Momordica Charantia: A Review of Its Effects on Metabolic Diseases and Mechanisms of Action

Abstract

The global rise in the prevalence of metabolic diseases such as diabetes, obesity, and dyslipidemia is a serious public health issue. The search for safe and effective complementary and alternative therapies to treat metabolic disorders is a key field of research. Momordica charantia (MC) is a tropical and subtropical vine of the Cucurbitaceae family used as a medicinal plant since ancient times. Although MC has been widely studied for its hypoglycemic potential, hypolipidemic and antiobesity effects have also been reported in preclinical studies and clinical trials. This study aims to review the metabolic effects of MC reported in clinical trials as well as its mechanisms of action.

Introduction

Medicinal plants have been used to treat different diseases throughout history. Momordica charantia (MC), commonly known as bitter melon, bitter gourd, karela, or balsam pear, is a widely used traditional plant due to its hypoglycemic effects among patients with diabetes mellitus. MC is a tropical and subtropical vine found in Asia, India, South America, East Africa, and the Caribbean.¹

Approximately 228 compounds have been isolated from MC. Charantin, polypeptide-p, cucurbitane-type triterpene glycosides, momordicin, and vicine are the most studied constituents.² The fruit and seeds of MC have been the most frequently used plant parts in animal models and clinical studies.^{3

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Furthermore, MC has shown to exert antidiabetic, antiobesity, and hypolipidemic effects through numerous mechanisms of action described in vitro and in animal model studies.^3,15,16 In view of these effects, MC could be established as a potential complementary or alternative medicine for people with metabolic diseases such as diabetes, prediabetes, obesity, and dyslipidemia. Therefore, this study aims to review the metabolic effects of MC reported in clinical trials and its multiple mechanisms of action.

Effect of MC on Metabolic Diseases

Diabetes mellitus and prediabetes

Type 2 diabetes mellitus (T2DM) is characterized by a progressive loss of adequate β-cell insulin secretion, frequently on the background of insulin resistance (IR).¹⁷

Several mechanisms related to the beneficial effects of MC on insulin secretion and insulin sensitivity have been described. Administration of MC fruit extract has shown to increase the number of β-cells, islet size, total β-cell area, and also induce the regeneration of β-cells in pancreatic islets of diabetic rats.^18
–20 Glucagon-like peptide-1 (GLP-1) is an incretin hormone that induces insulin secretion, and the aqueous extract of MC fruit has shown to significantly increase GLP-1 level in diabetic rats.²¹

Inhibition of protein tyrosine phosphatase 1B (PTP1B) is associated with an increment in insulin sensitivity. In db/db mice, saponin and lipid fractions of MC fruit reduced PTP1B activity in skeletal muscle.²² MC fruit extract supplementation improved insulin sensitivity by increasing skeletal muscle insulin-stimulated insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation in high-fat diet-fed Wistar rats.²³ Similar results were observed in another study in mice fed a high-fat diet.²⁴

MC fruit extract improved protein and mRNA expression of glucose transporter type 4 (GLUT4) in skeletal muscle of rats fed a high-fructose diet.²⁵ It has been reported that triterpenoids isolated from MC can stimulate GLUT4 translocation to the cell membrane in muscle and adipocyte cell lines. This effect was associated with an increased activity of the adenosine monophosphate-activated protein kinase (AMPK) pathway.²⁶ Scientific evidence suggests that MC can also improve insulin sensitivity through the regulation of peroxisome proliferator-activated receptor gamma (PPARγ)-mediated pathway. MC fruit extract increased mRNA expression of PPARγ in adipose tissue, and improved IR in rats and mice fed with high-fructose and high-fat diets, respectively.^25,27

There are multiple mechanisms behind the glucose lowering effects of MC. Cucurbitane-type triterpene glycosides isolated from MC fruit have shown to exert α-glucosidase inhibitory activity.²⁸ In streptozotocin-induced diabetic rats, supplementation with MC powder fruit also showed a significant decrease in maltase and lactase activities.²⁹ In addition, the administration of MC juice to streptozotocin-induced diabetic rats significantly reduced Na+/K+-dependent absorption of glucose by the intestinal mucosa.³⁰ In diabetic animal models, it has been shown that MC can also regulate the activity of important pathways in carbohydrate metabolism by stimulating glycolysis, glycogenesis, the pentose phosphate pathway, and also by inhibiting gluconeogenesis and glycogenolysis.³

Several clinical trials conducted in patients with T2DM have evaluated the efficacy and safety of MC (Table 1). Recently, a randomized, double-blind, placebo-controlled study was conducted by Kim et al. in ninety patients with T2DM. Subjects were randomly allocated to receive MC fruit extract (2380 mg daily) or placebo for 12 weeks. Exclusion criteria included treatment with alpha-glucosidase inhibitors, but patients could be under treatment with other antidiabetic agents. Fasting plasma glucose (FPG) levels (145.9 ± 34.5 mg/dL vs. 140.5 ± 31.9 mg/dL, P = .014) and the homeostasis model assessment of IR (HOMA-IR) (2.4 [1.3–3.5] vs. 1.8 [1.3–2.8], P = .017) significantly decreased in the MC group. There were no significant changes in glycated hemoglobin A1c (A1C) and the HOMA of β-cell function (HOMA-β) after the administration of MC.⁴

Table 1.

Effect of Momordica Charantia on Glycemic Control Parameters

Authors, year	Study population	Intervention	Outcome measures
Authors, year	Study population	Intervention	Baseline vs. endpoint	Mean change from baseline
Kim et al. (2020)⁴	Ninety T2DM patients	2380 mg/day of MC fruit extract for 12 weeks	FPG (145.9 ± 34.5 mg/dL vs. 140.5 ± 31.9 mg/dL, P = .014) HOMA-IR (2.4 [1.3–3.5] vs. 1.8 [1.3–2.8], P = .017) HOMA-β (30.7 [14.7–46.3] vs. 28.3 [17.1–46.2], P = .331) A1C (7.0 ± 0.5% vs. 7.0 ± 0.7%, P = .235)	FPG −5.4 mg/dL HOMA-IR −0.6 HOMA-β −2.4 A1C 0%
Cortez-Navarrete et al. (2018)⁵	Twenty-four T2DM patients	2000 mg/day of MC fruit powder for 12 weeks	FPG (8.2 ± 1.4 mmol/L vs. 7.4 ± 2.9 mmol/L) 2-h plasma glucose after OGTT (17.1 ± 3.7 mmol/L vs. 13.2 ± 4.3 mmol/L, P < .01) A1C (7.8 ± 0.8% vs. 7.1 ± 1.3%, P < .05) Total insulin secretion (0.29 ± 0.18 vs. 0.41 ± 0.29, P = .028) First phase insulin secretion (557.8 ± 645.6 vs. 1135.7 ± 725.0, P = .043) Insulin sensitivity (2.4 ± 1.4 vs. 2.1 ± 1.6)	FPG −0.8 mmol/L 2-h plasma glucose after OGTT −3.9 mmol/L A1C −0.7% Total insulin secretion +0.12 First phase insulin secretion +577.9 Insulin sensitivity −0.3
Krawinkel et al. (2018)¹¹	Fifty-two prediabetic patients	2500 mg/day of MC whole fruit powder for 8 weeks	FPG (5.3 ± 0.52 mmol/L vs. 5.1 ± 0.5 mmol/L) A1C (5.9 ± 0.43% vs. 5.8 ± 0.3%) Insulin (25.1 ± 15.94 μU/mL vs. 26.0 ± 14.8 μU/mL)	FPG −0.2 mmol/L A1C −0.1% Insulin −0.9 μU/mL
Suthar et al. (2016)⁷	Eighty-five T2DM patients	1200 mg/day of dry MC fruit juice powder for 90 days	FPG (150.02 ± 35.2 mg/dL vs. 128.13 ± 16.8 mg/dL) PPG (202.4 ± 56.7 mg/dL vs. 157.45 ± 17.9 mg/dL) A1C (7.87 ± 1.0% vs 7.08 ± 0.9%)	FPG −21.89 mg/dL PPG −44.95 mg/dL A1C −0.79%
Rahman et al. (2015)⁸	Ninety-five T2DM patients	Group I 2000 mg/day of MC fruit powder for 10 weeks Group II 4000 mg/day of MC fruit powder for 10 weeks	Group I A1C (8.25 ± 0.70% vs. 7.40 ± 0.50%, P ≤ .05) FPG (146 ± 13.40 mg/dL vs. 133.70 ± 11.50 mg/dL, P ≤ .05) 2-h plasma glucose after OGTT (241.30 ± 15.60 mg/dL vs. 235.00 ± 19.50 mg/dL) Group II A1C (8.30 ± 0.55% vs. 7.15 ± 0.60%, P ≤ .02) FPG (141.60 ± 15.20 mg/dL vs. 126.40 ± 11.90 mg/dL, P < .04) 2-h plasma glucose after OGTT (247.00 ± 21.90 mg/dL vs. 240.70 ± 25.10 mg/dL)	Group I A1C −0.85% FPG −12.3 mg/dL 2-h plasma glucose after OGTT −6.3 mg/dL Group II A1C −1.15% FPG −15.2 mg/dL 2-h plasma glucose after OGTT −6.3 mg/dL
Fuangchan et al. (2011)⁹	One hundred twenty-nine T2DM patients	Group I 500 mg/day of MC dried fruit powder for 4 weeks Group II 1000 mg/day of MC dried fruit powder for 4 weeks Group III 2000 mg/day of MC dried fruit powder for 4 weeks	Group I Fructosamine (316.2 ± 56.9 μmol/L vs. 312.7 ± 54.1 μmol/L) FPG (140.3 ± 17.4 mg/dL vs. 140.9 ± 29.4 mg/dL) 2-h plasma glucose after OGTT (272.0 ± 44.5 mg/dL vs. 266.6 ± 59.6 mg/dL) Group II Fructosamine (323.7 ± 51.0 μmol/L vs. 313.5 ± 54.1 μmol/L) FPG (139.5 ± 16.0 mg/dL vs. 141.6 ± 27.4 mg/dL) 2-h plasma glucose after OGTT (271.2 ± 50.4 mg/dL vs. 255.4 ± 74.6 mg/dL) Group III Fructosamine (326.8 ± 52.8 μmol/L vs. 316.6 ± 48.1 μmol/L, P < .05) FPG (139.9 ± 15.8 mg/dL vs. 137.6 ± 18.1 mg/dL) 2-h plasma glucose after OGTT (242.6 ± 47.7 mg/dL vs. 242.2 ± 59.2 mg/dL)	Group I Fructosamine −3.5 μmol/L FPG +0.6 mg/dL 2-h plasma glucose after OGTT −5.4 mg/dL Group II Fructosamine −10.2 μmol/L FPG +2.1 mg/dL 2-h plasma glucose after OGTT −15.8 mg/dL Group III Fructosamine −10.2 μmol/L FPG −2.3 mg/dL 2-h plasma glucose after OGTT −0.4 mg/dL
Lim et al. (2010)⁶	Forty T2DM patients	Group I 60 mg/kg/day of MC dried leaves powder (single dose) Group II 80 mg/kg/day of MC dried leaves powder (single dose) Group III 100 mg/kg/day of MC dried leaves powder (single dose)	Group I Insulin, 15 min after dose (22.45 ± 6.7 μIU/mL vs. 37.29 ± 6.47 μIU/mL) Group II Insulin, 15 min after dose (25.11 ± 6.5 μIU/mL vs. 40.3 ± 6.28 μIU/mL) Group III Insulin, 15 min after dose (24.65 ± 9.6 μIU/mL vs. 48.49 ± 9.26 μIU/mL, P < .05)	Group I Insulin +14.84 μIU/mL Group II Insulin +15.19 μIU/mL Group III Insulin +23.84 μIU/mL
Dans et al. (2007)¹⁰	Forty T2DM patients	3000 mg/day of MC fruit and seed powder for 3 months	A1C (7.92 ± 0.59% vs. 8.2 ± 1.25%) FPG (8.4 ± 2.24 mmol/L vs. 7.99 ± 0.77 mmol/L)	A1C +0.28% FPG −0.41 mmol/L
John et al. (2003)¹²	Fifty T2DM patients	6000 mg/day of MC whole fruit powder for 4 weeks	FPG (150.1 ± 26.9 mg/dL vs. 150.0 ± 35.3 mg/dL) PPG (264.4 ± 32.8 mg/dL vs. 230.4 ± 61.2 mg/dL) Fructosamine (350.8 ± 56.8 μmol/L vs. 319.1 ± 60.7 μmol/L)	FPG −0.1 mg/dL PPG −34 mg/dL Fructosamine −31.7 μmol/L

A1C, glycated hemoglobin A1c; FPG, fasting plasma glucose; HOMA-IR, homeostasis model assessment of insulin resistance; HOMA-β, homeostasis model assessment of β-cell function; MC, Momordica charantia; OGTT, oral glucose tolerance test; PPG, postprandial plasma glucose; T2DM, type 2 diabetes mellitus.

Insulin secretion and insulin sensitivity were also evaluated in a randomized, double-blind, placebo-controlled clinical trial by Cortez-Navarrete et al. in 24 patients with newly diagnosed T2DM without pharmacological treatment. Subjects were randomly assigned to two groups: 12 patients received MC fruit powder (2000 mg/day divided into two oral doses of 500 mg capsules twice daily for 12 weeks), while the other 12 patients received placebo. The insulinogenic index, the Stumvoll index, and the Matsuda index were used to estimate total insulin secretion, the first phase of insulin secretion, and insulin sensitivity, respectively.

In the MC group, there were significant increases in total insulin secretion (0.29 ± 0.18 vs. 0.41 ± 0.29, P = .028) and in the first phase of insulin secretion (557.8 ± 645.6 vs. 1135.7 ± 725.0, P = .043), however, insulin sensitivity was not modified. A1C (7.8 ± 0.8% vs. 7.1 ± 1.3%, P < .05) and 2-h serum glucose levels (17.1 ± 3.7 mmol/L vs. 13.2 ± 4.3 mmol/L, P < .01) also significantly decreased after MC administration. The reduction in FPG was not statistically significant.⁵

A study conducted by Lim et al. also reported a favorable effect of MC on insulin secretion in a double-blind clinical trial in 40 T2DM patients. Subjects were randomly allocated to three single oral doses of MC tablets from dried leaves (60, 80, or 100 mg/kg/day) or placebo. Insulin concentrations were measured at 0, 15, 30 min, 1, 2, and 4 h after the given dose. The three MC groups increased plasma insulin levels compared with placebo. During the initial 15-min postmeal interval, the dose of 100 mg/kg/day significantly increased insulin secretion compared with the other MC doses and placebo (P < .05).⁶

Suthar et al. compared the efficacy of MC versus placebo as adjuvant therapy for patients with T2DM in an open-label, randomized, active-controlled trial. Eighty-five subjects were randomized in a 3:1 ratio (MC: placebo). Sixty-four patients received three 400 mg capsules (1.2 g/day) of dry MC fruit juice powder, while 21 patients received placebo for 90 days. Patients were included if they were on a stable regimen with at least one antidiabetic agent. No significant changes from baseline to endpoint were reported in FPG (150.02 ± 35.2 mg/dL vs. 128.13 ± 16.8 mg/dL) and postprandial plasma glucose (PPG) levels (202.4 ± 56.7 mg/dL vs. 157.45 ± 17.9 mg/dL). However, when compared with the placebo group, FPG and PPG levels in the MC group showed significant reductions (P = .013 and P = .002, respectively). The reduction in A1C did not reach statistical significance.⁷

Rahman et al. conducted a randomized, double-blind, parallel-group trial in T2DM patients to evaluate the antidiabetic effect of MC compared with glibenclamide. Ninety-five subjects were randomly assigned to two different doses of MC fruit powder administered orally (group I: 2 g/day and group II: 4 g/day) or glibenclamide (group III: 5 mg/day) for 10 weeks. MC was administered in the form of 1000 mg capsules.

Significant decreases were observed in the mean levels of A1C at the endpoint compared with baseline in group I, group II, and group III (8.25 ± 0.70% vs. 7.40 ± 0.50%, P ≤ .05; 8.30 ± 0.55% vs. 7.15 ± 0.60%, P ≤ .02; 8.45 ± 0.60% vs. 6.90 ± 0.75%, P < .005, respectively). FPG levels also significantly decreased from baseline to endpoint in the three intervention groups (group I: 146 ± 13.40 mg/dL vs. 133.70 ± 11.50 mg/dL, P ≤ .05; group II: 141.60 ± 15.20 mg/dL vs. 126.40 ± 11.90 mg/dL, P < .04; group III: 143.50 ± 18.40 mg/dL vs. 117 ± 10.30 mg/dL, P < .003). No significant change in 2-h plasma glucose levels after an oral glucose tolerance test (OGTT) was observed after the intervention. The study concluded that MC had a weaker hypoglycemic effect compared with glibenclamide.⁸

Additional clinical trials have also compared the hypoglycemic effect of MC with other oral hypoglycemic agents. Fuangchan et al. carried out a randomized, double-blind, active-controlled trial in 129 newly diagnosed T2DM patients. The study compared three different MC doses (500, 1000, and 2000 mg) with metformin (1000 mg/day). Each capsule contained 500 mg of MC dried fruit powder. After 4 weeks of intervention, a significant reduction in mean fructosamine levels was observed in the 2000 mg/day MC group (−10.2 μmol/L [326.8 ± 52.8 μmol/L vs. 316.6 ± 48.1 μmol/L, P < .05]) and the metformin group (−16.8 μmol/L [308.3 ± 68.1 μmol/L vs. 291.5 ± 51.9 μmol/L, P < .05]).⁹ There were no significant changes in FPG levels and 2-h plasma glucose after an OGTT after MC administration.

Dans et al. conducted the first randomized-controlled trial to determine if adding MC to standard therapy could decrease A1C compared with placebo. Forty patients with newly diagnosed or poorly controlled T2DM were randomized to receive either two capsules (500 mg of fruit and seed powder per capsule) of MC thrice daily or placebo for 3 months. No significant differences in A1C and FPG levels were observed after MC administration.¹⁰

Although most clinical trials have focused on T2DM patients, few clinical trials have been conducted in other populations with positive effects on glycemic control parameters. The effect of 2.5 g of whole MC fruit powder was evaluated by Krawinkel et al. in 52 prediabetic individuals in a randomized, placebo-controlled, single-blind, crossover clinical trial. The duration of each intervention was 8 weeks and a 4-week washout period in between. The study reported a significant difference in the change of FPG levels in the MC group (−0.31 mmol/L, P ≤ .01) compared with the placebo group. However, no significant differences in FPG, A1C, and insulin levels were observed after the intervention with MC.¹¹

Finally, John et al. carried out a randomized, placebo-controlled clinical trial in 50 T2DM patients, and after 4 weeks of intervention with 6000 mg/day of MC whole fruit powder no significant changes in FPG, PPG, and fructosamine levels were reported.¹²

On the contrary, numerous studies conducted in animal models have also evaluated the hypoglycemic potential of MC, and favorable effects have been reported in glucose levels and A1C.^{22,25,31
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Obesity

The global prevalence of obesity has nearly tripled since 1975 and continues to grow at a pandemic rate.³⁴ Research on the antiobesity effects of nutraceuticals has become a major topic of interest in recent years.

Various mechanisms of the antiobesity effect of MC have been described. One possible mechanism through which MC lowers body weight (BW) could be due to increased lipolytic activity. MC supplementation with a high-fat diet raised serum-free fatty acid concentration (P < .05). Free fatty acids can be used as substrates for the uncoupling protein-mediated adaptive thermogenesis, an important mechanism that contributes to the homeostatic energy balance in rodents.³⁵ In addition, MC enhances hepatic PPARα mRNA expression, which is linked to fatty acid oxidation in the liver and cellular uptake of free fatty acids.²⁷

MC can also suppress the visceral fat accumulation and inhibit adipocyte hypertrophy of diet-induced obese rats, reducing mRNA gene expression of enzymes involved in the synthesis and uptake of fatty acids by downregulating the expression of lipogenic genes in adipose tissue.³⁶ Besides, the bioactive compounds α-momorcharin and β-momorcharin have shown lipogenic activity stimulating adipocyte differentiation through an insulin signaling-regulated pathway.^37,38

An in vitro study reported that MC is effective in reducing lipid accumulation in primary human adipocytes by regulating adipogenic transcription factors (PPARγ and sterol regulatory element binding protein-1c) and adipocytokine gene expression.³⁹ Another mechanism by which MC decreases adiposity is related to an increment of lipid oxidative enzyme activities and the expression of uncoupling proteins (UCP 1 and UCP2).^3,40

The reduction of BW, visceral fat mass, and adiposity after MC administration has been previously reported in animal studies.^{27,35,41
–43} Furthermore, MC administration has shown to prevent and reduce adiposity caused by a high-fat diet in rats.³⁵

Regarding human studies, even though there is still a lack of research in obese population, several studies have shown that MC has antiobesity activity (Table 2).^5,13,14

Table 2.

Effect of Momordica Charantia on Anthropometric Measures

Authors, year	Study population	Intervention	Outcome measures
Authors, year	Study population	Intervention	Baseline vs. endpoint	Mean change from baseline
Kim et al. (2020)⁴	Ninety T2DM patients	2380 mg/day of MC fruit extract for 12 weeks	BMI: only baseline results were reported 25.3 ± 3.8 kg/m²	Endpoint measures were not reported; however, no significant changes were observed in BMI after MC administration
Cortez-Navarrete et al. (2018)⁵	Twenty-four T2DM patients	2000 mg/day of MC fruit powder for 12 weeks	BW (79.4 ± 9.2 kg vs. 78.0 ± 9.2 kg, P < .01) BMI (29.1 ± 2.4 kg/m² vs. 28.3 ± 1.9 kg/m², P < .01) Fat (36.7 ± 7.8% vs. 36.3 ± 7.6%, P < .05) WC (106 ± 12 cm vs. 104 ± 11 cm, P < .05)	BW −1.4 kg BMI −0.8 kg/m² Fat −0.4% WC −2.0 cm
Soo et al. (2018)¹³	Eighty osteoarthritis patients	4500 mg/day of MC fruit powder for 3 months	BW (70.42 ± 11.29 kg vs. 69.34 ± 11.10 kg, P < .001) BMI (27.29 ± 4.03 kg/m² vs. 26.68 ± 4.00 kg/m², P < .001)	BW −1.08 kg BMI −0.61 kg/m²
Krawinkel et al. (2018)¹¹	Fifty-two prediabetic patients	2500 mg/day of MC whole fruit powder for 8 weeks	BMI (29.6 ± 2.5 kg/m² vs. 29.6 ± 2.4 kg/m²)	BMI −0 kg/m²
Kinoshita and Ogata (2018)⁴⁴	Forty-three healthy patients	300 mg of MC extract for 30 days	BW (62.5 ± 13.7 kg vs. 62.1 ± 13.5 kg) BMI (23.1 ± 4.6 kg/m² vs. 22.9 ± 4.5 kg/m²)	BW −0.4 kg BMI −0.2 kg/m²
Rahman et al. (2015)⁸	Ninety-five T2DM patients	Group I 2000 mg/day of MC fruit powder for 10 weeks Group II 4000 mg/day of MC fruit powder for 10 weeks	Group I BW (69.50 ± 10.70 kg vs. 67.65 ± 11.32 kg) Group II BW (73.90 ± 12.20 kg vs. 70.80 ± 10.50 kg)	Group I BW −1.85 kg Group II BW −3.1 kg
Tsai et al. (2012)¹⁴	Forty-two patients diagnosed with MetS	4800 mg/day of MC whole fruit for 3 months	Baseline results were reported by gender BW men (82.4 kg) BW women (77.1 kg) BMI men (28.4 kg/m²) BMI women (30.0 kg/m²) WC men (98.4 cm) WC women (94.4 cm)	WC total −1.32 cm WC men −2.55 cm WC women −0.08 cm BW and BMI endpoint measures were not reported; however, no significant changes were observed after MC administration
Dans et al. (2007)¹⁰	Forty T2DM patients	3000 mg/day of MC fruit and seed powder for 3 months	BMI (26.37 ± 4.75 kg/m² vs. 26.33 ± 4.87 kg/m²)	BMI −0.04 kg/m²

BMI, body mass index; BW, body weight; MetS, metabolic syndrome; WC, waist circumference.

In the study conducted by Cortez-Navarrete et al. in T2DM patients, results showed significant decreases in BW (79.4 ± 9.2 vs. 78.0 ± 9.2 kg, P < .01), body mass index (BMI) (29.1 ± 2.4 vs. 28.3 ± 1.9 kg/m², P < .01), fat percentage (36.7 ± 7.8% vs. 36.3 ± 7.6%, P < .05), and waist circumference (WC) (106 ± 12 vs. 104 ± 11 cm, P < .05) after MC administration for 12 weeks (2000 mg/day).⁵ Soo et al. published a single-blinded, placebo-controlled, randomized study in 80 osteoarthritis patients who received MC fruit powder (three 500 mg per capsule taken thrice daily) or placebo for 3 months. After MC administration, a significant reduction in BW (70.42 ± 11.29 kg vs. 69.34 ± 11.10 kg, P < .001) and BMI (27.29 ± 4.03 kg/m² vs. 26.68 ± 4.00 kg/m², P < .001) was observed.¹³

Tsai et al. evaluated the effect of MC in a preliminary, open-label, uncontrolled trial in 42 patients diagnosed with metabolic syndrome (MetS). Patients received MC (4.8 g of lyophilized whole fruit in capsules) for 3 months. Compared with the baseline value (visit 1), there were significant decreases in WC at visit 3 (−2.52 cm, P < .0001), visit 4 (−2.09 cm, P = .002), and visit 5 (−1.36 cm, P = .042); however, at the end of the intervention (visit 7) the reduction in WC did not reach statistical significance.¹⁴

Nonetheless, accumulating evidence indicates some conflicting results regarding the antiobesity effects of MC. The study published by Kim et al. showed no significant change in BMI in T2DM patients after MC administration (2380 mg/day) for 12 weeks.⁴ Krawinkel et al. also did not report a significant change in BMI after MC administration (2.5 g of whole fruit powder) for 8 weeks in prediabetic patients.¹¹ These results are similar to those reported by Kinoshita and Ogata in a randomized, double-blind, placebo-controlled study in 43 healthy adults who were allocated to receive three capsules daily (100 mg) of hot-water MC extracts or placebo during 30 days. In this trial, no significant differences were found in BW and BMI after MC administration.⁴⁴

The study by Rahman et al. evaluated the effect of two doses of MC fruit powder (group I: 2 g/day; group II: 4 g/day) and glibenclamide (5 mg/day) on BW in T2DM patients. A mean change in BW from baseline to endpoint (10 weeks) was observed among patients who received MC; however, it was not statistically significant.⁸ In addition, the study carried out by Dans et al. in T2DM patients did not find a significant effect of MC (two capsules of 500 mg thrice daily for 3 months) on BMI.¹⁰

Dyslipidemia

Dyslipidemia is characterized by abnormal lipid levels in the blood, such as overproduction or deficiency; however, the excess of lipids occurs more frequently.⁴⁵ It is an important risk factor for coronary artery disease and stroke, and is strongly associated with the presence of obesity and IR.⁴⁶ The effect of MC on the lipid profile (total cholesterol [TC], triglycerides [TG], and lipoproteins) has been proven by several in vitro studies and animal models through multiple mechanisms of action.^{31,47

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MC has manifested hypolipidemic activity through the regulation of PPARs-associated pathways.⁵⁵ Momordin, an MC protein, upregulates the expression of PPARδ. Upregulation of PPARδ is associated with an increment in high-density lipoprotein cholesterol (HDL-c) levels through an increase of cholesterol efflux in cells secondary to an increase in the expression of the reverse cholesterol transporter adenosine triphosphate-binding cassete A1.^56,57

The effects of MC have also been studied on PPARγ, which increases its activity and leads to the suppression of assembly and secretion of very low-density lipoproteins (VLDLs), which is also achieved by the increase of insulin sensitivity produced by the activation of the phosphatidylinositol 3-kinase signaling pathway by MC.^22,58 Moreover, through the activation of AMPK, PPARα, and PPARγ, an inhibition of cholesterol synthesis through the inactivation of the 3-hydroxy-3-methylglutaryl coenzyme A reductase has been observed, which leads to a decrease of Apo B secretion, VLDL, and low-density lipoprotein cholesterol (LDL-c) synthesis and an increase of HDL-c synthesis.^3,59

To the best of our knowledge, only one clinical trial has established the effect of MC on the lipid profile as a primary objective (Table 3). The study was conducted by Kinoshita and Ogata in healthy adults who received 100 mg of MC extract or placebo capsules thrice daily for 30 days. No significant differences were found after MC administration in TC, HDL-c, LDL-c, and TG levels. Even though the differences in the lipid profile after the intervention with MC were not significant, the MC group exhibited lower LDL-c levels compared with the control group (P = .02).⁴⁴

Table 3.

Effect of Momordica Charantia on Lipid Profile

Authors, year	Study population	Intervention	Outcome measures
Authors, year	Study population	Intervention	Baseline vs. endpoint	Mean change from baseline
Kim et al. (2020)⁴	Ninety T2DM patients	2380 mg/day of MC fruit extract for 12 weeks	TC (155.4 ± 28.6 mg/dL vs. 154.6 ± 35.2 mg/dL, P = .690) TG (137.1 ± 83.3 mg/dL vs. 128.9 ± 76.9 mg/dL, P = .680) HDL-c (49.3 ± 12.1 mg/dL vs. 48.6 ± 14.1 mg/dL, P = .589) LDL-c (94.9 ± 26.0 mg/dL vs. 95.0 ± 26.0 mg/dL, P = .563)	TC −0.8 mg/dL TG −8.2 mg/dL HDL-c −0.7 mg/dL LDL-c 0.1 mg/dL
Kinoshita and Ogata (2018)⁴⁴	Forty-three healthy patients	300 mg/day of MC extract for 30 days	TC (224.3 ± 35.6 mg/dL vs. 225.1 ± 38.8 mg/dL) LDL-c (129.0 ± 28.9 mg/dL vs. 123.4 ± 32.0 mg/dL) HDL-c (70.8 ± 19.4 mg/dL vs.69.6 ± 19.1 mg/dL) TG (132.8 ± 108.4 mg/dL vs. 192.1 ± 229.8 mg/dL)	TC 0.8 mg/dL LDL-c −5.6 mg/dL HDL-c −1.2 mg/dL TG 59.3 mg/dL
Cortez-Navarrete et al. (2018)⁵	Twenty-four T2DM patients	2000 mg/day of MC fruit powder for 12 weeks	TC (4.89 ± 0.73 mmol/L vs. 4.68 ± 1.02 mmol/L) TG (2.31 ± 1.25 mmol/L vs. 1.93 ± 0.92 mmol/L) HDL-c (1.13 ± 0.18 mmol/L vs.1.05 ± 0.31 mmol/L) LDL-c (2.69 ± 0.80 mmol/L vs. 2.75 ± 0.96 mmol/L) VLDL (8.26 ± 4.48 mmol/L vs. 6.92 ± 3.32 mmol/L)	TC −0.21 mmol/L TG −0.38 mmol/L HDL-c −0.08 mmol/L LDL-c 0.06 mmol/L VLDL −1.34 mmol/L
Krawinkel et al. (2018)¹¹	Fifty-two prediabetic patients	2500 mg/day of MC whole fruit powder for 8 weeks	TC (4.3 ± 0.85 mmol/L vs. 4.3 ± 0.8 mmol/L) HDL-c (0.9 ± 0.3 mmol/L vs.0.9 ± 0.4 mmol/L) TG (1.6 ± 0.7 mmol/L vs. 1.57 ± 0.53 mmol/L)	TC 0 mmol/L HDL-c 0 mmol/L TG −0.03 mmol/L
Suthar et al. (2016)⁷	Eighty-five T2DM patients	1200 mg/day of dry MC fruit juice powder for 90 days	TC (152.69 ± 27.27 mg/dL vs. 146.48 ± 28.74 mg/dL) HDL-c (48.56 ± 5.93 mg/dL vs. 47.52 ± 9.28 mg/dL) LDL-c (81.82 ± 24.15 mg/dL vs. 77.45 ± 26.10 mg/dL) VLDL (22.31 ± 4.20 mg/dL vs. 21.51 ± 3.95 mg/dL) TG (111.55 ± 20.98 mg/dL vs. 107.56 ± 19.75 mg/dL)	TC −6.21 mg/dL HDL-c -1.04 mg/dL LDL-c -4.37 mg/dL VLDL-c -0.8 mg/dL TG −3.99 mg/dL
Rahman et al. (2015)⁸	Ninety-five T2DM patients	Group I 2000 mg/day of MC fruit powder for 10 weeks Group II 4000 mg/day of MC fruit powder for 10 weeks	Group I TC (218.25 ± 10.70 mg/dL vs. 214.50 ± 14.50 mg/dL) LDL-c (149.70 ± 18.20 mg/dL vs. 146.50 ± 11.50 mg/dL) HDL-c (48.15 ± 4.90 mg/dL vs. 50.0 ± 3.50 mg/dL) TG (163.20 ± 17.50 mg/dL vs. 159.80 ± 16.70 mg/dL) TC/HDL-c ratio (4.53 ± 1.10 vs. 4.29 ± 1.20) LDL-c/HDL-c ratio (3.10 ± 1.35 vs. 2.93 ± 1.10) Group II TC (227.10 ± 15.50 mg/dL vs. 221.0 ± 11.60 mg/dL) LDL-c (154.0 ± 15.50 mg/dL vs. 148.90 ± 16.40 mg/dL, P < .01) HDL-c (47.60 ± 5.70 mg/dL vs. 51.20 ± 4.20 mg/dL) TG (168.0 ± 13.40 mg/dL vs. 154.20 ± 11.80 mg/dL, P ≤ .05) TC/HDL-c ratio (4.77 ± 1.60 vs. 4.31 ± 1.35) LDL-c/HDL-c ratio (3.23 ± 1.52 vs. 2.89 ± 1.31)	Group I TC −3.75 mg/dL LDL-c -3.2 mg/dL HDL-c 1.85 mg/dL TG −3.4 mg/dL TC/HDL-c ratio −0.24 LDL-c/HDL-c ratio −0.17 Group II TC −6.1 mg/dL LDL-c -5.1 mg/dL HDL-c 3.6 mg/dL TG −13.8 mg/dL TC/HDL-c ratio −0.46 LDL-c/HDL-c ratio −0.34
Tsai et al. (2012)¹⁴	Forty-two patients diagnosed with MetS	4800 mg/day of MC whole fruit for 3 months	Baseline results were reported by gender TC men (195.2 mg/dL) TC women (204.9 mg/dL) TG men (234.0 mg/dL) TG women (188.4 mg/dL) HDL-c men (41.5 mg/dL) HDL-c women (49.3 mg/dL) LDL-c men (125.5 mg/dL) LDL-c women (134.9 mg/dL)	Endpoint measures were not reported; however, no significant changes were observed in TC, TG, HDL-c, and LDL-c after MC administration
Dans et al. (2007)¹⁰	Forty T2DM patients	3000 mg/day of MC fruit and seed powder for 3 months	TC (5.25 ± 1.46 μmol/L vs. 5.08 ± 1.39 μmol/L)	TC −0.17 μmol/L

HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides; VLDL, very low-density lipoprotein.

The effect of MC on the lipid profile has also been reported as a secondary objective in several clinical trials in patients with T2DM and MetS. In the study conducted by Rahman et al. in T2DM patients, significant differences in LDL-c and TG concentrations were found in the group that received 4 g/day of MC (group II) for 10 weeks (154.0 ± 15.50 mg/dL vs. 148.90 ± 16.40 mg/dL, P < .01 [−5.10 mg/dL] and 168.0 ± 13.40 mg/dL vs. 154.20 ± 11.80 mg/dL, P ≤ .05 [−13.80 mg/dL], respectively). In both MC groups (group I: 2 g/day; group II: 4 g/day), the ratios of TG/HDL-c and LDL-c/HDL-c improved from baseline to endpoint; however, these differences were not statistically significant.⁸

In the study carried out by Dans et al. in patients with T2DM, the administration of 3000 mg/day of MC for 3 months decreased TC levels by 0.17 ± 0.86 μmol/L, which was not considered statistically significant; yet no other lipid was evaluated in this study.¹⁰ Suthar et al. reported a nonsignificant decrease in the mean change from baseline to endpoint in TC, TG, HDL-c, LDL-c, and VLDL levels in both treatment (1.2 g/day of MC fruit juice powder for 90 days) and placebo groups in T2DM patients with previous hypoglycemic therapy.⁷ Similar results were observed in the study conducted by Cortez-Navarrete et al. in T2DM patients. After 3 months of intervention with MC (2000 mg/day), no significant differences were observed in TG, TC, HDL-c, LDL-c, and VLDL concentrations.⁵

In a more recent study published by Kim et al. in patients with T2DM, no significant changes were found in TC, TG, HDL-c, or LDL-c levels after the administration of 2380 mg/day of MC fruit extract for 12 weeks.⁴

Also, in the trial conducted by Krawinkel et al. in prediabetic patients, no significant differences were found in TC, HDL-c, or TG levels after the administration of MC whole fruit powder (2500 mg/day) for 8 weeks.¹¹

Similarly, no significant differences were found in TG, TC, LDL-c, and HDL-c concentrations with MC supplementation (4.8 g/day) for 3 months in the study carried out by Tsai et al. in MetS patients.¹⁴

Adverse Events

Although no large-scale studies have been conducted to establish the safety of MC,⁶⁰ several clinical trials have reported the presence of adverse events. Hypoglycemia has been the most studied adverse event. Some anecdotal cases of hypoglycemic coma and convulsions due to the consumption of MC tea in children have been reported.⁶¹

There are several reports of the antifertility activity of MC. Some studies report that an extract of MC seeds could have activity on spermatogenesis, and induce histological changes in testis and accessory reproductive organs of mice.⁶² Also, in female rats, a decrease of plasma progesterone and estrogen levels in a dose-dependent manner of an aqueous leaf extract has been reported.⁶³

The seeds and outer rind of MC contain a toxic lectin that inhibits protein synthesis in the intestinal wall.⁶⁴ Clinical trials have reported that a high dose (250–500 g) of MC fruit caused abdominal pain and diarrhea in patients with diabetes mellitus.^4,65 Lectin also significantly inhibited DNA and protein synthesis in normal and leukemic human peripheral blood lymphocytes.⁶⁶ It has also been reported to be toxic to keratinocytes and fibroblasts in vitro after the administration of 500 and 600 μg/mL of an ethanolic extract.⁶⁷

Hematological effects have also been reported. For instance, the aqueous extract of MC leaves significantly decreased hemoglobin concentrations in albino rats.⁶⁸ Vicine, a glycosidic compound isolated from MC, has been associated with the induction of favism, which is characterized by hemolytic anemia.⁶⁹ At the neurological level, headaches have been reported after the ingestion of MC seeds, without information of its severity and duration.⁷⁰

In terms of herb–drug interactions, no formal studies have been carried out to investigate the interaction of MC with other drugs. There are few reports of its additive effects with other blood glucose lowering agents, especially with sulfonylureas.^71
–73

Finally, in the clinical trial carried out by Suthar et al. in T2DM patients using stable antidiabetic agents for 6 months, no adverse events, deaths, or significant changes in vital signs or hematological parameters were reported.⁷ Nonetheless, more studies are needed to determine the safety of MC in combination with other antidiabetic agents.

Conclusions

In conclusion, MC has been used for the treatment of various kinds of diseases for centuries. Evidence in animal models and clinical trials indicates that MC can improve several glycemic control parameters (FPG, PPG, and A1C).

The antiobesity and hypolipidemic activities of MC have been demonstrated in in vitro and animal models; however, in human studies the effect of MC on BW and lipid profile has been evaluated mainly in diabetic population, and the evidence shows some contradictory results. The multiple mechanisms of action reported suggest that MC has an excellent potential to prevent and treat obesity and dyslipidemia.

Rigorous clinical trials with better methodological quality, adequate sample size, randomized, placebo controlled, and with standardized MC preparations are needed to evaluate if the effects observed in animal models and clinical studies can be replicated in other populations and, thus determine if MC could be established as an alternative or complementary treatment for metabolic diseases. At the same time, potential adverse effects should also be investigated, especially during long-term consumption.

Footnotes

Acknowledgment

The authors thank L. Michele Brennan-Bourdon, PhD, Executive Editor of Scientific Authoring, for the English editorial assistance.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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