treatment of Type 2 Diabetes
al., 2019). The stable levels of glucose are maintained by a complicated mechanism containing hepatic
glycogenolysis and gluconeogenesis. After a meal, pancreatic β-cells secrete insulin preventing hepatic
glucose output and stimulating the glucose absorption into peripheral tissues (Alvim et al., 2015). The
World Health Organization has suggested that the oral glucose tolerance test (OGTT) is designed for
the diagnostic criteria of diabetes with fasting glucose 7.0 mmol/L or more. In addition, the expert
committee of the American Diabetes Association recommended a cut-point for the diagnostic criteria
at 6.5% or more of HbA1c level (Forouhi & Wareham, 2010). The aim of these therapeutic options is
to maintain patient blood glucose levels close to physiological range and to prevent serious symptoms
as well as late complications in the long term. The antidiabetic therapy currently contains oral drugs
reducing hyperglycaemia and exogenous insulin injection as a last method (Ferhati et al., 2019). This
book chapter will focus on proposing or determining a mechanism of action for antidiabetic agents
employed in the treatment of T2D.
MOLECULAR MECHANISM OF TYPE 2 DIABETES TREATMENT
AMP-Activated Protein Kinase (AMPK)
The AMPK heterotrimeric complex contains α-catalytic subunit with β and γ-regulatory subunits. Twelve
different AMPK molecules are comprised of four isoforms of α and β subunits (α
isoforms of γ subunit (γ
, γ2, γ3) (Alvim et al., 2015). Recent studies show the important role of AMPK
1
, α2, β1,β2) and three
1
in glucose uptake with in muscle cells in T2D patients. After the skeletal muscles contract, the glucose
uptake is prompted by increasing AMP/ATP ratio and decreasing creatine/phosphocreatine ratio. The
levels of AMP increase significantly leading to AMPK activation via residual threonine phosphorylation
172
) in the α-subunit by LKBI (upstream serine-threonine kinase) (Alvim et al., 2015). Another study
(Thr
also reported that AMPK activated by metformin based on the interaction between AMPK, LKBI and
axin in liver in vivo, HEK (Human embryonic kidney)-293 cells and embryonic fibroblasts of mouse
(Carling, 2017). The 5- aminoimidazole-4-carboxamide-1-β-D-ribonucleoside (AICAR) activation is
similar to AMP affecting AMPK. In vitro studies suggested that the glucose transport was increased
considerably by exposing to AICAR of rat muscles cells (Alvim et al., 2015).
The decrease in cold stimulated glucose uptake into brown-adipose tissue (BAT) as well as adipose
tissue AMPK was exhibited at obese and T2D patients. White adipose tissue (WAT) is known as a storage
repository and endocrine organ, in contrast, BAT can preserve thermal homeostasis via the dissipation of
large amount of energy in the heat-form. Many persuasive evidences have showed that AMPK regulated
the BAT development, preservation of mitochondrial activity of BAT and browning of WAT. In addition,
the activation of APMK in muscle and liver increases fatty acid uptake, oxidation and repress lipid and
cholesterol accumulation towards the therapeutic benefit in T2D people (Desjardins & Steinberg, 2018).
T2D treatments with metformin, the sodium glucose cotransporter-2-inhibition (SGT2i) such as canagliflozin drug increase significantly AMPK activation in the liver by restraining mitochondrial function.
Various natural products that decreased hyperglycaemia such as quercetin, berberine and resveratrol also
stimulate AMPK via mitochondrial function (Desjardins & Steinberg, 2018).
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Medicinal Plants for the Treatment of Type 2 Diabetes
Protein tyrosine phosphatase 1B (PTP1B)
The superfamily of protein tyrosine phosphatases (PTPs) and protein tyrosine kinases (PTKs) has a regulatory capacity for insulin and leptin signaling pathways via transfer of phosphate groups from specific
tyrosine (Tyr) residues or addition of phosphate groups to Tyr. Hence, PTPs and PTKs are involved in
T2D by the coordinated action as potential targets (Jänne et al., 2009).
PTP1B is a non-transmembrane protein tyrosine- phosphatase associated with negative modulating
insulin and leptin signaling in the cells. It is capable of the dephosphorylation of the activated insulin
receptor (IR) and the IR substrates after autophosphorylating several tyrosine residues on the intracellular kinase domain of IR-β subunit (Jin et al., 2019). PTP1B and T cell protein-tyrosine phosphatase
(TCPTP) were deleted in the hypothalami of obese mice leading to improve leptin and insulin sensitivity,
suppress feeding and enhance browning to reduce adiposity and increase glucose metabolism (Dodd et
al., 2019). A vivo assay has reported that 5’-AMP (pAMP) was promoted in plasma of obese diabetic
mice and exogenous 5’-AMP induced hyperglyceamia as T2D in wild mice. In addition, these adenine
nucleotides also associate with the activity of PTP1B in type 2 diabetes (Yang et al., 2019).
α- Glucosidase
α-glucosidase, an enzyme at intestinal brush border, is responsible for hydrolysis of disaccharides.
Inhibition of α-glucosidase induces to poor and slow absorption of carbohydrates and lead to blood
glucose reduction after a meal. In addition, this inhibition may also promote the liberation of glucagon
like peptide-1 which may increase to their effects on blood glucose levels (Health, 2017). α-glucosidase
inhibitors (AGIs) were recommended as efficiently first-line agents or in combination with other drugs
for T2D treatment. However, some studies have reported that the use of AGIs induced various unusual
adverse hepatic cases and increase of liver function impairment was exhibited in patients using acarbose
compared to patients without this drug. Moreover, flatulence, diarrhea, abdominal bloating and discomfort are common side effects of this agents (Inzucchi et al., 2015).
α-Amylase
α-amylase is also a member of α- glucosidase family which is necessary for the hydrolysis of α-1,4glycosidic bonds in starch, glycogen, oligo and polysaccharides. There are two types of α- amylase in
human body: salivary enzymes and pancreatic enzymes, both of them participate in the digestion which
produces glucose, maltose and oligo saccharides. These monosaccharides absorbed into the circulation
cause an increase of blood glucose level, which is associated with obesity, type 2 diabetes and other
metabolic diseases (Boehlke et al., 2015). Human α- amylase is encoded on chromosome 1 as member
of a multigene family and the different isozymes are only expressed in the salivary glands as well as
pancreas. The amy 1 gene encodes the former amylase expressed in the salivary, mammary and lacrimal
glands, while the pancreas secrete amylase isozyme encoded by the amy 2 gene (Tundis et al., 2010).
α-amylases have been widely researched as potential targets for the treatment of T2D. α- amylase inhibition does not base on regulation of hormones like insulin and glibenclamide, whose use in the long term
may develop the tolerance of these drugs (Bueno et al., 2019).
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Medicinal Plants for the Treatment of Type 2 Diabetes
Advanced Glycation End Products (AGEs)
Glycation plays an important role in instinctive destruction of cellular and extracellular proteins in living organisms. Advanced glycation end products (AGEs) are proteins and/or lipids becoming glycated
and oxidized after constant connection between reducing sugars (e.g., glucose) or short-chain aldehydes
(e.g., glycoaldehyde) and amino groups and/or high level of oxidative stress. There are three independent
pathways creating AGEs in vivo: the Maillard reaction, the Polyol Pathway and the increase of oxidative
stress causing the synthesis of a-dicarbonyl compounds such as glycolaldehyde, glyceraldehyde, glyoxal,
methylglyoxal and 3-deoxyglucosone. These reactive intermediates can further respond with circulating
proteins via a reversible Schiff base and Amadori products leading to additionally form AGEs like glucosepane associated with the mechanism of diabetic complications (Deluyker et al., 2017). The receptor
for advanced glycation end products (RAGE) belongs to the superfamily of immunoglobulins known as
a multi-ligand transmembrane receptor on several cell types including cardiomyocytes, endothelial cells,
macrophages, lymphocytes and ðbroblasts. High-mobility group protein (B)1, Mac-1, amyloid-β-protein,
phosphatidylserine and S-100 calcium-binding protein along with AGEs are among the most recognized
ligands of RAGE (Sanajou et al., 2018). AGEs-RAGE interaction can generate reactive oxygen species
(ROS) by activating nicotinamide adenine dinucleotide phosphate oxidase. ROS cause the alteration of
the protein structure and function as well as the impairment of excitation–contraction coupling at the
cellular level leading to develop cardiac dysfunction (Hegab et al., 2012). In addition, activation of the
AGE-RAGE axis relates to stimulate intracellular oxidative stress formation and activation of NF-κB
in vascular wall cells, resulting in promotion of atherosclerosis/inflammation-related gene expression
associated with vascular complications in diabetes (Yamagishi et al., 2015). Matsui et al. reported that
a RAGE-aptamer abrogated conceivably several diabetes related to renal impairments such as increase
in macrophage inðltration, surge of proðbrotic cytokines and proinñammatory as well as activation of
AGE-RAGE-oxidative stress axis (Matsui et al., 2017).
Based on above mentioned targets, several antidibetic drugs have been studied and used for T2D
patients such as metformin, sulfonylureas, Glinides, SGLT2i, AGIs However, the treatment with these
drugs in long term may cause a number of side effects including diarrhea, flatulence, weight again, nausea, especially, risk of hypoglycemic and therefore, we review different natural products as an important
alternative source of promising candidates against T2D.
NATURAL PRODUCTS USED FOR THE TREATMENT OF TYPE 2 DIABETES
Salvia Miltiorrhiza Bge.
Salvia miltiorrhiza (Labiatae) known as traditional Chinese medicine has been widely used for the
treatment of cerebrovascular diseases- and coronary artery diseases (Huang et al., 2015). The phytochemicals of S. miltiorrhiza reveal that it may include hydrophilic and lipophilic compounds such as
caffeic acid, isoferulic acid, protocatechuic acid, protocatechuic aldehyde, ferulic acid, rosmarinic acid,
dihydrotanshinone I, przewalskin, cryptotanshinone, tanshinone I, tanshinone IIA, salvianolic acid B and
salvianolic acid A (Zhong et al., 2009). In a vivo study, salvianolic acid B (SalB) has been a beneficial
effects on insulin action, glycogen production and activity of antioxidant enzymes, leading to improve
the symptoms of diabetes mellitus. According to this study, SalB (100 and 200 mg/kg) significantly in-
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Medicinal Plants for the Treatment of Type 2 Diabetes
hibited hyperglycaemia and enhanced sensitivity of insulin. Furthermore, the significant decrease of total
cholesterol, non-esterified fatty acids, hepatic and muscle glycogen as well as the increase of high-density
lipoprotein cholesterol were demonstrated in diabetic mice induced by high-fat diet and streptozotocin
(Huang et al., 2015). Another polyphenolic compound, Salvianolic acid A (SalA) notably reduced fasting
blood glucose, 24-h food and water intake, concurrently enhanced mitochondrial function of hepatic and
skeletal muscle tissues. In addition, SalA caused the activation of AMPK phosphorylation via Ca(2+)/
calmodulin-dependent protein kinase β (CaMKKβ)/AMPK signaling and independent of liver kinase 1
(LKB1)/AMPK pathways (Qiang et al., 2015). In a mouse model with diabetic nephropathy, S. miltior-
rhiza extracts ameliorated high levels of 24-h urinary protein excretion and reduced the kidney levels of
transforming growth factor β1, monocytes/macrophages and the receptor for RAGE (Lee et al., 2011).
Qian et al. (2012) showed that reduction of oxidative stress was induced by a decrease in the production
of malondialdehyde at day 30, simultenously increasing the formation of serum glutathione and activity
of antioxidant enzymes such as superoxide dismutase, paraoxonase and glutathione reductase at day 60
after administration of Salvia miltiorrhiza aqueous extract in T2D patients with chronic heart disorder
(Qian et al., 2012).
Punica granatum
An in vitro study examining a number of phenolic components in the extracts of whole pomegranate
containing seeds, peels, flowers and juice found that they had an ability to decrease carbohydrate digestion enzyme activity. The methanolic flower extract prevented α-amylase and α-glucosidase activity,
while the metabolic peel extract and two active compounds (gallic acid, ellagic acid) displayed selective
α-glucosidase inhibition (Kam et al., 2013). In another in vitro screening assay, the methanolic extract of
P. granatum rind inhibited three metabolism-related enzymes: hyaluronidase, tyrosinase and α-amylase
leading to therapeutic applications in many chronic diseases such as diabetes, hypertension and cancer.
The main active compound identified in this extract was quercetin and its inhibitory activities against
these enzymes was competitive, un-competitive and non-competitive, respectively (Ahmed et al., 2019).
The P. granatum seed oil (PSO) also has several bioactive components utilized into controling insulin
resistance as well as diet-induced obesity. Three dietary fatty acids isolated from PSO included punicic
acid, oleic acid, and linoleic acid, which prevented adipogenesis of human adipose-derived mesenchymal stem cells, improved inflammation, reduced glucose uptake and ATP formation. Furthermore,
the study showed that these fatty acids were found to regulate the mRNA expression of the studied
obesity-associated gene transcripts (Trichur Khabeer et al., 2019). Banihani et al. (2014) investigated
the influence of pomegranate juice (PJ) on fasting serum glucose (FSG) levels and insulin levels in 85
participants with type 2 diabetes. They observed significant decrease of FSG levels, insulin resistance
and increase of β-cell function at 3 hours after oral administration of 1.5 mL of PJ, per kg body weight.
This effect did not relate to the sex of participants and was less potent in elderly patients (Banihani et
al., 2014). These studies suggest that Punica granatum extract may be an effective source for the treatment of type 2 diabetes.
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