Antidiabetic activity of Coccinia grandis (L.) Voigt: Bioactive constituents, mechanisms of action, and synergistic effects

INTRODUCTION

Diabetes mellitus is a chronic condition caused by abnormal glucose metabolism with hyperglycemia as its main feature. The world population suffering from diabetes (aged 20–79 years) was 463 million in 2019 (9.3% of the world’s total population). It is estimated that this number will rise to 578 million (10.2%) in 2030 and 700 million (10.9%) in 2045 (IDF, 2019). Diabetes is one of the top 10 causes of death worldwide. Approximately 90% of people with diabetes mellitus have the type two form, which is associated with population aging, obesity, and economic advancement, as well as urbanization, which is in turn associated with a more sedentary lifestyle and higher consumption of unhealthy foods (Basu et al., 2013; Hu, 2011; Viljoen and Sinclair, 2011).

Patients with diabetes are more likely than healthy people to develop severe and life-threatening complications, reduced quality of life, and undue family stress. Type 2 diabetes is usually treated with antidiabetic drugs, such as sulfonylureas, metformin, acarbose, thiazolidinediones, and meglitinides. However, the use of these drugs has disturbing adverse effects, such as nausea, vomiting, diarrhea, dilution anemia, weight gain, improved risk of heart failure and fractures, fever, hypoglycemia, and decreased appetite (Andersen and Christensen, 2016; Gómez-Huelgas et al., 2018; Kancherla et al., 2017; Loke et al., 2009; Seaquist et al., 2013).

In view of the side effects of the abovementioned medications, the treatment of diabetes has shifted to the use of natural remedies. Herbal medicines are chosen for the treatment of diabetes because they are effective, easy to find, easy to process, free of side effects, and affordable (Arumugam et al., 2013). The phytochemicals contained in herbal medicines are responsible for their antidiabetic activity. It is known that herbal medicines contain phenolics, flavonoids, terpenoids, alkaloids, and other phytochemicals that exert antidiabetic-related effects, such as lowering blood glucose levels, lipid peroxidation, and insulin resistance, increasing insulin levels, inhibiting hexokinase enzyme activity, and acting as antioxidant and anti-inflammatory agents (Modak et al., 2007; Mukherjee et al., 2013). It is currently estimated that 75%–80% of individuals worldwide depend on herbal remedies for some of their healthcare needs (Ekor, 2014; Karunamoorthi et al., 2013; Kumar et al., 2014).

One of several medicinal herbs traditionally used to treat diabetes is Coccinia grandis (L.) Voigt. This plant has been widely used by the people of India and Sri Lanka for generations to treat various diseases (Attanayake et al., 2016). Coccinia grandis contains phytochemicals such as cephalandrine a, cephalandrine b, cephalandrol, lupeol, taraxerol, β-sitosterol, tritriacontane, taraxerone, and stigmast-7-en-3-one (Tupe et al., 2015). Each part of this plant has been studied either as a single extract or even in combination with other plants or with oral hypoglycemic agents for its antidiabetic function. A number of findings have been published on the mechanism of action of C. grandis in lowering blood glucose levels.

Plant extracts have been used not only in single formulas but also in combinations to increase efficacy and decrease side effects. This combination approach provides effective glycemic control for diabetes treatment (Bell, 2013; Sekar et al., 2019). Combinations of two or more extracts often exert synergistic pharmacological effects. In this review, we discuss the antidiabetic effect of C. grandis and provide insight into its mechanism of action. We also address the synergistic impact of combining extracts of this plant with those of other plants or with oral antidiabetic drugs. Electronic databases (PubMed and Google Scholar) were used to search for relevant articles published from 1988 to 2020 with the keywords “antidiabetic/antihyperglycemic activity of Coccinia grandis,” “Coccinia indica,” “Cephalandra indica,” “ivy gourd,” “combination effect,” and “antidiabetic synergistic effect.”

PLANT IDENTITY

Coccinia grandis (L.) Voigt or ivy/little gourd (in English) belongs to the family Cucurbitaceae. It is a creeping plant that can climb quickly over trees, shrubs, and fences (Wasantwisut and Viriyapanich, 2003). According to the scientific nomenclature, some synonyms for C. grandis are Coccinia cordifolia, C. indica, C. indica Naud., and Bryonia grandis (Holstein, 2015). Coccinia grandis originates from tropical areas of Asia and Africa. This plant thrives in Thailand, India, Malaysia, Indonesia, and the Philippines. People in different countries label this plant with specific local names, for example, kundree, olekavi, and telacucha (India), tum leung (Thailand), papasan and boluteke (Indonesia), and pepasan (Malaysia) (Jamwal and Kumar, 2016; Sakharkar and Chauhan, 2017; Wasantwisut and Viriyapanich, 2003). The taxonomic classification of C. grandis is the following (Monalisa et al., 2014):

Kingdom: Plantae.

Division: Tracheophyta.

Class: Magnoliopsida.

Order: Cucurbitales.

Family: Cucurbitaceae.

Genus: Coccinia grandis Wight & Arn.

Species: Coccinia grandis (L.) Voigt.

The leaf structure ranges from pentagon to heart-like, and the leaves, arranged alternately along the length of the stem (Fig. 1), have a hairless upper surface and a hairy lower surface (Pekamwar et al., 2013). The flowers of C. grandis are white, large, and star shaped, while the fruits are soft and green. The fruit is ovate to ellipsoid in shape and becomes bright red when ripe (Ediriweera and Ratnasooriya, 2009). Coccinia grandis is a dioecious plant, so if seeds and fruit are required, both male and female plants should be planted. At 20°C, the seeds normally germinate in 2–4 weeks (Waisundara et al., 2015). Coccinia grandis has been utilized as a herbal medicine in India for hundreds of years. It has also been recorded in the Ayurvedic medical system (Wakte and Patil, 2019).

PHYTOCHEMICAL CONSTITUENTS

Coccinia grandis is a plant with bioactive phytochemicals that offer many advantages in the treatment of diabetes mellitus. Some researchers have demonstrated the phytochemical content of this plant. Cephalandrine A, cephalandrine B, cephalandrol, β-sitosterol, and triacontane were discovered in the ethanolic extract of leaves and aerial parts of C. grandis (Deokate and Khadabadi, 2011), while rutin, quercetin-3-O-neohesperidoside, kaempferol-3-O-rutinoside, kaempferol-3-O-neohesperidoside, kaempferol-3-O-glucoside, kaempferol-hexoside, oleuropein, and ligstroside were found in the methanolic extract of the leaves (Al-Madhagy et al., 2019). The existence of quercetin in the extract of C. grandis aerial parts was also reported by Randhawa et al. (2015). In the root extract, the presence of lupeol, β-sitosterol, β-amyrin, coccinioside-k, stigmast-7-en-3-one, flavonoid glycoside ombuin, 3-O-arabinofuranoside, and 3-O-β-(α-l-arabinopyranosyl)-(1→2)–β-d-glucopyranosyl-(1→3)-β-hydroxylup–20(29)-en-28-oic acid was reported (Deokate and Khadabadi, 2011). The methanolic fruit extract contained 2-methoxy-4-vinylphenol, phenol-2-methoxy-5(1-propenyl), undecanol, 2(3h)-furanone, phenol, 3,7,11,15-tetramethyl-2-hexadecen-1-ol, 2.4-bis(1,1-dimethylethyl), benzofuranone, 2-methyl-z,z-3, 13-octadecadienol 9,12-octadecadienoic acid, hexadecanoic acid methyl ester, β-sitosterol acetate, tocopherol, stigmatosterol, ethisteron, campoesterol, and campesterol. Some phytochemicals found in the aqueous fruit extract were hexadecanoic acid methyl ester, dodecanedioic acid, isosteviol, biphenyl, α-tocopherol, hexadecanoic acid, n-pentadecanoic acid, oleic acid, linoleic acid, and lukianol (Kondhare and Lade, 2017).

Figure 1. Coccinia grandis (L.) Voigt. [Click here to view]

Among the phenolic groups, flavonoids are the most abundant and are known to have potential antidiabetic activity (Mukhopadhyay and Prajapati, 2015; Patra and Chua, 2011). Flavonoids comprise more than 4,000 different compounds that occur naturally in plants (Jasmin and Jaitak, 2019). Some flavonoids play a role in reducing hyperglycemia through the increased proliferation of β-cells, stimulation of insulin secretion, reduced apoptosis, and control of liver glucose metabolism (AL-Ishaq et al., 2019). As shown in Figure 2, four flavonoid compounds have been identified in C. grandis extract, namely, quercetin (1), kaempferol (2), ombuin (3), and rutin (4).

One of the flavonoid compounds most studied for its antidiabetic activity is quercetin. This compound is also able to overcome complications related to diabetes mellitus. The mechanism of action by which quercetin and its glycosides exert antidiabetic activity has been reported previously and is presented in Figure 3. In human intestinal Caco-2 cells, quercetin inhibited glucose transporter 2 (GLUT2) and decreased glucose and fructose uptake by 75% (Kwon et al., 2007). Quercetin was also reported to inhibit the activity of two hydrolytic enzymes (α-amylase and α-glucosidase), which degrade carbohydrates to simple sugars. This mechanism delayed the digestion of carbohydrates and controlled postprandial blood glucose (Kumar et al., 2013; Limanto et al., 2019). Pancreatic β-cell protection against oxidative stress is another mechanism by which quercetin exhibits antidiabetic activity. Oxidative stress results from reactive oxygen species (ROS) overproduction and causes damage to the β-cells in the pancreas. The treatment of streptozotocin (STZ)-induced diabetic rats with quercetin protected β-cells directly through reduced levels of nitric oxide and malondialdehyde (MDA) and indirectly through increased antioxidant enzymes activity. In this study, insulin secretion was found to be increased (Adewole et al., 2007). The 5’ adenosine monophosphate-activated protein kinase (AMPK) pathway was induced by quercetin glycoside extracted from Vaccinium vitis-idaea (Eid et al., 2010). An increase in glucose transporter 4 (GLUT4) expression was observed in diabetic rats treated with quercetin. This increase in GLUT4 expression stimulated the uptake of glucose in muscle cells (Alam et al., 2014). The liver is one of the organ targets of antidiabetic drugs that lower the blood glucose level. Hyperglycemia occurs with hepatic glucose overproduction in a process called gluconeogenesis. Quercetin suppressed gluconeogenesis in an AMPK-dependent manner by inhibiting the glucose-6-phosphate dehydrogenase (G6PDH) enzyme in the isolated perfused liver and hepatoma H4II cells (Eid et al., 2015; Gasparin et al., 2003). Glucose uptake in the liver occurred by stimulating the activity of key enzymes that participated in glycolysis and the pentose phosphate pathway (Yang et al., 2018).

Figure 2. Flavonoid compounds found in C. grandis extracts. [Click here to view]

Figure 3. Schematic overview of the antidiabetic activity of quercetin, the main flavonoid in C. grandis. GLUT2: glucose transporter 2, AMPK: 5? adenosine monophosphate-activated protein kinase, GLUT4: glucose transporter 4, ↑: increase, and ↓: decrease. [Click here to view]

ANTIDIABETIC ACTIVITY

Chronic hyperglycemia is the main characteristic of diabetes mellitus, which is caused by imperfections in the secretion and/or action of insulin (American Diabetes Association, 2009). The presence of insulin as an anabolic hormone can generate carbohydrate, lipid, and protein metabolic abnormalities (Kharroubi and Darwish, 2015). Preclinical studies regarding the antidiabetic activities of C. grandis have been previously reported in the literature. The mechanisms by which C. grandis exerts antidiabetic activity have been proposed and summarized in Table 1. These mechanisms of action include stimulation of insulin secretion, regeneration of β-cells, restoration of antioxidant enzymes, enhancement of glucose uptake, regulation of metabolic enzymes, amelioration of lipid profiles, and inhibition of digestive enzymes. Here we summarize how C. grandis exerts antidiabetic activity via the aforementioned mechanisms of action.

Pancreatic β-cell regeneration and increased insulin secretion

In the pancreatic islets, also known as islets of Langerhans, insulin is produced by β-cells (Da Silva Xavier, 2018). The function of β-cells can be affected by hyperglycemia that involves complex and multifactorial mechanisms. Some evidence suggests that the mechanisms involved include ROS production, gene transcription alteration, and protein-expression-mediated oxidative stress and increased β-cell apoptosis (Alsahli and Gerich, 2010). Regeneration of pancreatic cells and restoration of insulin secretion are assisted by reduced intact free radicals and increased antioxidant enzyme activity. In several studies, C. grandis extract was discovered to decrease blood glucose levels by regenerating β-cells and increasing insulin secretion. According to Sudha et al. (2011), the water, chloroform (60%), and ethanol (70%) fruit extracts of C. grandis [250 mg/kg body weight (b.w.)] lowered the blood glucose levels of diabetic rats induced by alloxan in 7 hours. Pal et al. (2013) found that giving the C. grandis mother tincture (750 μl/kg b.w.) to STZ- induced diabetic rats for 3 weeks stimulated insulin secretion and also β-cell regeneration in the pancreatic islets, thus decreasing blood glucose levels. A mother tincture is a type of homeopathic medicine made from specific plant or animal extracts. In order to make a mother tincture, plant or animal material is extracted with alcohol or water in a particular ratio (Banerjee, 2002; Scheepmaker and Gower, 2011). Enhancement of insulin expression was observed when diabetic rats induced by high-fat-fructose and STZ were given the mother tincture or its active ingredients, i.e., 6-centesimal (6C) and 30-centesimal (30C). In this research, a dose of 20 μl/100 g b.w. was applied twice daily for 30 days. Centesimal is a term of homeopathic dilution in which an amount of the mother tincture is diluted with alcohol or distilled water by a factor of 100 at each stage and then vigorously shaken (“succussion”) in a new vial (Sampath et al., 2013). The administration of the water extract of C. grandis leaves (0.75 g/kg b.w.) orally to diabetic rats induced by STZ for 30 days revealed that the serum insulin, C-peptide, islet diameter, and islet count were increased significantly (Attanayake et al., 2015). The same findings were also confirmed when alloxan-induced rats were given the C. grandis leaf aqueous extract (0.75 g/kg b.w., orally) for 30 days (Attanayake et al., 2019).

Insulin secretion is also affected by the excessive secretion of the growth hormone (GH) produced by the pituitary gland. This hormone inhibits insulin secretion by damaging the pancreatic β-cells. Releasing factors and inhibitory factors (IF) released by hypothalamic neurons are responsible for GH secretion. Rastogi et al. (1988) revealed that the administration of the C. grandis mother tincture (usually prepared as homeopathic therapy, in 41% alcohol v/v) to diabetic rats induced by alloxan with doses of 25–100 μml/100 g b.w. for 30 days was observed to normalize blood glucose levels and maintained the levels for 14–20 days after drug withdrawal. Additionally, the pancreatic β-cell count was also reported to reach the normal range. These effects were probably caused by the release of IF, which inhibited the secretion of GH from the adenohypophysis, thus regenerating and restoring the β-cell count.

Table 1. Preclinical study of C. grandis extracts. [Click here to view]

SYNERGISTIC EFFECT AND COMBINATION OF EXTRACTS

The antidiabetic activity of a plant extract might be increased by combining it with other extracts and/or drugs that have similar activity. The synergistic effect of these combinations can increase efficacy and decrease side effects. Synergism is the effect that occurs when the combined effects of two or more drugs are greater than the sum of their individual effects. This occurs because the phytochemical compounds in the combined extracts act on different targets in the pathogenic process; consequently, the overall therapeutic efficacy is increased (Rasoanaivo et al., 2011). The combination index (CI) has been used frequently to determine the interactions between the components of the combined extracts. This approach was introduced by Chou and Talalay using median effect principles (Chou and Talalay, 1984) and was computerized later using CompuSyn software (Chou, 2006). The formula used for the calculation of the CI was as follows:

$\mathrm{CI}=\frac{{\mathit{D}}_{1(\mathit{x})}}{{\mathit{E}}_{1(\mathit{x})}}+\frac{{\mathit{D}}_{2(\mathit{x})}}{{\mathit{E}}_{2(\mathit{x})}},$

where D_1(x) and D_2(x) are the concentrations of each extract/drug in combination that produced an x effect and E_1(x) and E_2(x) are the concentrations of each extract/drug alone that produced the same effect. Synergy, additivity, and antagonism interactions are implied by CI values of <1, 1, and >1, respectively (Wong et al., 2019).

The combination of C. grandis extract with other extracts/drugs has been mentioned in several publications (Table 2). The combination of C. grandis leaves and the Abroma augusta root aqueous extract (300 mg/kg b.w.) exhibited antihyperglycemic and antihyperlipidemic activities better than the single plant extract in STZ-induced albino rats for 8 weeks. These results provide evidence of a synergistic interaction between C. grandis and A. augusta (Eshrat, 2003). The synergistic interaction was also reported by Mallick et al. (2007), who combined the C. grandis leaf extract and Musa paradisiaca root extract. Both plant materials were extracted in a 2:3 ratio with water and methanol. The combined extract (1:1) at a dose of 80 mg/100 g b.w. was administered orally to diabetic rats induced by STZ for 14 days. The combined extract exhibited higher antihyperglycemic activity than the single extract in terms of reducing the level of fasting blood glucose and raising the glucose tolerance and the level of serum insulin. In addition, the combined extract greatly increased glucose-6-phosphatase, G6PDH, hexokinase, and glycogen levels in the liver. Further research conducted by Mallick et al. (2009) indicated that the combination of the C. grandis leaves and M. paradisiaca root aqueous-methanol extract was able to modulate the protein involved in the regulation of metabolic disorders as well as diabetes. Interestingly, it also showed a protective effect against diabetes by increasing the capacity of β-cell regeneration. The aqueous extract of C. grandis and Morinda citrifolia fruits (300 mg/kg b.w.) reduced serum glucose and increased serum insulin in alloxan-induced diabetic rats in 30 days (Prakash et al., 2010). Synergism was also reported by other researchers who combined whole plant methanolic extracts of C. grandis and Trigonella foenum-graecum L. Alloxan-induced diabetic rats were given this combined extract at doses of 125 mg/kg b.w. (C. grandis) and 250 mg/kg b.w. (Trigonella foenum-graecum L.) for 21 days (Ruby et al., 2014). The level of blood glucose was found to be decreased significantly. This finding suggested that the combined extract was more active than the single extract. Saklani et al. (2012) found that giving alloxan-induced diabetic rats a petroleum ether-methanol extract of C. grandis and Salvadora oleoides leaves (150 mg/kg b.w.) for 15 days decreased blood glucose levels, compared with administration of the standard drug glipizide. Furthermore, the combined extract had a major impact on lipid profiles, alanine aminotransferase/aspartate amino transferase (AST) activity, and serum creatinine and urea levels. Recently, Putra et al. (2020) reported that the aqueous extract of C. grandis leaves and Averrhoa bilimbi fruits showed higher in vitro DPPH radical-scavenging and α-amylase inhibition activities than that of the single extract.

Table 2. The combination of C. grandis extracts and synthetic drugs. [Click here to view]

In addition to the combination with other plant extracts, C. grandis was also combined with antidiabetic drugs as reported by Eliza and Usha (2011), who combined the ethanolic leaf extract of C. grandis at doses of 100, 150, and 200 mg/kg b.w. with the antidiabetic drug glibenclamide (0.125 mg/kg b.w.). Alloxan-induced diabetic rats were given the extract-drug combination orally at 15 days intervals. After 45 days of therapy, the extract-drug combination lowered the concentration of blood glucose and normalized TC and TG levels. Additionally, GSH and lipid peroxide levels were also reduced. The C. grandis leaf extract (200 mg/kg b.w.) combined with acarbose (5 mg/kg b.w.) reduced blood glucose levels compared with the single extract and drug administered to STZ-induced diabetic rats with a high-fat diet (HFD) for 8 weeks. This combination also showed stronger antioxidant activity (SOD, CAT, TBARS, and GSH) than the single extract and drug (Kohli and Kumar, 2014). The combination effect of the C. grandis ethanolic leaf extract and pioglitazone was recently reported by Basavarajappa et al. (2020). The combination of extract (200 mg/kg b.w.) and pioglitazone (7 mg/kg b.w.) was given orally to HFD-fed STZ-induced diabetic rats for 7 weeks. They discovered that the extract-drug combination normalizes blood glucose levels and lipid profiles and decreases oxidative stress more efficiently than a single extract and pioglitazone alone. In rats treated with the extract-drug combination, an improved renal protection effect was also observed.

CONCLUSION

This review provides comprehensive information regarding the activity of C. grandis as an antidiabetic remedy. This plant is a promising agent for treating diabetes mellitus. The mechanism of action of these plant extracts in lowering blood glucose levels has been elucidated, i.e., by pancreatic β-cell regeneration, insulin secretion stimulation, antioxidant enzyme restoration, glucose uptake enhancement, metabolic enzyme regulation, lipid profile amelioration, and digestive enzyme inhibition. The combination of the C. grandis extract with other plant extracts and antidiabetic drugs showed a synergistic effect that is beneficial for increasing efficacy and safety.

ACKNOWLEDGMENTS

The authors gratefully acknowledge Universitas Gadjah Mada through the Rekognisi Tugas Akhir Tahun 2021 program, Grant No. 3190/UN1/DITLIT/DIT-LIT/PT/2021, for financial support.

AUTHORS’ CONTRIBUTIONS

I Made Wisnu Adhi Putra initiated and drafted the review article. Nanang Fakhrudin, Arief Nurrochmad, and Subagus Wahyuono conducted revisions and reviews on the initial draft prior to submission to the journal website

CONFLICT OF INTEREST

All authors declare no conflicts of interest.

ETHICAL APPROVAL

This article does not contain any studies with human participants or animals performed by any of the authors.

LIST OF ABBREVIATIONS

ALP: Alkaline phosphatase; AMPK: 5’ adenosine monophosphate-activated protein kinase; AST: Aspartate amino transferase; b.w.: Body weight; CAT: Catalase; CI: Combination index; 2-DG: 2-Deoxyglucose; DPPH:1,1-Diphenyl-2-picrylhydrazyl; FFA: Free fatty acid; G6PDH: Glucose-6-phosphate dehydrogenase; GLUT1: Glucose transporter 1; GLUT2: Glucose transporter 2; GLUT4: Glucose transporter 4; GH: Growth hormone; GSH: Reduced glutathione or Glutathione with sulfhydryl group; GPx: Glutathione peroxidase; GR: Glutathione reductase; GST: Glutathione S-transferase; HDL: High-density lipoprotein; HFD: High-fat diet; IC50: The half maximal inhibitory concentration; IF: Inhibitory factors; i.p.: Intraperitoneal; LDL: Low-density lipoprotein; MDA: Malondialdehyde; mRNA: Messenger ribonucleic acid; ROS: Reactive oxygen species; SGPT: Serum glutamic pyruvic transaminase; SGOT: Serum glutamic oxaloacetic transaminase; SOD: Superoxide dismutase; STZ: Streptozotocin; TC: Total cholesterol; TBARS: Thiobarbituric acid-reactive substances; TG: Triacylglycerol; VLDL: Very low-density lipoprotein.

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