Potential of Clinacanthus Nutans as an Alternative Therapeutic Agent for Diabetes Mellitus

Full text

Potential of Clinacanthus Nutans
as an Alternative Therapeutic Agent
for Diabetes Mellitus
Nurlaili Susanti(B)
UIN Maulana Malik Ibrahim, Malang, Indonesia
nurlaili.susanti@kedokteran.uin-malang.ac.id
Abstract. Target various aspects of the pathway in DM. One of plant traditionally
used in Southeast Asia for diabetes treatment is Clinacanthus nutans (CN). Several
studies have proven the pharmacological activity of CN as an antidiabetic. This
study aims to review the potential of CN as an antidiabetic and discuss its possible
mechanism of action. We present a literature review of original article regarding
the antidiabetic effect of CN using invitro and/or invivo models. The article were
obtain through Google Scholar database from 2012–2020 using the keywords
“Clinacanthus nutans”, “antidiabetic”, and “hypoglycemia”. A total of 39 article
were obtained, 25 articles were excluded being not relevant and the remaining 14
articles were selected for the study. CN possess antidiabetic effect through inhibi-
tion α-glucosidase, increasing insulin secretion and improving insulin resistance.
This effect related to its antioxidant activity. Clinacanthus nutans can be selected
as a source of industrial product development for the treatment of DM according
to its medicinal value. The mechanism of action is still unclear, so further research
are needed.
Keywords: Medicinal plants ·Clinacanthus nutans ·antidiabetic ·antioxidant
1 Introduction
Diabetes Mellitus (DM) is a chronic metabolic disorder characterized by deficiency of
insulin secretion, insulin action, or both leading to hyperglycemia (ADA, 2019). Chronic
hyperglycemia lead to multiple abnormalities including macrovascular complications
(coronary heart disease, stroke and peripheral vascular disease) and microvascular com-
plications (end-stage renal disease, retinopathy and neuropathy) (Zheng et al. 2018;
Harding et al. 2019). DM has become a metabolic disease with the highest prevalence in
the world, according to IDF (2019), the global prevalence of DM was around 463 million
(9.3% of the entire population) in 2019 and is estimated to increase to 578 million in
2030 and 700 million in 2045 with a death rate of 4.2 million in 2019.
Although insulin and currently available hypoglycemic drugs can control hyper-
glycemia, it’s not completely prevent long-term vascular complications in diabetic
patients (Thrasher, 2017). In addition, some of the side effects of these drugs cannot
be tolerated by patients such as weight gain, hypoglycemia, and abdominal discomforts
© The Author(s) 2023
Y. Yueniwati et al. (Eds.): ICoMELISA 2021, AHSR 57, pp. 27–36, 2023.
https://doi.org/10.2991/978-94-6463-208-8_6

28 N. Susanti
Fig. 1. Morphology of C. nutans leaves (Kamarudin et al. 2017)
(Stein et al. 2013). Therefore, investigation for new antidiabetic agents have continued.
Medicinal plants that have been widely used empirically in traditional medicine practices
have gained attention as antidiabetics, not just for safer alternative drugs, but also multi-
tasking abilities for targeting various aspects in the treatment of diabetes include lowering
blood glucose, increasing insulin biosynthesis, improving insulin resistance, enhancing
the antioxidant system and prevent long-term complications due to hyperglycemia (Patel
et al. 2012).
Clinacanthus nutans, family of Acanthaceae, is widely used in Malaysia, Thailand,
and Indonesia as a traditional medicine for treatment of various diseases including herpes
infection, cancer, diabetes, and skin disorder (Tan et al. 2020). It’s commonly called
Sabah Snake Grass in Malaysia, or phaya yo in Thailand, or dandang gendis in Indonesia.
Traditionally, it is commonly consumed as raw vegetables, juices, or herbal teas (A. Alam
et al. 2016). The leaves of C. nutans are pale green, narrow oblong with sharp shoots,
2–12 cm long and 0.5–1.5 cm wide. There are 6–7 pairs of lines that stand out on
the leaf surface and are covered by fine hairs (Kamarudin et al. 2017). Many studies
have reported the pharmacological activities of C. nutans including antiviral (Kunsorn
et al. 2013), antibacterial (Arullappan et al. 2014), antivenom (Daduang et al. 2005),
antiinflammatory (Mai et al. 2016), anticancer (Wang et al. 2019), antioxidant (Kong
et al. 2016), neuroprotective (Azam et al. 2019), analgetic (Zakaria et al. 2019), and
antidiabetic (Umar Imam et al. 2019). However, there has not been a comprehensive
literature review on the antidiabetic potential of C. nutans. In this review, the beneficial
effects and proposed mechanisms of C. nutans in diabetes are discussed (Fig. 1).
2 Methods
We present a literature review involved research article using Google Scholar database
from 2012–2020. Search conducted with the keywords “Clinacanthus nutans” “antidi-
abetic” or “hypoglycemic”. The articles were selected first by the title, then by the
summary, and finally by reading the full text. The inclusion criteria are research article
on the the antidiabetic effect of C. nutans using invitro or invivo models. Articles were
excluded if they were review articles, editorial material and book chapters.

Potential of Clinacanthus Nutans as an Alternative Therapeutic Agent 29
3 Result
A total of 39 article were obtained, 25 articles were excluded being not relevant to the
scope of this review and the remaining 14 articles were selected for the study. After
selecting these articles, we conducted a review by mainly assessing author name, pub-
lication year, objective, research model, type of extract and dose, and main findings of
each research.
4 Discussion
4.1 Antidiabetic Activity of C. Nutans Using Invitro Studies
A search of in vitro studies on the antidiabetic activity of C. nutans found 6 relevant arti-
cles (Table 1). All studies evaluated the inhibitory activity of CN against α-glucosidase
and α-amylase. α-glucosidase is an enzyme that hydrolyze carbohydrates into glucose in
the small intestine, whereas α-amylase is the enzyme that hydrolysis of alfa-1,4-glucan
bonds in starch, maltodextrins and maltooligosaccharides into simple sugars (dextrin,
maltotriose, maltose and glucose) (Tundis et al. 2010). Although this enzymes is not
directly implicated in the etiology of diabetes, the inhibition of α-glucosidase and α-
amylase can significantly reduce the post-prandial glucose levels and therefore can be an
important strategy in the management of metabolic disorders, including type 2 diabetes
mellitus (Riyaphan et al. 2018).
Lee et al. (2014) demonstrated that the methanol extracts of C. nutans inhibited α-
glucosidase activity (leaf 13.57% and stem 17.67%) at concentration of 5 mg/mL. Wong
Table 1. Brief Summary of Invitro Studies on Antidiabetic activity of C. nutans
No Reference Methods Study model Treatment Inhibitory Effect
1(Lee et al.
2014)
invitro α-glukosidase
inhibition test
methanol extract leaf 13.57%, IC50
19.09 μg/mL
stem 17.67%, IC50
19.74 μg/mL
2(Wong et al.
2014)
invitro α-glukosidase
inhibition test
aqueos extract 88.2%, IC50
30 μg/mL
3(Khoo et al.
2015)
invitro α-glukosidase
inhibition test
ethanol extract Leaf 41.7%, stem
35.7%
IC50 not
determined
4(M. A. Alam
et al. 2017)
invitro α-glukosidase
inhibition test
methanol extract 72.16%, IC50
37.47 μg/mL
5(Abdullah &
Kasim, 2017)
invitro α-amylase
inhibition test
ethanol extract 64.25%, IC59
4.28 μg/mL
6(Murugesu
et al. 2018)
invitro α-glukosidase
inhibition test
methanol extract IC50 3,07 μg/ml

30 N. Susanti
et al. (2014) found that the aqueous extract of C. nutans in a higher dose (50 mg/mL)
showed high levels of inhibition α-glucosidase activity (88.2%, IC50: 30 mg/mL). Khoo
et al. (2015) showed that the ethanol extract of C. nutans inhibited α-glucosidase activity
up to 41% at concentration of 5 mg/mL. Alam et al. (2017) reported on the α-glucosidase
inhibitory activity of C. nutans methanol extract showed that butanol fraction had signif-
icantly higher α-glucosidase inhibitory activity (72.16%, IC50: 37.47 μg/mL), which is
close to the standard quercetin (positive control) (IC50: 38.54 μg/mL). Murugesu et al.
(2018) demonstrated that the methanol extracts of C. nutans with n-hexan and ethyl
asetat fraction showed inhibition α-glucosidase activity (IC50 3,07 μg/ml). Abdullah &
Kasim (2017) demonstrated that the ethanol and aqueous extracts of C. nutans inhibited
α-amylase activity (64.25%). Based on this study, the methanolic extract of C. nutans
leaves was the type of extract that showed the best α-glucosidase inhibitory activity,
where the butanol fraction showed a greater inhibitory effect. In addition, there was a
significant correlation of the α-glucosidase inhibitory with the antioxidant activity and
the total flavonoid contents of the fractions (Alam et al. 2017).
4.2 Antidiabetic Activity of C. Nutans Using Invitro Studies
In experimental studies with in vivo models (Tab. 3), the effect of C. nutans was observed
in various doses from 15 mg/kg to 500 mg/kg with different treatment periods between
9 to 28 days. Antidiabetic effect has been shown from C. nutans leaves extracted with
aqueos, methanol and ethanol solvents. The glucose-lowering effectof C. nutans has been
reported significantly in several studies, including administration of aqueous extract of C.
nutans leaves 150 mg/kg for 9 days in mice induced by alloxan 50 mg/kg (Nurulita et al.
2012), administration of ethanolic extract of C. nutans leaves 15 mg/kg for 14 days in rats
induced by a diet high in fat and fructose (Retnaningsih et al., 2019), and administration
of ethanol extract of C. nutans leaves 75 mg/kg for 14 days in rats induced by STZ
50 mg/kg (Dewinta et al. 2020).
The effect of C. nutans in increasing serum insulin concentration significantly was
reported in study by Umar Imam et al. (2019) on administration of leaves aqueous extract
200 mg/kg for 28 days in high fat diet (HFD) and streptozotocin (STZ) induced rats. The
other study by Sarega et al. (2016a) on administration of leaves aqueous and methanolic
extracts at doses of 500 and 250 mg/kg for 7 weeks in high fat and high cholesterol
(HFHC) rats enhances serum insulin. There are no data suggesting that increased insulin
secretion is due to improvement in pancreatic βcell dysfunction. Studies on insulin
resistance using a homeostatic model have shown that aqueous and methanolic extracts
of C. nutan leaves can increase insulin sensitivity marked by decreased insulin resistance
biomarkers retinol binding protein 4 (RBP4) and mediated through upregulation of
the gene encoding insulin receptor substrate (IRS), phosphatidylinositol-3-phosphate
(PI3K), adiponectin and leptin receptors (Sarega et al. 2016b).
Oxidative stress has a significant role to trigger insulin resistance and contribute to
development of type 2 diabetes (Pitocco et al. 2013). Many studies have been demon-
strated the antioxidant properties of C. nutans using invitro method (Yong et al. 2013;
Arullappan et al. 2014; Wong et al. 2014). The majority study use DPPH method because
its an easy, fast, and reliable method that does not require a special device and reactions,
as compared to other antioxidant assays (Aksoy et al. 2013). In vivo studies on the

Potential of Clinacanthus Nutans as an Alternative Therapeutic Agent 31
antioxidant activity of C. nutans have been reported in 2 articles. Sarega et al. (2016a)
demonstrated that the antioxidant activity of C. nutans is associated with the ability to
modulate the expression of various antioxidant genes including superoxide dismutase,
catalase, glutathione reductase, and glutathione peroxidase. Umar Imam et al. (2019)
showed that C. nutans extract at a dose of 200 mg/kg for 4 weeks could significantly
reduce markers of oxidative stress and increase total antioxidant levels in rats model
of type 2 DM. Based on the data, it appears that the antioxidant activity of C. nutans
occurs through mechanisms, including the ability to scavenge free radicals and modulate
expression various antioxidant enzyme.
Obesity and dyslipidemia are health problems that contribute to impaired glucose
homeostasis in diabetes. It affects a large number of people with sedentary lifestyles
where physical activity is reduced and calorie intake is high. Free fatty acids promote
oxidative stress and increase lipid peroxidation, which are implicated in the etiology
of diabetes (Matsuda & Shimomura, 2013). Sarega et al. (2016a) reported that after
7 weeks of C. nutans treatment in mice fed a high-fat and high-cholesterol diet, they
showed improvements in their lipid profiles, including a decrease in total cholesterol
(TC), TG, LDL-C, and VLDL-C levels and an increase in HDL-C levels. Abdulwahid
Kurdietal.(2019) showed that a high-fat diet treated with C. nutans (1500 mg/kg) led
to significant reductions in body weight and relative visceral fat.
The beneficial effect of C. nutans on sorbitol-related complications was evaluated
by Umar Imam et al. (2019). The results showed that aqueous extract of C. nutans could
be reduced the sorbitol contents in the kidney and nerve significantly suggests that it
could be used to manage diabetic neuropathy and nephropathy due to sorbitol accumula-
tion in these organs. Diabetes is also associated with complications of the development
of atherosclerosis and cardiovascular disease. Administration of C. nutans in study by
Azemietal.(2020) could to increase endothelial vasodilation and reduce endothelial con-
traction through expression of eNOS protein thereby improving endothelial dysfunction
in diabetic rats.
4.3 Antidiabetic Mechanism of C. nutans
The research articles in this review indicate that C. nutans extract has potential as an
antidiabetic. The exact mechanism by which C. nutans exhibits antidiabetic activity
needs to be clarified by further studies, the proposed mechanism is shown in Fig. 2.C.
nutans reduces the absorption of carbohydrates from the small intestine and prevents a
postprandial rise in blood glucose levels. C. nutans reduces fasting hyperglycemia pos-
sibly due to decreased endogenous glucose production in the liver. C. nutans increases
insulin secretion from pancreatic βcells. C. nutans reduces insulin resistance in periph-
eral tissues which may be associated with reduced obesity, improved lipid profile,
reduced oxidative stress and increased antioxidant enzymes. C. nutans prevents dia-
betes complications due to accumulation of sorbitol in kidney, lens, and nerves and
restores endothelial dysfunction in diabetes.

32 N. Susanti
Table 2. Brief Summary of Invitro Studies on Antidiabetic activity of C. nutans
No Reference Methods Study model Trea t m ent Effect
1(Nurulita et al.
2012)
in vivo Mice
induced by
aloxan
50 mg/kg
Leaves aqueos
extract dose 50,
100, and 150*
mg/kg for 9 days
↓FBG
2(Umar Imam et al.
2019)
In vivo Rat induced
by HFD and
STZ
35 mg/kg
Leaves aqueos
extract dose 100
and 200* mg/kg
for 28 days
↓FBG
↑insulin
↓Total cholesterol, ↓
LDL, ↓TG, ↑HDL
↓liver F2-isoprostane
↑liver total
antioxidant status
↑aldose reductase in
kidney, lens, and nerve
↓sorbitol
dehydrogenase in
kidney, lens, and nerve
no histologic changes
in kidney and liver
3(Retnaningsih et al.
2019)
in vivo Rat induced
by high fat
and fructose
diet
Leaves ethanol
extract dose 15*,
31, 47 mg/kg for
14 days
↓FBG
4(Azemi et al. 2020)in vivo Rat induced
by HFD and
STZ
40 mg/kgBB
Leaves
methanol extract
dose 500 mg/kg
for 28 days
↓FBG
↑
endothelial-dependent
vasodilatation
↓
endothelial-dependent
contraction
↑eNOS protein
expression
5(Dewinta et al.
2020)
in vivo Rat induced
by STZ
50 mg/kgBB
Leaves ethanol
extract dose 75*,
150, 300 mg/kg
for 14 days
↓FBG
(continued)

Potential of Clinacanthus Nutans as an Alternative Therapeutic Agent 33
Table 2. (continued)
No Reference Methods Study model Treatment Effect
6 (Sarega et al.
2016b)
in vivo rat induced
by high fat
and
cholesterol
diet
Leaves aqueos
and methanol
extract dose
500*, 250*,
125mg/kg for
7 weeks
↓dyslipidemia
↑serum and hepatic
markers of antioxidant
status (SOD, GPx)
↓Serum markers of
oxidative stress
(F2-isoprostane)
↓Hepatic markers of
oxidative stress
(MDA)
mRNA levels of
hepatic antioxidant
genes (SOD, CAT,
GPx, and GSR)
7(Sarega et al.
2016b)
in vivo rat induced
by high fat
and
cholesterol
diet
Leaves aqueos
and methanol
extract dose
500*, 250*,
125mg/kg for
7 weeks
↓FBG
↑Insulin
↓HOMA-IR
↓serum RBP4
↑serum adiponektin
↓serum leptin
↑mRNA levels of
insulin
resistance-related
genes (IRS, PI3K,
reseptor adiponektin
dan reseptor leptin)
8(AbdulwahidKurdi
et al. 2019)
in vivo Mice
induced by
HFD
Leaves
methanol extract
dose
500,1000,1500*
mg/kg for
21 days
↓body weight
↓visceral fat
↓muscle saturated
fatty acid
compositions
Fig. 2. Schematic pathways for the antidiabetic activity of C. nutans,↑: increase; ↓: decrease.

34 N. Susanti
5 Conclusions
Many studies have shown that C. nutans extracts possess antidiabetic effect with the
mechanism as α-glucosidase inhibitor, decreasing hepatic glucose production, increas-
ing insulin secretion, and improving insulin resistance. Given the increasing interest in
plant resources as potentially cost-effective and safer alternatives, these plants have the
potential to be a good source of functional ingredients as antidiabetics. There is a need to
further evaluate the potential use of C. nutans in modulating cellular signaling pathways
in diabetes and also to confirm the bioactive compounds responsible for the observed
effects.
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The images or other third party material in this chapter are included in the chapter’s Creative
Commons license, unless indicated otherwise in a credit line to the material. If material is not
included in the chapter’s Creative Commons license and your intended use is not permitted by
statutory regulation or exceeds the permitted use, you will need to obtain permission directly from
the copyright holder.