A Comprehensive Review of the Effects of Psidium guajava and Syzygium cumini Leaves on Diabetes Mellitus

Abstract

Diabetes is a chronic metabolic disorder characterized by elevated blood sugar levels because of insulin resistance or insufficient insulin production. The early detection and management of diabetes are essential to control diabetes and prevent the progression of this disease. Natural remedies have attracted attention for their potential role in the treatment of diabetes. Psidium guajava and Syzygium cumini have shown significant hypoglycemic, antioxidant and anti-inflammatory properties because of the presence of quercetin, rutin and gallic acid. This review aims to provide evidence supporting the beneficial effects of P. guajava and S. cumini leaves as sustainable substitutes for synthetic drugs, highlighting their therapeutic potential in diabetes treatment.

INTRODUCTION

Diabetes is an endocrine system disorder characterized by abnormally high blood glucose levels. Moreover, it is one of the most common and rapidly increasing diseases worldwide (Cho et al., 2018). According to studies, approximately 463 million individuals worldwide (9.3% of adults aged 20 and 79 years) are estimated to have diabetes. In addition, this number is expected to increase to 700 million by 2045 (Saeedi et al., 2019). Uncontrolled diabetes can lead to acute, potentially fatal effects, including hyperglycemia with ketoacidosis or hyperglycemic hyperosmolar nonketotic syndrome, accompanied by symptoms such as polyuria, polydipsia, polyphagia, weight loss, growth impairment, and increased susceptibility to specific diseases (Ramachandran, 2014).

To control diabetes and reduce new cases, early intervention at the pre-diabetes stage through improved dietary and physical activity habits, frequent assessments, and knowledge of diabetes symptoms is crucial (Ramachandran, 2014). In addition, to combat the burden of this disease, new therapeutic approaches are needed. The use of medicinal plants is one approach that patients with diabetes can easily and affordably use for the prevention and treatment of this disease (Yedjou et al., 2023). According to Wu and Wang (2023), plant derivatives efficiently reduce blood sugar and improve insulin sensitivity in diabetics. Plant polyphenols that possess few side effects can help in treating insulin resistance, which is linked to mitochondrial stress, by affecting insulin signaling and oxidative stress (Wu and Wang, 2023).

Previous studies have shown that Psidium guajava, commonly known as guava leaves (GL) and Syzygium cumini, generally known as jamun leaves (JL), can regulate blood glucose levels (Cheng et al., 2009; Díaz-de-Cerio et al., 2016). However, the full therapeutic potential of these compounds remains unknown because their bioavailability depends on a number of factors, including biological processes and individual consumption habits. Although some reviews discuss how natural remedies can lower blood sugar, many either ignore leaves, including GL and JL, or do not thoroughly examine their mechanisms. This review fills the knowledge gap by gathering recent data on the effectiveness of GL and JL consumption in the treatment of type 2 diabetes.

The findings from research done on GL and JL during the past 15 years have been showcased to connect the effects to their potential uses in health benefits. We searched electronic databases including PubMed, Google Scholar, Scopus, and Science direct, for variants of the following terms: “guava leaves,” “jamun leaves,” “Psidium guajava,” “Syzygium cumini,” “pre-diabetes,” “quercetin,” and “diabetes mellitus.” We included clinical studies that met the criteria of study participants being diagnosed with pre-diabetes and randomly assigned to receive the intervention. The database search yielded a total of 296 records. Among them, 245 studies were screened on the basis of the title, and only 222 studies selected based on the eligibility criteria. After reading the complete texts of the studies, 124 studies that met the inclusion criteria were selected, and only 39 randomized controlled trials were included in the comprehensive review. The study selection procedure is shown in Fig. 1.

Fig. 1.

Process of study selection. RCT, randomized controlled trial.

NATURAL REMEDIES FOR DIABETES PREVENTION

Herbal medicine is classified as complementary medicine. People find it appealing that their blood sugar levels could be improved without the use of prescription medications or insulin injections. For the treatment of type 2 diabetes, natural therapeutic products concentrate on the same primary pathophysiological mechanisms as pharmaceutical agents, including controlling insulin secretion and improving insulin resistance and sensitivity (Duarte et al., 2020). There is growing evidence on the safety and efficacy of using natural methods to prevent diabetes and improve the quality of life. The leaves of various plants have been found to exhibit the ability to act as hypoglycemic agents, prevent or decrease oxidative stress, and prevent diseases related to glycolipid metabolism (Tang et al., 2023).

Different parts of plants, including the roots, stems, leaves, flowers, and fruits, contain significant levels of flavonoids and are used to treat and prevent various illnesses, including diabetes, obesity, cancer, hypertension, cardiovascular disease, and neurological disorders (Millar et al., 2017; Kopustinskiene et al., 2020). In addition to that, there have been significant changes in markers linked to glucose metabolism in the leaves of several plant species, which effectively lower blood sugar levels and reduce the potential damage that hyperglycemia may induce on various target organs (Tang et al., 2023). The health benefits of natural antioxidants, especially plant polyphenols, have been widely recognized. Considering that oxidative stress is linked to several pathological illnesses, including diabetes and cardiovascular diseases, natural antioxidants might be able to decrease its harmful effects (Younis et al., 2022). The different natural remedies for preventing diabetes prevention are shown in Table 1 (Dehpour et al., 2009; Kumar et al., 2009; Kim et al., 2012; Lee et al., 2012; Haber et al., 2013; Jeon et al., 2013; Nagella et al., 2014; Alinejad-Mofrad et al., 2015; Khandouzi et al., 2015; Perrone et al., 2015; Al-Brakati, 2016; Kaur et al., 2016; Makhdoomi Arzati et al., 2017; Noor et al., 2017; Sidana et al., 2017; Kim et al., 2018; Latifi et al., 2019; Carvalho et al., 2020; Vidhya Rekha et al., 2022; Arabshomali et al., 2023; Das et al., 2023; Luo et al., 2023; Nyakundi and Yang, 2023).

Table 1.

Natural remedies for diabetes management

Study	Source	Phenolic compound	Function
Haber et al. (2013); Luo et al. (2023)	Fenugreek (Trigonella foenum-graecum) seeds	Diosgenin Luteolin Quercetin	↑ β-Cell protection ↓ Oxidative stress ↓ Inflammation
Alinejad-Mofrad et al. (2015); Noor et al. (2017); Kim et al. (2018)	Aloe vera (Aloe barbadensis miller)	Aloe-emodin	↓ Blood glucose levels ↑ Insulin secretion
Kim et al. (2012); Lee et al. (2012); Jeon et al. (2013)	Ashwagandha (Withania somnifera)	Saponins Polysaccharides Alkaloids Withanolides	Regulate blood sugar levels ↓ Inflammation β-Cells protection
Sidana et al. (2017); Das et al. (2023)	Jamun (Syzygium cumini) seeds	Jamboline Ellagic acid	↓ Fasting blood glucose ↓ Post-prandial plasma glucose levels ↓ HbA1c levels ↓ Oxidative stress
Kumar et al. (2009); Vidhya Rekha et al. (2022)	Neem (Azadirachta indica) leaves	Quercetin Kaempferol Nimbin Nimbidin	↓ Blood sugar levels ↑ Insulin sensitivity ↓ Oxidative stress ↑ β-Cell protection Anti-inflammatory
Arabshomali et al. (2023); Nyakundi and Yang (2023)	Papaya (Carica papaya) leaves	Quercetin Kaempferol Caffeic acid	β-Cells protection ↓ Fasting plasma glucose levels ↓ HbA1c levels ↓ Reactive oxygen species production
Nagella et al. (2014); Al-Brakati (2016); Kaur et al. (2016)	Garlic (Allium sativum)	Quercetin Allicin Alliin	↑ Insulin sensitivity ↓ Oxidative stress ↓ Blood sugar levels ↓ Inflammation
Dehpour et al. (2009); Latifi et al. (2019)	Asafoetida (Ferula assa-foetida)	Bisabolol Quercetin	↓ Blood glucose levels ↑ Insulin secretion
Perrone et al. (2015)	Turmeric (Curcuma longa)	Curcumin Curcuminoids	↓ Oxidative stress Anti-inflammatory ↓ Fasting blood glucose ↓ HbA1c levels
Khandouzi et al. (2015); Makhdoomi Arzati et al. (2017);Carvalho et al. (2020)	Ginger (Zingiber officinale)	Quercetin Zingerone Gingerenone	↓ HbA1c levels ↓ Fasting blood glucose levels

Plant-based diabetes treatment offers a natural and perhaps safer alternative to synthetic medications, which may have drawbacks like side effects, high long-term costs, and the possibility of resistance. Therefore, understanding the interactions between these bioactive phytochemicals in the human body is crucial for the treatment of diabetes mellitus. Moreover, the use of natural plants and herbs could pave the way for developing novel medications derived from plants and for applying plant-based treatments for diabetes mellitus.

GUAVA LEAVES AND THEIR PHYTOCHEMICAL PROPERTIES

The therapeutic properties of GL make it useful in both traditional medicine and meals. GL are rich in many bioactive substances, particularly phenolic compounds, which exhibit anti-inflammatory and antioxidant properties (Naseer et al., 2018). GL contain various phytochemicals, including quercetin, avicularin, apigenin, guaijaverin, kaempferol, hyperin, myricetin, gallic acid, catechin, epicatechin, chlorogenic acid, epigallocatechin gallate, and caffeic acid, which have been studied for their potential health benefits (Shabbir et al., 2020; Zhu et al., 2020; Pereira et al., 2023). Phenolic compounds are the primary bioactive components that give GL their antioxidant and hypoglycemic qualities and are important for controlling the body’s physiological and metabolic processes (Díaz-de-Cerio et al., 2016). Studies using GL extracts both in vitro and in vivo have demonstrated their antihyperglycemic and hypoglycemic properties (Cheng et al., 2009). Zhang et al. (2016) found that GL contain phytochemicals that inhibit α-glucosidase and α-amylase. This prevents the rapid release of glucose from complex carbohydrates, thereby regulating blood glucose levels.

Studies have also investigated into the possibility of using GL extracts to treat diarrhea (Dewi et al., 2013). Moreover, GL have been shown to exhibit significant antitumor effects because they contain triterpenoids, sesquiterpenes, tannins, psiguadials, volatile oils, flavonoids, benzophenone glycosides, and other quinones. In addition, GL can be used to treat infections by producing reactive oxygen species, inhibiting microbial cell wall development, disrupting and lysing cells, hindering biofilm formation, repressing DNA replication and transcription, decreasing ATP production, and suppressing bacterial toxins. GL exhibit potent antimicrobial properties because of their organic and inorganic antioxidants and anti-inflammatory compounds (Mickymaray, 2019). The different phytochemicals of GL that can help prevent diabetes are listed in Table 2 (Wei et al., 2012; Ahrens and Thompson, 2013; Bak et al., 2013; Niture et al., 2014; Al-Numair et al., 2015; Ahangarpour et al., 2016; Dhanya et al., 2017; Ghorbani, 2017; Duarte et al., 2019; Lalitha et al., 2020; Rahimifard et al., 2020; Shabbir et al., 2020; Li et al., 2021; Liu et al., 2021; Zhou et al., 2021a; Mirza et al., 2022; Qian et al., 2022; Nor et al., 2023; Song and Yu, 2024; Yao et al., 2024).

Table 2.

Phytochemicals in guava leaves and their antidiabetic properties

Study	Phytochemical	Antidiabetic properties
Dhanya et al. (2017); Shabbir et al. (2020); Song and Yu (2024)	Quercetin	↓ Blood glucose levels Strong antidiabetic agent Anti-inflammatory ↑ Insulin sensitivity
Bak et al. (2013); Rahimifard et al. (2020)	Gallic acid	↑ Insulin sensitivity ↓ Blood glucose levels ↓ Hyperglycemia risk
Duarte et al. (2019);Li et al. (2021)	Guaijaverin	↓ Fasting blood glucose levels ↓ HbA1c levels
Niture et al. (2014);Ghorbani (2017)	Rutin	↓ Blood sugar levels ↑ Insulin secretion Inhibits glucose absorption
Ahangarpour et al. (2016)	Catechin	↑ Insulin sensitivity ↓ Blood glucose levels ↓ Inflammation Antioxidant protection for β-cells
Wei et al. (2012);Mirza et al. (2022)	Syringic acid	Anti-inflammatory ↓ Cellular glucose absorption ↑ Insulin sensitivity ↓ Blood glucose levels ↓ Oxidative stress on β-cells
Al-Numair et al. (2015); Yao et al. (2024)	Kaempferol	↓ Blood sugar levels ↓ Oxidative stress ↓ Inflammation ↑ Glucose uptake ↑ Protection of pancreatic β-cells
Liu et al. (2021);Zhou et al. (2021a)	Hyperin	↓ Blood sugar levels ↑ Insulin sensitivity ↓ Oxidative stress ↓ Inflammation ↑ Cellular glucose uptake
Ahrens and Thompson (2013);Lalitha et al. (2020); Qian et al. (2022)	Myricetin	↑ Cellular glucose absorption ↓ Blood glucose levels ↑ Insulin sensitivity ↓ Oxidative damage ↓ Inflammation Protection of pancreatic β-cells
Nor et al. (2023)	Avicularin	↓ Fasting blood sugar levels ↑ Insulin sensitivity ↓ Inflammation ↑ Glucose uptake ↓ Oxidative stress

GUAVA LEAVES FOR DIABETES MANAGEMENT

GL possess antidiabetic and antioxidant properties, and they have long been used as a traditional treatment for diabetes. According to Luo et al. (2019), GL dramatically reduce blood sugar and cholesterol levels while boosting antioxidant activity. GL exhibit hypoglycemic effects that are associated with important metabolic pathways, including amino acid metabolism, and lower blood glucose and lipid levels in individuals with type 2 diabetes. The metabolism of cysteine, methionine, and branched-chain amino acids was found to play significant roles in the treatment of diabetes (Xu et al., 2020). GL have potent antiglycemic and antioxidant qualities that lower glycation markers, lipid peroxidation, and blood sugar in diabetics. GL can inhibit advanced glycation and products that lead to diabetes complications and increase antioxidant enzyme activity. These findings demonstrate their potential as a natural antidiabetic and oxidative stress-protective agent (Soman et al., 2010). GL have been used in numerous investigations and trials as a potential diabetes preventive medication. GL-based trials to prevent diabetes are shown in the Table 3 (Shen et al., 2008; Shukla and Dubey, 2009; Guo et al., 2013; Jayachandran et al., 2018; Yang et al., 2020; Jiang et al., 2021; Rajput and Kumar, 2021; Tella et al., 2022; Rahman et al., 2023).

Table 3.

Psidium guajava leaves for diabetes management

Study	Study design	Duration	Result
Shen et al. (2008)	Diabetic subjects were observed in acute and long-term feeding test	−	Significantly ↓ in blood sugar levels (P<0.05)
Shukla and Dubey (2009)	Six groups of subjects were created, and each group received a different dosage of GL, with the exception of the control group	13 days	↓ Blood glucose levels by 18.88%
Guo et al. (2013)	2 g/kg of GL daily given to diabetic individuals daily	6 weeks	↓ Blood glucose levels after 60 and 120 min
Jayachandran et al. (2018)	Subjects were divided into seven groups, and each group received a different dosage of GL, with the exception of the control group	45 days	Significant ↓ in plasma glucose levels (P<0.05) with 200 mg/kg of GL
Yang et al. (2020)	Individuals were divided into three groups, and each group received a different dosage of GL, with the exception of the control group	8 weeks	↓ Fasting plasma glucose levels by 35.4%
Jiang et al. (2021)	Used network pharmacology to identify the active compounds of GL and their effects on diabetes	−	Regulate insulin resistance Glucose metabolism ↓ Blood sugar levels
Rajput and Kumar (2021)	Subjects were given 200 mg/kg body weight of GL	−	↓ Blood glucose levels in diabetic patients to 96.01 mg/dL (P<0.05)
Tella et al. (2022)	Participants were given 400 mg/kg body weight of GL	14 days	Improved glucose metabolism
Rahman et al. (2023)	Randomized control study on type 2 diabetes with 24 participants	28 days	↓ Fasting blood glucose levels

GL, guava leaves; −, not available.

JAMUN LEAVES AND THEIR PHYTOCHEMICAL PROPERTIES

JL contain phytochemicals, including gallic acid, tannins, malic acid, jambolin, ellagic acid, jambosine, antimellin, betulinic acid, eicosane, quercetin, crategolic acid, sitosterol, myricetin, and kaempferol (Jagetia, 2017; Ahmed et al., 2019). Among them, crategolic acid (often referred to as maslinic acid), acts as an antidiabetic factor that could help keep blood glucose levels within the normal range and therefore support the treatment of diabetes (Mkhwanazi et al., 2014). The different phytochemicals present in JL and their antidiabetic properties are listed in Table 4 (Gupta et al., 2011; Ahrens and Thompson, 2013; Al-Numair et al., 2015; Hung et al., 2015; Ko et al., 2016; Dhanya et al., 2017; Fatima et al., 2017; Alkhalidy et al., 2018; Ponnulakshmi et al., 2019; Guo et al., 2020; Lalitha et al., 2020; Shabbir et al., 2020; Solverson, 2020; Les et al., 2021; Zhou et al., 2021b; Qian et al., 2022; Wang et al., 2022; Xie et al., 2022; Das et al., 2023; Song and Yu, 2024; Yao et al., 2024).

Table 4.

Phytochemicals in jamun leaves and their antidiabetic properties

Study	Phenolic compound	Antidiabetic properties
Ko et al. (2016); Zhou et al. (2021b); Xie et al. (2022)	Betulinic acid	↑ Insulin signaling ↓ Oxidative stress ↓ Inflammation ↑ Glucose tolerance ↑ Diabetic wound healing
Fatima et al. (2017); Guo et al. (2020)	Ellagic acid	↑ Insulin secretion ↑ Insulin-to-glucose ratio ↓ Glucose intolerance ↓ Fasting blood glucose levels Improves the antioxidant status
Hung et al. (2015); Wang et al. (2022)	Maslinic acid	↓ Plasma glucose levels ↓ HbA1c levels ↓ Oxidative stress ↓ Inflammation ↑ Antioxidant defense
Dhanya et al. (2017);Shabbir et al. (2020); Song and Yu (2024)	Quercetin	↓ Blood sugar levels ↑ Insulin sensitivity ↓ Oxidative stress ↓ Inflammation ↑ Glucose metabolism Protection of pancreatic β-cells
Solverson (2020); Les et al. (2021)	Anthocyanin	↑ Insulin sensitivity ↓ Blood sugar levels Protection of β-cells ↓ Inflammation ↓ Breakdown of carbohydrates
Das et al. (2023)	Jambosine	↓ Blood glucose levels ↑ Insulin sensitivity ↑ Carbohydrate metabolism regulation ↓ Hyperglycemia
Ahrens and Thompson (2013);Lalitha et al. (2020); Qian et al. (2022)	Myricetin	↑ Cellular glucose absorption ↓ Blood glucose levels ↑ Insulin sensitivity ↓ Oxidative damage ↓ Inflammation Protection of pancreatic β-cells
Al-Numair et al. (2015); Alkhalidy et al. (2018); Yao et al. (2024)	Kaempferol	↓ Blood sugar levels ↓ Oxidative stress ↓ Inflammation ↑ Glucose uptake ↑ Protection of pancreatic β-cells
Gupta et al. (2011); Ponnulakshmi et al. (2019)	Sitosterol	↓ Blood glucose levels Improves glycemic control

JAMUN LEAVES FOR DIABETES MANAGEMENT

According to Fatema et al. (2017), JL are traditionally used in managing diabetes due to their ability to regulate blood glucose levels and improve insulin sensitivity. Their antioxidant and anti-inflammatory properties also contribute to reducing the complications associated with diabetes. JL aid in blood sugar control because of the presence of anthocyanins, ellagic acid, and hydrolyzable tannins, which help manage the conversion of carbohydrates into glucose. JL can effectively alleviate diabetes-related symptoms, including excessive thirst and frequent urination (Chaudhary et al., 2017). JL have been the subject of many studies and trials as a potential treatment for diabetes prevention. The trials that investigated the use of JL for diabetes prevention are presented in Table 5 (Rekha et al., 2010; Deb et al., 2013; Ayya et al., 2015; Maheswararao, 2016; Jagetia, 2017; Raza et al., 2017; Sidana et al., 2017; Biswas and Sen, 2018; Mulkalwar et al., 2021).

Table 5.

Syzygium cumini leaves for diabetes management

Study	Study design	Duration	Result
Rekha et al. (2010)	Individuals were divided into four groups and treated with different doses of JL except for the control group	15 days	↓ Blood glucose levels ↓ Serum insulin levels
Deb et al. (2013)	Diabetics were administered 50 or 100 mg/kg of JL	21 days	↓ Serum glucose levels
Ayya et al. (2015)	Subjects were divided into two groups and treated with JL	60 days	↓ Fasting blood glucose levels by 37% ↓ Post-prandial blood glucose levels by 44%
Maheswararao (2016)	100 mg/kg of JL was given to diabetic individuals	20 days	↓ Blood glucose levels
Sidana et al. (2017)	JL was supplemented as powder	90 days	↓ Fasting plasma glucose levels by 30% Long-term glucose management
Biswas and Sen (2018)	200 and 400 mg/kg body weight of JL was orally administered	3 weeks	↓ Fasting blood glucose levels by 46.67%－52.67%
Jagetia (2017)	Subjects were treated with 400 mg/kg of JL	90 days	↓ Blood glucose levels by 30%
Mulkalwar et al. (2021)	200 mg/kg body weight of JL was administered	8 weeks	Significant in blood glucose levels (P<0.05)
Raza et al. (2017)	Individuals were divided into four groups and treated with different doses of JL	60 days	↓ Blood glucose levels by 14.36%

JL, jamun leaves.

PHENOLIC COMPOUNDS FOR MAINTAINING BLOOD GLUCOSE LEVELS

Phenolic compounds obtained from plants have been shown to improve endothelial dysfunction, modulate lipid metabolism and adipocyte differentiation, improve glucose tolerance and insulin sensitivity, decrease oxidative stress, and suppress inflammation and apoptosis, suggesting that they may have an antidiabetic effect (Millar et al., 2017; Kopustinskiene et al., 2020). The dosage of phenolic compounds for maintaining blood glucose levels is listed in Table 6 (Gupta et al., 2011; Bak et al., 2013; Kim et al., 2014; Niture et al., 2014; Shi and Williamson, 2016; Alkhalidy et al., 2018; Ibitoye and Ajiboye, 2018; Zheng et al., 2018; Yao et al., 2019; Amor et al., 2020; Lalitha et al., 2020; Amadi et al., 2021; Liu et al., 2021; Nazir et al., 2021; Oršolić et al., 2021; Song et al., 2021; Chen et al., 2022; Gao and Wu, 2022; Hong et al., 2023).

Table 6.

Dosage of the phenolic compounds for maintaining blood glucose levels

Study	Bioactive compound	Dosage	Duration	Result	Trial
Zheng et al. (2018)	Anthocyanins	320 mg/d	4 weeks	−	The dosages were given to patients with type 2 diabetes
Amadi et al. (2021)	Avicularin	5000 mg/kg body weight	12 weeks	−	The study was conducted on rats
Kim et al. (2014)	Betulinic acid	10 mg/kg body weight	3 weeks	Blood glucose levels decreased by 34%	The trials were conducted on mice
Song et al. (2021)	Betulinic acid	200 mg/kg	After 120 minutes	Blood glucose levels decreased by 70%	The experiment was conducted on albino mice
Chen et al. (2022)	Betulinic acid	20 mg	7 days	−	The trials were conducted on mice
Ibitoye and Ajiboye (2018)	Caffeic acid	40 mg/kg body weight	6 weeks	−	The trials were conducted on mice
Oršolić et al. (2021)	Caffeic acid	50 mg/kg body weight	7 days	Blood glucose levels decreased by 9.9%	The study was conducted on Swiss mice
Nazir et al. (2021)	Catechin	50 mg/kg body weight	21 days	Blood glucose levels decreased by 55.56%	The study was conducted on rats
Amor et al. (2020)	Ellagic acid	600 mg/kg body weight	After 12 hours	Blood glucose levels decreased by 52%	The experiment was conducted on murine mice
Bak et al. (2013)	Gallic acid	10 mg/kg/d	2 weeks	−	The trials performed on mice
Hong et al. (2023)	Gallic acid	30 mg/kg/d	4 weeks	Blood glucose levels decreased by 10.67%	The experiment was conducted on mice
Liu et al. (2021)	Hyperin	40 mg	12 weeks	Blood glucose levels decreased by 15.1%	The experiment was conducted on mice
Alkhalidy et al. (2018)	Kaempferol	50 mg/kg body weight	4 weeks	Blood glucose levels decreased by 18.06%	The experiment was conducted on rats
Gao and Wu (2022)	Maslinic acid	20 mg/kg body weight	8 weeks	Blood glucose levels decreased by 28%	The trials were conducted on mice
Lalitha et al. (2020)	Myricetin	20 mg/kg body weight	14 weeks	Blood glucose levels decreased by 28%	The trials were conducted on rats
Niture et al. (2014)	Rutin	50 mg/kg body weight	3 weeks	−	The trials were conducted on rats
Gupta et al. (2011)	Sitosterol	20 mg/kg/d	21 days	Serum glucose levels decreased by 50.4%	The experiment was conducted on male albino Wistar rats
Shi and Williamson (2016)	Quercetin	500 mg	4 weeks	Fasting blood glucose levels decreased by 11.1%	Males were chosen for the trial
Yao et al. (2019)	Quercetin	20.9 mg	1 week	−	A Chinese population was selected for the study

−, not available.

Quercetin, which is one of the most abundant flavonoids in the plants, has been associated with many desirable physiological functions, including a decreased incidence of type 2 diabetes mellitus in epidemiological studies (Yao et al., 2019). In vivo and in vitro studies have shown the antidiabetic potential of quercetin by triggering insulin production (Bardy et al., 2013). Since quercetin is an enzyme that is known to reduce blood glucose levels, it is used as hypoglycemic medicinal product (Shabbir et al., 2020). Because of its effective antidiabetic properties, quercetin may help decrease blood sugar and improve insulin sensitivity. In addition, quercetin appears to affect numerous elements and signaling pathways linked to insulin resistance and the etiology of type 2 diabetes. Furthermore, quercetin influences the major pathways implicated in the etiology of diabetes complications, including diabetic nephropathy, and has the potential to prevent and improve these consequences. The anti-inflammatory and antioxidant qualities of quercetin may be responsible for these beneficial benefits (Yao et al., 2019).

According to De Bruyn et al. (2015), quercetin is a potentially useful natural substance that modulates several diabetes targets and important signaling pathways. Quercetin reduces hyperglycemia by promoting insulin production, preventing the degeneration of pancreatic β-cells, and enhancing the antioxidant defense state of cells. In addition, quercetin has a safer profile than antidiabetic medications that are marketed for sale. Quercetin’s versatile mechanisms of action include enhanced glucose utilization in peripheral tissues, reduction of intestinal glucose absorption, and secretion of insulin and insulin-sensitizing actions. The significant anti-inflammatory and antioxidant properties of quercetin are assumed to contribute to its therapeutic potential as an antidiabetic medication (Eid and Haddad, 2017).

DISCUSSION

Diabetes is a type of metabolic illness characterized by hyperglycemia because of deficiencies in insulin production, insulin action, or both (American Diabetes Association, 2011). Managing this disorder can be difficult because of these interconnected issues. Recently, natural remedies, including the consumption of GL and JL, have attracted considerable attention because of their possible benefits in diabetes management and prevention owing to their rich flavonoid content (Huang et al., 2021; Jiang et al., 2021; Mulkalwar et al., 2021; Chu et al., 2022).

GL can reduce blood glucose levels because of the presence of bioactive compounds, including flavonoids and tannins that inhibit enzymes involved in carbohydrate metabolism, which reduces the absorption of glucose and increases insulin sensitivity, making it an effective natural treatment for those suffering from pre-diabetes (Zhang et al., 2016). GL possess notable antidiabetic properties that aid in blood glucose regulation because of their active compounds, which help in enhancing insulin sensitivity and minimize diabetes-related complications (Díaz-de-Cerio et al., 2016). According to De Bruyn et al. (2015), quercetin, which is a potentially useful natural substance present in GL, modulates several diabetes targets and important signaling pathways by promoting insulin production, preventing the degeneration of pancreatic β-cells, and enhancing the antioxidant defense state of the cells. GL have long been used to treat diabetes because of their antihyperglycemic qualities, which inhibit alpha-glucosidase enzymes, lowering blood glucose levels after meals and in certain clinical trials improving metabolic markers (Yang et al., 2020).

Dhanya et al. (2017) found that quercetin, the active ingredient in JL, decreased the blood glucose levels in the diabetic subjects. Moreover, quercetin had the ability to decrease oxidative stress, which helps to reduce the risk of diabetes. According to Liu et al. (2007) reported that patients with diabetes who took crategolic acid, an active component of JL, experienced a decrease in blood glucose levels and a partial modulation of glucose metabolism through a reduction in insulin resistance. The health-promoting properties of JL are related to their phytochemical foundation. These phytochemicals play an important role in promoting insulin production and protect the pancreatic cells that produce it (Bardy et al., 2013).

Recent developments have brought focused on the potential of JL and GL as functional foods for diabetes treatment. In addition, studies indicate that GL and JL may decrease inflammation and oxidative stress, two major causes of diabetes complications. The inclusion of GL and JL in dietary interventions for diabetes management is supported by the findings of these trials. Moreover, the development of fortified foods and supplements using these leaves offers a viable way to incorporate natural antidiabetic treatments into regular meals, enhancing individualized nutrition plans for the treatment of chronic illnesses.

Rahman et al. (2023) found that fasting glucose levels decreased after 28 days of GL administration; however, the study lacked follow-up data to determine whether these effects were sustainable beyond the intervention period. In addition, the study did not assess the potential side effects or metabolic adaptations that may occur with continued use. In another study, Tella et al. (2022) observed that a 14-day GL treatment led to improved glucose metabolism. However, the study had a relatively small sample size, limiting the utility of its findings. Furthermore, it did not explore potential confounding factors, including dietary intake, physical activity, or genetic variations that could influence glycemic responses. Similarly, Shukla and Dubey (2009) observed β-cell regeneration and decreased blood glucose levels after 13 days of GL administration. However, their study relied on animal models, making it difficult to apply the results directly to human populations. Moreover, the mechanism underlying the observed β-cell regeneration was not fully elucidated, necessitating further biochemical and histological analyses. Despite the promising results of these short-term studies, their limited duration restricts the ability to draw long-term conclusions regarding the sustained effects of GL on glucose metabolism and overall diabetes management.

Four medium-term studies lasting six to eight weeks provide further insights into the prolonged benefits of GL. Guo et al. (2013) indicated that six weeks of GL treatment enhanced insulin sensitivity and glucose tolerance. However, their study did not account for potential variations in insulin secretion, and the sample population was not diverse, which could impact the applicability of the findings to broader groups. Jayachandran et al. (2018) conducted a 45-day study and found that GL administration led to reductions in plasma glucose levels, with the most pronounced effects observed at a specific dosage. However, the study did not explore potential adverse effects at higher dosages, which could be a critical consideration for therapeutic applications. Yang et al. (2020) reported improvements in fasting plasma glucose levels and insulin sensitivity after eight weeks of GL treatment. Although the findings were promising, the study did not examine the molecular pathways involved in glucose regulation, limiting its mechanistic insights. In addition, the sample size of the trial was not large enough to detect subtle variations across different subgroups, including those with varying degrees of insulin resistance. Similarly, Shen et al. (2008) demonstrated improved glucose utilization and plasma insulin levels with prolonged GL intake. However, this study did not investigate potential metabolic shifts that could result from long-term GL supplementation, including changes in lipid metabolism, gut microbiota composition, or liver function.

Two long-term studies exceeding 10 weeks provided a more comprehensive evaluation of the hypoglycemic effects of GL. Chu et al. (2022) reported that a 12-week intervention using the highest dose of GL significantly reduced fasting plasma glucose starting from the first week, indicating a potent and sustained hypoglycemic effect. However, the study did not assess organ-specific effects, including hepatotoxicity or renal function impairment, which are crucial factors for long-term safety. In addition, the study lacked a placebo-controlled design, which could have strengthened the validity of its findings. Jiang et al. (2021) used a network pharmacology approach to identify the active compounds in GL and their molecular targets, suggesting that GL may regulate glucose metabolism, insulin resistance, and associated signaling pathways. However, experimental validation is needed to confirm the predicted interactions in vivo because network pharmacology relies on computational models. Moreover, this study did not address individual variability in response to GL treatment, which may be influenced by genetic and environmental factors. Although these studies provided valuable information on the long-term efficacy of GL, they did not comprehensively evaluate their effects on organ health, gut microbiota, or potential metabolic changes resulting from prolonged use. Further studies are needed to establish the long-term safety, optimal dosage, and therapeutic potential of GL in diabetes management.

Similarly, several studies have investigated the effects of JL on blood glucose regulation in diabetic subjects through short- and long-term interventions. Four studies, which lasted three to eight weeks, fall under the short-term category. Biswas and Sen (2018) administered 200 and 400 mg/kg doses of JL for three weeks, both of which led to immediate reductions in fasting blood glucose levels. However, their study was limited to a single healthcare facility, restricting its external validity. Furthermore, the fixed training period and limited access to comprehensive patient records further constrained the study’s findings. In addition, factors, including variations in dietary adherence and potential observer bias could have influenced the results, affecting their broader applicability. Deb et al. (2013) evaluated the effects of JL at doses of 50 and 100 mg/kg over a 21-day period. They observed reductions in blood glucose levels. However, the study lacked sufficient data on the potential rebound effects following the discontinuation of JL treatment. Without long-term follow-up, it remains uncertain whether the observed benefits persist or if the glucose levels return to the baseline. Mulkalwar et al. (2021) performed an eight-week study and found that JL exert dose-dependent antihyperglycemic effects, with the most substantial reductions occurring at higher doses. However, they study did not explore whether JL exerts additional metabolic benefits beyond glycemic control, including improvements in lipid profiles or inflammatory markers.

Three long-term studies, which lasted for 60 to 90 days, provided a more extensive evaluation of JL’s potential. Sidana et al. (2017) found that the consumption of 10 g of JL daily for 90 days resulted in a 30% reduction in fasting plasma glucose and an improvement in HbA1c levels, suggesting significant long-term benefits in glucose control. However, they did not investigate the potential adverse effects associated with prolonged JL consumption, including gastrointestinal disturbances or interactions with other medications. Furthermore, the study design did not include a control group, limiting the study’s ability to establish causality. Raza et al. (2017) demonstrated a 14.36% reduction in blood glucose levels after 60 days of JL supplementation. Although the findings highlight the potential of JL as a long-term treatment, the study did not consider lifestyle factors, including dietary habits or physical activity, which could have influenced glucose levels. In addition, variations in sample demographics, including age and disease severity, were not thoroughly accounted for, making it challenging to generalize the results to diverse populations. Overall, these long-term studies underscore the ability of JL to provide sustained improvements in glycemic control, suggesting their suitability as a natural therapeutic option for diabetes management.

The level of evidence supporting the current review is still low because of the small number of human studies and their numerous limitations, including single-center studies, small sample sizes and poor methodological quality. Moreover, the precise processes in which GL and JL control blood glucose and their impacts on insulin resistance, bioavailability, and molecular pathways remain unclear. The effects of GL and JL on the gut microbiota, glucose metabolism, and pancreatic β-cell function also need to be investigated. To ascertain their potential for inclusion in functional foods and to comprehend their pharmacological characteristics and long-term impacts, more carefully planned clinical trials with larger sample sizes are needed. In-depth clinical trials may lead to a novel plant-based treatment for diabetes that is affordable and long-lasting, thereby addressing this global health issue.