Diabetes mellitus (DM) is a chronic metabolic disease characterised by persistent hyperglycaemia due to impaired insulin secretion, insulin action or both (Kharroubi and Darwish, 2015; Artasensi et al., 2020). It can be divided into type 1 DM (T1DM) and type 2 DM (T2DM). T1DM is characterised by an absolute insulin deficiency, which is often accompanied by symptoms such as thirst, weight loss and polyuria and accounts for 10% of DM cases (Sun et al., 2021). T2DM, on the other hand, is characterised by insulin resistance in the target tissue, relatively insufficient insulin secretion and resulting dysfunction of the β-cells, which often causes no symptoms (Nyenwe et al., 2011). The DM condition leads to long-term complications affecting various organs, including the eyes, kidneys, nerves, heart and blood vessels. There are several factors that can lead to DM, such as genetic inheritance, viral infections, unhealthy lifestyle and other physical or chemical damage that leads to the destruction of β-cells (Roglic, 2016).

The global prevalence of DM is increasing at an alarming rate and poses major challenges for healthcare systems worldwide (Hossain et al., 2024). A recent study highlights that the global prevalence of DM is estimated to reach 700 million people by 2045 if current trends continue, emphasising the urgent need for effective prevention and management strategies (Sun et al., 2022). Another study notes that the prevalence of DM is particularly high in low- and middle-income countries, where health systems are often less well equipped to cope with the disease burden (Dendup et al., 2018).

Currently, conventional treatments for DM mainly focus on controlling blood glucose levels through the use of medications such as insulin, metformin and other antidiabetic drugs (Weinberg Sibony et al., 2023). However, they often have side effects and do not address the multifactorial nature of the disease. For example, long-term use of certain medications can lead to gastrointestinal problems, weight gain and an increased risk of cardiovascular events (Shurrab and Arafa, 2020). In addition, these treatments do not adequately target the underlying causes of DM, such as insulin resistance and beta-cell dysfunction.

As a result, there is growing interest in alternative and complementary therapies, including herbal medicines, for the treatment of diabetes. Botanical drugs offer a holistic approach by targeting multiple metabolic pathways involved in the development of DM (Pang et al., 2019). They are often considered to have few side effects and may offer additional benefits such as antioxidant and anti-inflammatory effects (Adam et al., 2022). In addition, conventional antidiabetic drugs may be costly or insufficiently available in low- and middle-income countries. Botanical drug treatments, especially those grown locally, are often considered more accessible and affordable (Mohan et al., 2020; Chaachouay and Zidane, 2024). Furthermore, integrative medicine, which combines evidence-based complementary practises with conventional treatments, is becoming increasingly important in modern healthcare systems. This has led to increased research into the antidiabetic properties of various botanical drugs, which have shown promising results in both preclinical and clinical studies (Vivó-Barrachina et al., 2022).

Botanical drugs represent a vast and invaluable reservoir of bioactive metabolites, many of which have a wide range of pharmacological properties. Due to their diverse mechanisms of action and generally lower risk of adverse effects, they represent a promising avenue for research and hold significant potential for improving the comprehensive treatment of DM (Yedjou et al., 2023). Gynura procumbens (Lour.) Merr. (GP) is an herbal plant rich in bioactive metabolites that may provide therapeutic benefits for a number of diseases. It is a perennial evergreen shrub belonging to the Asteraceae family (Tan et al., 2016). It is called ‘Sambung Nyawa’ or Sabungai in Malay (Jobaer et al., 2023), ‘bai bing cha’ by Chinese and Malay communities (Murugaiyah et al., 2018), and ‘pyar-hmee’ in Myanmar (Aung et al., 2021). It is also known as ‘longevity spinach’ (Jobaer et al., 2023). This green vegetable is typically small-growing and reaches a height of around 1–3 m (Tan et al., 2016). It also has yellow, slender and panicle-shaped flower heads that are 1–1.5 cm long and ovate-elliptical or lanceolate leaves that are 3.5–8 cm long and 0.8–3.5 cm wide. This edible herbaceous plant is widely distributed in Malaysia, Indonesia, Thailand, Vietnam and China. In Thailand, the GP leaves are used as a popular vegetable for a variety of culinary creations and play an important role in dishes such as chilli paste, curries, salads and soups and can be enjoyed both raw and cooked (Kaewseejan et al., 2015). In Malaysia, it is often eaten uncooked with rice and used as an ingredient in salads and ulam (Hew and Gam, 2011).

This plant has long been used in traditional medicine for the treatment of diabetes, hyperlipidaemia, kidney disease, hypertension, fever, constipation, skin irritation, migraine, rheumatism, haemorrhoids and colon cancer (Zhang and Tan, 2000; Rosidah et al., 2009; Hassan et al., 2010; Mohamed et al., 2023). In addition, this plant has a variety of therapeutic properties, such as anti-hyperlipidaemic, anti-inflammatory, antibacterial, antifungal, antihypertensive, antioxidant and anticancer properties (Iskander et al., 2002; Kim et al., 2011; Algariri et al., 2013; Hew et al., 2013; Jarikasem et al., 2013; Jeon and Kwon, 2016). Since it is a natural-based product, it is a better option with minimal side effects compared to the commercially available synthetic drugs. The availability of GP at a reasonable price and easy accessibility makes it a significant alternative to modern medicine, which is important specifically for an underprivileged community. Furthermore, the increasing use of GP as a natural remedy has led to this plant having potential for commercial cultivation and processing of organic products due to the growing markets for herbal raw materials and processed products.

Therefore, this review aims to summarise the current information on the potential health benefits of GP in DM and its complications from animal models and in vitro studies. The traditional use of this plant in folk medicine combined with scientific validation emphasises its potential as a complementary therapy for the treatment of DM.

The nutritional analysis of GP leaves revealed that they contain 13.59% crude fibre and 16.92% ash. Its nutritional properties, especially the high fibre content and low glycaemic profile, increase the antidiabetic potential of GP and make it a promising candidate for dietary intervention for the prevention or treatment of T2DM (Nath et al., 2023). In addition, GP leaves contain a low composition of protein (6.2%), moisture (6.2%), carbohydrate (0.4%), and fat (0.07%) (Nath et al., 2023). This is important as it can help reduce the risk of various chronic diseases, such as type 2 diabetes by improving insulin sensitivity, regulating blood glucose levels, and reducing the risk of developing diabetes (Jobaer et al., 2023). The nutritional contents of the GP extract are listed in Table 1.

Meanwhile, phytochemical studies of GP have revealed a diverse phytochemical metabolite, with a predominance of polyphenolic metabolites, especially phenolic acids and flavonoids, extracted from various solvents. Of the phenolic acids, gallic acid, protocatechuic acid, p-hydroxybenzoic acid, vanillic acid and syringic acid, which belong to the hydroxybenzoic acid subclass were consistently detected. They can be detected in the aqueous, ethanolic and ethyl acetate fractions of the leaves (Kaewseejan et al., 2015; Liu et al., 2019). Caffeic acid, p-coumaric acid, ferulic acid and sinapic acid, which belong to the hydroxycinnamic acids, can be found in both polar (aqueous, methanol) and semi-polar (ethyl acetate) extracts, indicating their solubility in a range of solvents (Kaewseejan et al., 2015; Alam et al., 2016; Liu et al., 2019; Kim et al., 2021). In addition, phenolic acids have been shown to lower blood glucose levels and protect against chronic diseases caused by hyperglycaemia through antioxidant protection (Deka et al., 2022).

Important flavonoids such as rutin (a quercetin glycoside), quercetin, myrricetin, kaempferol, apigenin and luteolin have been found in several extracts, reflecting their richness and structural diversity within the plant matrix (Kaewseejan et al., 2015; Liu et al., 2019; Kim et al., 2021). These metabolites act on multiple diabetes targets and regulate key signalling pathways that improve both the symptoms and complications of T2DM (Dhanya, 2022). Furthermore, chlorogenic acid, a biologically active caffeoylquinic acid ester, was exclusively detected in the methanolic extract. This indicates its preferential solubility in more polar organic solvents (Kim et al., 2021).

In addition to polyphenols, the methanolic extract of GP also contained considerable amounts of non-phenolic bioactive metabolites, including coumarins such as oxypeucedanin and isoimperatorin, which are known for their anti-inflammatory and vasodilatory effects (Kim et al., 2021; Flores-Morales et al., 2023; Kubrak et al., 2025). Indole-derived compounds such as indole-3-carboxylic acid and kynurenic acid, a tryptophan metabolite with neuroprotective properties, have also been identified and broaden the pharmacological spectrum of the plant (Kim et al., 2021).

On the other hand, the methanolic extract of GP also contained numerous lipophilic metabolites. These include lutein, a potent antioxidant involved in chlorophyll biosynthesis and known for its antimicrobial properties. Several triterpenoids such as lupeol, β-amyrin and friedelanol acetate, which are associated with antidiabetic, anti-inflammatory, anticancer and hepatoprotective activities have also been detected in the methanolic extract of GP (Szakiel et al., 2012; Saha and Bandyopadhyay, 2020; Kim et al., 2021; Jobaer et al., 2023; Dalimunthe et al., 2024). In addition, phytosterols such as stigmasterol and a mixture of stigmasterol and β-sitosterol have also been identified, which are known for their cholesterol-lowering effect as well as their cytoprotective potential and reduced hyperglycaemic effects (Vezza et al., 2020; Jobaer et al., 2023). The antidiabetic effect of stigmasterol may be due to the regeneration of the pancreatic β-cells of Langerhans and thus the secretion of insulin, which controls blood glucose levels (Eidi et al., 2006; Nualkaew et al., 2015).

However, the non-specific bioactivity of natural products is often a hurdle in their bioassay evaluation, including GP (Baell, 2016). Some of its metabolites can behave as pan-assay interference compounds (PAINS), causing false positive signals in various assays and thus complicating their interpretation. For example, the pyrrolizidine alkaloids in GP are known to cause interference in a variety of bioassays due to their reactive nature and the formation of DNA adducts (Ji et al., 2019). Lupeol, stigmasterol and β-sitosterol can interfere with enzyme assays and receptor binding studies due to their structural similarity to endogenous steroids and thus bind non-selectively to other non-endogenous targets (Jobaer et al., 2023). In addition, polyphenolic metabolites such as chlorogenic acid, caffeic acid and various flavonoids could also interfere with redox-based assays (Kim et al., 2021). In addition, some pharmacological profiles of GP may also correspond to mechanisms typical of PAINS. For example, its anti-inflammatory activities have been shown to inhibit the NF-κB signalling pathway and downregulate the expression of pro-inflammatory cytokines such as IL-1β and TNF-α (Wong et al., 2015; Tan et al., 2022). These activities, which involve multiple signalling pathways, are often considered characteristic of PAINS.

Nonetheless, the potential for interference by PAINS does not undermine the medical value of GP. Evidence from a wide range of in vitro and in vivo studies, as well as from thousands of years of traditional use, has provided a solid basis for its efficacy and safety. This evaluation can be further enhanced by modern analytical and computational techniques. High-resolution techniques, in particular UHPLC-QTOF-MS/MS and HPLC-MS, and the use of computational tools such as molecular docking and molecular dynamics simulations enable the prediction of binding affinities and target interactions. These strategies are particularly useful for the identification of compounds with high promiscuity and thus potential PAINS properties (Tithi et al., 2023). By integrating such approaches, researchers can minimise concerns about assay interference and detect consistent, target-specific biological effects across multiple experimental platforms.

Table 2 provides an overview of the phytochemical metabolite found in GP.

The pharmacokinetics of GP have significant implications for its potential therapeutic use; however, they are far from clear. The antidiabetic effect of GP, which is attributed to increased glucose uptake and improved insulin sensitivity, may also be associated with metabolic interactions (Hassan et al., 2010; Guo W. et al., 2021). There are also scants in vivo reports on the absorption, distribution, metabolism and excretion profiles of GP and its active fractions. However, useful information can be extrapolated from the known phytochemical profile of this plant and pharmacokinetic studies on structurally related metabolites.

It has been hypothesised that the absorption of polyphenolic metabolites extracted from GP may be poor. The flavonoids and phenolic acids generally have low oral bioavailability due to a high degree of first-pass metabolism (Xin et al., 2011; Ye et al., 2023). However, there is evidence that the presence of other molecules in GP can increase its absorption. For example, chlorogenic acid (CA), a predominant phenolic metabolite of GP, was found to increase intestinal absorption and improve bioavailability when combined with other phytochemicals in plants, with the improvement increasing from 6.7% (CA alone) to 16.0% (Wang et al., 2022). Pharmacokinetic analyses of the total extract are also not available, and the distribution of GP metabolites in the body remains unknown. However, similar flavonoids and phenolic acids have been found to accumulate in metabolically active organs such as adipose tissue, intestine, liver, kidneys and lungs (Ye et al., 2023). These results are in line with previous studies that have shown that GP molecules are widely distributed in numerous tissues, possibly leading to hepatoprotective and nephroprotective effects (Tahsin et al., 2022).

In addition, the metabolites of GP are generally expected to undergo phase I and phase II metabolism, namely, oxidative, reductive, hydrolytic, glucuronidated and sulphated, and methyl-mediated metabolic reactions, which mainly occur in the liver and gastrointestinal tract (Xin et al., 2011; Wang et al., 2022; Ye et al., 2023). Flavonoids and phenolic acids from GP are also likely to be metabolised via these pathways, leading to the formation of conjugated metabolites that can be detected in plasma after oral administration. Such modulating effects may also contribute to its antidiabetic effect. Although the excretion patterns of GP metabolites are not well studied, it is assumed that, like other plant polyphenols, they are mainly excreted via the kidneys and bile (Ye et al., 2023).

Overall, the data available to date indicate that the biological effects of GP are significantly influenced by its low bioavailability, extensive metabolism and wide tissue distribution. Further studies are needed to clarify this involvement and to translate the molecular understanding to the clinical level of GP-targeted therapy.

Previous studies have documented the potential antidiabetic effect of GP, which is characterised by a reduction in blood glucose levels and improved glucose tolerance in DM. A total of 16 studies were found including four in vitro studies and 12 in vivo studies.

Preclinical studies have generally shown that GP is safe for consumption at various doses. For example, the study by Algariri et al. (2014) showed that the maximum dose of the extract of 2000 mg/kg in an acute toxicity test did not result in any treatment-related mortality during the 14-day observation period (Algariri et al., 2014). In addition, the acceptable daily intake (ADI) was set at 700 mg/kg/day. At the same time, the growth rate and indices of liver, kidney and haematopoietic function were also unaffected, indicating that the extract is safe and no acute toxicity was observed, as the LD50 for female rats is above 2000 mg/kg.

Furthermore, administration of 2 and 4 g/kg GP to rats in a 14-day toxicity trial did not cause any abnormalities in serum biochemical parameters (liver and kidney) or the structure of their organ tissues, with a zero-mortality rate even after the experimental period (Jabbar et al., 2023). The possibility of safe therapeutic use is supported by the absence of adverse effects on organ function, biochemical parameters and histological structures. These results may indicate that GP is a safe candidate of complementary therapy for the treatment of DM, as it has a wide safety margin. Despite the encouraging preclinical results, long-term toxicity, reproductive safety and human clinical studies are still scarce. To ensure the safety of the extract for long-term use in DM, these factors still need to be thoroughly investigated.

Despite these encouraging data on the potential antidiabetic properties of GP, the evidence for its efficacy in the treatment of DM is still inconsistent. Future experimental research should focus on the testing of plant extracts for which comprehensive phytochemical fingerprints should be established according to the ConPhyMP guidelines to improve reproducibility and transparency in phytochemical pharmacology (Heinrich et al., 2022). This includes comprehensive taxonomic authentication using voucher specimens, comprehensive reporting of collection and extraction conditions, and the use of more than one orthogonal analytical technique, such as UHPLC-QTOF-MS/MS, HPLCMS, GCMS and HPTLC, to generate robust chemical fingerprints.

In addition, the lack of standardisation of the extract preparation can lead to different concentrations of the bioactive metabolites, which poses a major challenge for reproducibility and efficacy. For example, aqueous extracts can have different pharmacological effects compared to ethanolic extracts due to differences in solubility and stability of the active metabolites. Thus, standardising the extraction method and ensuring a consistent phytochemical profile is crucial to improve the reproducibility of results and demonstrate the clinical utility of GP in the treatment of DM.

In addition, the bioactive compound responsible for the observed effects was not clearly identified and quantified in some studies. The different study designs and the lack of clinical trials may also contribute to some inconsistencies and limit the generalisability of the results. To clarify these issues, more comprehensive studies are needed to identify the bioactive compounds and molecular targets as well as the mechanisms of action and to assess long-term safety. Potential risks that may be associated with prolonged use of GP, such as hepatotoxicity, nephrotoxicity and other systemic effects, also need to be carefully assessed. An understanding of the pharmacokinetics and pharmacodynamics of GP will also support its integration into current treatment regimens.

However, studies on the safety and efficacy, dose and long-term effects of GP in humans in clinical trials are very limited. Most current studies are conducted to investigate the underlying mechanisms and pharmacodynamics in controlled laboratory settings that have not yet been translated to the clinical. Accordingly, the lack of comprehensive clinical data on this product has greatly hindered its inclusion in evidence-based medical systems and practises. Therefore, clinical studies need to be conducted to assess safety, tolerability and dose in healthy humans. This will allow the identification of relevant biomarkers that should be useful not only for monitoring the efficacy of the therapy, but also for the early detection of signs of toxicity. These studies should also include long-term use to detect any chronic toxicities or late-onset adverse effects.

GP shows promising potential as an antidiabetic agent and has an effect comparable to metformin. By targeting the AGE-RAGE and PI3K/AKT signalling pathways, GP could help to reduce insulin resistance and increase insulin production. However, the evidence remains mixed, as other studies have presented varying results on the efficacy of GP in the treatment of diabetes. This could be due to the lack of standardisation of the extract preparation, insufficient information on the bioactive substance responsible for the observed effects and the lack of clinical studies. Therefore, more comprehensive studies including clinical trials are needed to clarify the discrepancies in the findings and provide a clearer effect of GP in alleviating DM. With these improvements, GP could complement standard DM treatments and offer patients a safer, more holistic approach.