Ginkgo biloba L. as a Potential Alternative Therapy to Improve the Management of Diabetes: An Overview on Phytochemical Insights, Mechanisms, and Therapeutic Applications

Abstract

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia and associated with severe complications, including cardiovascular diseases, neuropathy, nephropathy, and retinopathy. Although synthetic antidiabetic drugs are available, the side effects and limited long-term effectiveness of these medications highlight the urgent need for safer, more potent alternative therapies. Ginkgo biloba L., a traditional medicinal plant rich in flavonoids, terpenoids, and bilobalide, has attracted attention for its potential role in diabetes management. This review critically evaluates the antidiabetic potential of G. biloba by analyzing evidence from in vitro, in vivo, and clinical studies. Moreover, this review highlights the pharmacological actions of G. biloba and its key bioactive compounds, focusing on their mechanisms of action, including the activation of adenosine monophosphate-activated protein kinase (AMPK), the translocation of glucose transporter type 4 (GLUT4), and the inhibition of protein tyrosine phosphatases. The review also discusses the therapeutic implications of G. biloba supplementation and identifies gaps in clinical validation, optimal dosing, and safety profiling. Preclinical studies have demonstrated that G. biloba improves glycemic control by enhancing glucose uptake, regulating insulin secretion, inhibiting α-glucosidase activity, and exerting antioxidant and anti-inflammatory effects. Additionally, clinical trials suggest that supplementation with G. biloba can reduce oxidative stress, improve lipid profiles, and mitigate diabetes-related complications. However, despite these promising outcomes, inconsistencies remain in present study designs, dosages, and patient populations, which question the validity of results. Furthermore, studies related to the antidiabetic effect and underlying mechanisms of G. biloba, such as modulation of AMPK pathways and GLUT4 expression, also remain inadequate and warrant further systematic investigation. G. biloba may still be considered a complementary treatment approach in managing diabetes due to its broad pharmacological activities and favorable safety profile. However, well-designed, large-scale clinical trials are crucial for establishing standardized dosing regimens, confirming long-term safety, and fully elucidating the mechanisms of action. Integrating G. biloba into therapeutic strategies could offer a natural, and effective adjunct for enhancing glycemic control and reducing diabetes-related complications.

Graphical abstract

Keywords

diabetes / G. biloba / glucose metabolism / insulin resistance / active compound

1. Introduction

Diabetes mellitus (DM) is a common metabolic disorder that affects global health, often leading to mild to severe complications [1]. It has become a significant public health concern in the twenty-first century [2], and is usually described as an emerging global health crisis. In 2021, approximately 537 million people aged 20 to 79 had DM, with figures expected to reach 643 million by 2030 and 783 million by 2045, thus posing significant challenges for patients and healthcare providers [3, 4]. DM is characterized by prolonged high blood glucose levels resulting from defective insulin secretion, insulin function, or both [5]. Diabetes is primarily classified into type 1 (T1D) and type 2 (T2D), each characterized by its differences in clinical and mechanistic features. T1D is associated with autoantibodies, loss of \beta-cell function, and C-peptide deficiency; it is commonly observed in younger individuals as an autoimmune disorder, where the body cannot produce insulin due to a defect in pancreatic \beta-cells [6, 7]. In contrast, type 2 diabetes mellitus (T2DM), responsible for over 90% of cases, is strongly linked to risk factors such as obesity, insulin resistance, metabolic dysfunction, and subclinical inflammation; this leads to impaired insulin secretion or receptor desensitization, resulting in ineffective glucose uptake [7, 8]. A sedentary lifestyle and diet with high levels of fat and carbohydrates are major contributors to T2D development [8]. As a chronic disorder, diabetes poses a significant risk of developing microvascular complications such as neuropathy, retinopathy, nephropathy, and macrovascular complications such as stroke, cardiovascular diseases, and peripheral artery disease [9]. Although managing glycemic levels has helped mitigate some complications, the overall morbidity rate still appears to rise. With no definitive cure available, developing novel therapies for diabetes management remains a critical priority [10]. Various antidiabetic agents facilitate the regulation of blood glucose by enhancing insulin activity or inhibiting enzymes such as DPP-4, SGLT-2, and \alpha-glucosidases; however, their effectiveness is often limited by insulin resistance and side effects like weight gain, hypoglycemia, kidney toxicity, and gastrointestinal discomfort [1].

Medicinal plants have been valued in traditional medicine as alternative treatments for decades, mainly when supported by scientific validation. Compared to synthetic drugs, they are often more affordable, with fewer adverse effects, and therapeutic benefits [11]. Despite advancements in phytochemical-based therapies for diabetes, its global prevalence and associated complications remain high, underscoring the urgent need for discovering more effective therapeutic compounds. Phytochemicals derived from herbs are increasingly recognized for their potential in managing metabolic disorders, particularly dyslipidemia and hyperglycemia [12]. Ginkgo biloba, the oldest surviving gymnosperm, often called “the living fossil”, has been used in traditional Chinese medicine for centuries. This dioecious tree exhibits diverse pharmacological properties, including neuroprotective, antioxidant, anticancer, hepatoprotective, and cardiovascular benefits, attributed to its roles as a free radical scavenger, membrane stabilizer, and platelet-activating factor inhibitor [13, 14]. It is widely marketed as a dietary supplement for metabolic disorders; however, its regulatory status and safety can vary depending on the country, thus concerns over potential adverse effects have been raised in some contexts [15]. Numerous preclinical and clinical studies have explored G. biloba’s potential for improving metabolic parameters. However, evidence regarding its specific antidiabetic mechanisms, such as adenosine monophosphate-activated protein kinase (AMPK) activation and GLUT4 translocation, remains fragmented and inconclusive, highlighting the need for a comprehensive systematic review [16]. G. biloba contains unique bioactive constituents, including acylated flavonol glycosides (ginkgoghrelins), ginkgolic acids, biflavones (ginkgetin), ginkgotides, and terpene trilactones (ginkgolides), making it valuable in herbal medicine. Studies investigating its leaf extracts, seeds, and key compounds like ginkgolide B and C have demonstrated beneficial effects such as weight loss, reduced adipose tissue, improved lipid profiles, enhanced glucose and insulin regulation, and positively impacting kidney function [17]. However, while many investigations have confirmed G. biloba’s antioxidant and general metabolic benefits, its direct effects on hyperglycemia, insulin resistance, and glucose metabolism are inconsistently reported across different experimental models [18]. Moreover, specific modulation pathways such as AMPK activation and GLUT4 translocation have not been comprehensively reviewed in the context of G. biloba for diabetes therapy, representing a significant knowledge gap. Given the escalating global burden of diabetes and the limitations of current pharmacotherapies, a deeper understanding of plant-based alternatives like G. biloba could offer promising complementary strategies. Building on traditional medicine knowledge and emerging antidiabetic research, this study critically reviews G. biloba’s role in controlling hyperglycemia and modulating key metabolic pathways. It aims to provide clearer, detailed insights compared to previous general studies, while highlighting future directions for therapeutic development.

2. Methodology

Literature Search Strategy

A comprehensive literature search was conducted using Google Scholar, PubMed, Cochrane Library, ScienceDirect, and Scopus databases. The search utilized the following keyword combinations with Boolean operators to maximize relevance and search coverage: “G. biloba” AND (“Diabetes Mellitus” OR “Diabetes” OR “Hyperglycemia”) AND (“antidiabetic” OR “insulin resistance” OR “glucose metabolism”). Additional keywords such as “isolated compounds” AND (“in vitro” OR “in vivo” OR “clinical trials”) were also employed to narrow the focus on studies that investigated the antidiabetic properties of compounds isolated from G. biloba. This review was limited to English-language studies published up to December 11, 2024, to ensure accessibility and ease of understanding. The selection process adhered to specific inclusion criteria, which included in vitro and in vivo studies, clinical trials, and research focusing on the antidiabetic effects of G. biloba and its isolated compounds. Key data extracted from the selected studies included: year of publication, tested compounds, experimental models (e.g., cell lines, animal models), observed outcomes, results, tested concentrations, and molecular mechanisms underlying the observed effects. Studies that did not meet these criteria or failed to report antidiabetic effects of G. biloba or its compounds were excluded from the review.

3. Therapeutic Applications

In this study, 85 articles reported the antidiabetic effects of G. biloba through in vitro, in vivo, and clinical trials. Most of these studies focused on G. biloba leaves or its isolated compounds. Tables 1A,1B,1C (Ref. [19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85]) provides an overview of the in vitro and in vivo studies examining the antidiabetic properties of G. biloba and its bioactive compounds.

3.1 Preclinical Studies of G. biloba in Diabetes Management

3.1.1 In Vitro Antidiabetic Activity

The aqueous extract of Ginkgo leaves at a 50 mg/mL dose demonstrated significant \alpha-glucosidase inhibition (65%), while the ethanolic extract showed even higher inhibition (95%). Both extracts exhibited comparatively lower \alpha-amylase inhibitory activity (45%). This greater selectivity toward \alpha-glucosidase over \alpha-amylase suggests that Ginkgo leaf extracts could be valuable for managing early-stage hyperglycemia in type 2 diabetes. High \alpha-glucosidase inhibition with moderate \alpha-amylase inhibition is desirable, as excessive \alpha-amylase inhibition may cause undigested starch accumulation in the colon, leading to gastrointestinal discomfort [19]. Similarly, the leaf extracts exhibited potent inhibitory effects on both \alpha-amylase (>70%) after the gastric and intestinal phases of digestion, and \alpha-glucosidase (>70%) after the intestinal phase, highlighting their potential as natural hypoglycemic agents, although the specific solvent system remains unspecified [20]. Similarly, an alkali-soluble acid extract derived from the seeds at a concentration of 20 mg/mL effectively suppressed \alpha-glucosidase activity, reinforcing its potential as a novel candidate for hypoglycemic intervention [21]. Table 1A (Ref. [19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34]) provides an overview of the in vitro studies examining the antidiabetic properties of G. biloba.

Skeletal muscle regulates blood glucose levels by facilitating glucose uptake through insulin-dependent and insulin-independent pathways. It serves as the primary site for glucose transport [22]. Two major independent signaling pathways govern this process in response to various stimuli. PI3-kinase, activated by insulin, is essential for promoting glucose uptake, with its impaired activation in skeletal muscle leading to reduced glucose transport. AMPK, another key regulatory protein primarily activated by cellular stress, plays a central role in maintaining energy homeostasis. It consists of two catalytic subunit isoforms, \alpha1 and \alpha2, with phosphorylation of the \alpha subunit being critical for its activation. AMPK \alpha1 is broadly expressed in tissues like skeletal muscle, liver, and pancreas, whereas AMPK \alpha2 is predominantly found in skeletal and cardiac muscle [23]. In support of AMPK’s role in glucose regulation, treatment with petroleum ether extracts of Ginkgo leaves at concentrations of 20 and 40 µg/mL was shown to activate the AMPK pathway, thereby promoting GLUT4 translocation to the plasma membrane and enhancing glucose uptake in C2C12 myotubes [22]. Furthermore, methanolic leaf extracts at 50 µg/mL stimulated glucose uptake in L6 skeletal muscle cells through PI 3-kinase and AMPK-mediated pathways, highlighting their contribution to maintaining glucose homeostasis [23]. Similarly, ethanolic extracts of the leaves at a concentration of 0.25 µg/mL successfully mimicked insulin-like effects on glucose metabolism and transport in smooth muscle cells, suggesting their potential application in diabetes management [24]. At a higher concentration of 200 µg/mL, ethanolic leaf extracts significantly enhanced the efficacy of bone marrow mesenchymal stem cells (BMSCs) in lowering blood glucose levels and reversing oxidative stress in diabetic rat models. In vitro, BMSCs exposed to H₂O₂ exhibited a significant reduction in cell viability (65.0 \pm 2.45% of the control); in comparison, BMSCs protected by ethanolic Ginkgo biloba extract (EGB) showed improved cell viability (94.5 \pm 3.31% of the control), further demonstrating the therapeutic potential of EGB in mitigating oxidative damage [25]. Insulin receptor substrate-2 (IRS-2) is the liver’s predominant isoform, compensating for the absent insulin receptor substrate-1 (IRS-1) in IRS-1 knockout models. Hepatic insulin signaling is primarily mediated through IRS-2. Moreover, treatment with leaf extracts at 10 mg/L in the L-02 cell line improved insulin sensitivity, primarily by upregulating IRS-2 transcription, indicating a possible mechanism for alleviating insulin resistance [26]. In pancreatic studies, exposure to 50 µg/mL of the extract exhibited a strong stimulatory effect on insulin secretion in INS-1 rat beta cells, signifying its potential role in improving pancreatic \beta-cell function [27]. Similarly, leaf extracts at 0.75 mg/mL and 1.0 mg/mL influenced the adipogenesis pathway in Swiss 3T3-L1 preadipocytes, accelerating preadipocyte maturation and stimulating the expression of mature adipocyte-specific proteins, which may have implications for metabolic regulation [28]. Renal studies revealed that treatment with leaf extracts at a concentration of 30 mmol/L significantly reduced the levels of transforming growth factor-\beta1 (TGF-\beta1), insulin-like growth factor-1 (IGF-1), and connective tissue growth factor (CTGF) in mesangial cells exposed to high glucose, indicating a protective effect against diabetic nephropathy [29]. Similarly, administration of G. biloba extract (EGb 761) at 25, 50, and 100 µg/mL in human umbilical vein endothelial cells (HUVECs) significantly reduced IHG-induced DNA oxidation, a key contributor to diabetes-associated vascular complications [30]. Furthermore, ginkgo vinegar at 0.4% concentration was found to suppress lipid accumulation in 3T3-L1 cells by downregulating the expression of CCAAT/enhancer-binding protein delta (C/EBP\delta) and peroxisome proliferator-activated receptor gamma signaling (PPAR\gamma), two crucial regulators of adipogenesis, suggesting its potential role in lipid metabolism modulation [31]. Heme oxygenase-1 (HO-1), also known as heat shock protein 32, was initially identified as the rate-limiting enzyme responsible for degrading heme into equimolar amounts of carbon monoxide (CO), biliverdin, and free iron. The induction of HO-1 is thought to involve the activation of signaling pathways such as mitogen-activated protein kinases (MAPKs) and transcription factors like nuclear factor erythroid 2-related factor 2 (Nrf2). Notably, treatment with leaf extracts at a concentration of 100 µg/mL significantly reduced high-glucose-induced endothelial adhesion and the expression of adhesion molecules in human aortic endothelial cells (HAECs), primarily through the upregulation of HO-1 via activation of the PI3K/Akt/eNOS and p38/MAPK signaling pathways [32]. In ocular studies, exposure to leaf extracts at 10, 20, and 40 µg/mL protected human lens epithelial cells (HLECs) from high-glucose-induced apoptosis by reducing oxidative stress, lowering the Bax-to-Bcl-2 ratio, and suppressing caspase-3 activity, suggesting their potential in preventing diabetic cataracts [33]. Finally, enteric glial cells (EGCs) treated with 25, 50, and 100 µg/mL of the extract demonstrated attenuation of hyperglycemia-induced damage, highlighting their significance in preserving gastrointestinal homeostasis under diabetic conditions [34]. Proposed in vivo and in vitro mechanisms of action of G. bilobain antidiabetic activity are given in Fig. 1.

3.1.2 In Vivo Antidiabetic Activity

G. biloba leaf extract initiates its protective effects primarily through activation of the Nrf-2/HO-1 pathway. The extract inhibits Keap1, a negative regulator of Nrf-2, allowing Nrf-2 to translocate into the nucleus where it binds to antioxidant response elements (ARE) and upregulates the expression of the HO-1 gene. The HO-1 enzyme catalyzes the conversion of heme into biliverdin, CO, and free iron, which collectively reduce oxidative stress in the cell. Concurrently, G. biloba stimulates the GLUT-4/IRS-1 signaling pathway, where it increases phosphorylation of IRS-1, activating downstream PI3K/AKT signaling. This cascade promotes the translocation and expression of GLUT-4 on the cell membrane, enhancing glucose uptake by cells. Additionally, G. biloba inhibits endoplasmic reticulum stress (ERS), preventing apoptosis of pancreatic \beta-cells, which are crucial for insulin secretion. It also reduces inflammatory cytokine levels by modulating the IRE1-JNK pathway, further alleviating cellular stress. Together, these molecular effects improve insulin sensitivity, increase glucose uptake, and provide overall anti-diabetic benefits by reducing oxidative damage, inflammation, and \beta-cell death (Fig. 2). Streptozotocin (STZ)-induced diabetic Wistar rats treated with intraperitoneal (I.P.) administration of leaf extracts at doses of 100, 200, and 300 mg/kg body weight exhibited significant antihyperglycemic, antioxidant, and antihyperlipidemic activities, demonstrating their potential therapeutic efficacy in diabetes management [35]. Table 1B (Ref. [35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63]) provides an overview of the in vivo studies examining the antidiabetic properties of G. biloba.

Another study reported that intraperitoneal administration of leaf extracts led to a marked reduction in serum glucose levels. At the same time, the treated diabetic rats maintained a higher body weight than the untreated group, further highlighting the metabolic benefits of the extract [36]. Oral administration of 0.11 g/kg/day of ethanolic leaf extracts effectively preserved pancreatic \beta-cell integrity, enhanced insulin expression, and improved antioxidant status in type 2 diabetic rats, suggesting its role in mitigating diabetes-induced pancreatic dysfunction [37]. Furthermore, supplementation with 50, 100, and 150 mg/kg/day of the extract significantly upregulated GLUT-4 and IRS-1 in hepatic tissues, resulting in pronounced antihyperglycemic effects in STZ-induced diabetic rats [38]. In another experimental setting, Wistar rats receiving 50 mg/kg of ethanolic leaf extracts via intraperitoneal injection exhibited notable cardioprotective effects, which may serve as an adjuvant therapy in preventing diabetic cardiomyopathy and related complications [39]. However, oral administration of 200 mg/kg of the extract throughout pregnancy failed to counteract the diabetes-associated rise in maternal glycemia, reduced pregnancy rates, impaired fetal development, and diminished antioxidant enzyme activity, indicating its limited efficacy in gestational diabetes management [40]. Moreover, intraperitoneal administration of 0.11 g/kg of the leaf extract demonstrated nephroprotective effects in type 2 diabetic rats by alleviating hyperlipidemia, uremia, oxidative stress, and renal dysfunction, suggesting its therapeutic potential in preventing diabetes-induced nephrotoxicity [41]. Proposed in vivo and in vitro mechanisms of action of G. biloba in antidiabetic activity have been given in Fig. 1.

Intragastric administration of 100 mg/kg of ethanolic leaf extract in streptozotocin (STZ)-induced diabetic Wistar rats significantly reduced blood glucose levels, reinforcing its potential as an antidiabetic agent [42]. Similarly, gavage administration of 50 mg/kg of the extract exhibited a neuroprotective effect on the jejunum submucous plexus and the myenteric plexus of the ileum, suggesting its role in preserving enteric nervous system integrity in diabetic conditions [43]. Oral administration of 100 mg/kg per day of the extract in male Wistar rats reduced blood glucose levels and influenced plasma drug concentrations, indicating potential pharmacokinetic interactions [44]. Additionally, another study reported that the same oral dosage modulated enzyme activities affected by diabetes, suggesting a broader metabolic regulatory effect [45]. In ApoE^-⁣/- diabetic mice, gavage administration of 200 or 400 mg/kg of the ethanolic extract effectively reduced diabetic myocardial damage by blocking endoplasmic reticulum stress (ERS), thereby preventing cardiomyocyte death, interstitial fibrosis, and intramyocardial inflammation [46]. Furthermore, in STZ-induced diabetic mice, 50 mg/kg of the extract significantly lowered blood triglyceride levels while increasing peroxisome proliferator-activated receptor-alpha (PPAR-\alpha) expression and liver lipoprotein lipase (LPL), alongside a reduction in body weight, demonstrating its lipid-modulating properties [47]. Moreover, gavage administration of 500 mg/kg G. bilobaextract (GBE), diluted in 2 mL of 0.9% saline to minimize potential toxicity, effectively prevented hyperglycemia and dyslipidemia in diet-induced obese diabetic rats. The treatment also significantly reduced food intake and body adiposity. Additionally, it downregulated protein tyrosine phosphatase-1B (PTP-1B) levels in the gastrocnemius muscle and enhanced insulin sensitivity by promoting Akt phosphorylation and IRS-1 activation, indicating a strong potential for improving insulin signaling and glucose metabolism [48]. Oral administration of 120 mg/kg of G. biloba extract (GBE) in STZ-induced diabetic albino rats demonstrated notable antidiabetic effects by significantly reducing blood glucose and lipid levels, potentiating its effect as a possible therapeutic agent for diabetes management [49]. Similarly, 100 mg/kg of GBE administered orally exhibited a protective effect against the destructive structural changes in the prostate gland caused by diabetes, suggesting its role in mitigating diabetic complications beyond glycemic control [50]. Intraperitoneal administration of 100 mg/kg of the extract, dissolved in a saline-based capsule, effectively lowered blood glucose levels in STZ-induced diabetic albino rats, further validating its antihyperglycemic potential [51]. In another study, oral administration of 50 mg/kg/day and 100 mg/kg/day of the extract led to a significant 31% reduction in fasting blood sugar (FBS) and a 57.6% increase in blood glutathione (GSH) levels. However, this reduction in FBS was lower than that achieved with troglitazone (47%) [52]. Additionally, a 100 mg/kg/day oral dose displayed promising therapeutic efficacy in preventing diabetes-induced structural damage in the prostate gland of adult male albino rats [53]. In STZ-induced DBA/2 mice, low (50 mg/kg/day) and high (200 mg/kg/day) oral doses of GBE provided protective effects against hyperglycemia-induced podocyte damage. This prevented diabetic nephropathy by activating the Nrf-2/HO-1 pathway, revealing a potential mechanistic target for diabetic kidney disease treatment [54]. Furthermore, in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, oral administration of 100 and 200 mg/kg of the extract protected against atherosclerosis, highlighting its cardiovascular benefits [55]. In male ApoE^-⁣/- diabetic mice, intragastric administration of Ginkgo biloba extract (GBE) at 200 mg/kg/day (low dose) and 400 mg/kg/day (high dose) significantly reduced serum glucose, inflammatory cytokines, and lipid levels, highlighting its potential in modulating lipid metabolism and systemic inflammation in diabetes. GBE was dissolved in normal saline for administration, as it offers lower toxicity than organic solvents, making it a suitable vehicle for intragastric delivery in mice [56]. Oral administration of 100 mg/kg/day of G. biloba extract (GBE) in normoglycemic male adult Wistar rats demonstrated its ability to enhance glucose and lipid metabolism by modulating the expression of key metabolic genes, suggesting its potential in preventing hyperglycemia and metabolic disorders [57]. Additionally, in STZ-induced Wistar albino rats, GBE at the same dosage exhibited antidiabetic, antihypertensive, and antilipidemic properties, reinforcing its multifaceted role in metabolic regulation [58]. In Sprague-Dawley rats, oral administration of 40 mg/kg of the extract provided a protective effect against hyperlipidemia, further validating its role in cardiovascular health [59]. In STZ-induced adult male Sprague-Dawley rats, varying doses of 50, 100, and 200 mg/kg/day dissolved in 1% CMC-Na exhibited a dose-dependent reduction in blood glucose levels, supporting its potential application in clinical treatment for type 2 diabetes mellitus (T2DM) [60]. At a higher dosage of 200 mg/kg/day, GBE exerted strong antihyperglycemic and antilipidemic effects while modulating key hepatic genes involved in glucose metabolism. Additionally, it controlled serum liver enzymes, urea, and creatinine levels, suggesting hepatoprotective and nephroprotective benefits [61]. In male Sprague-Dawley rats, oral administration of 200 mg/kg/day of GBE, extracted using methanol, demonstrated a significant role in amino acid metabolism, which was linked to improvements in pancreatic \beta-cell function, inflammatory response, oxidative stress reduction, and enhanced liver and renal function [62]. Furthermore, in high-fat diet (HFD)-induced obese mice, oral administration of 100, 200, and 400 mg/kg of GBE significantly reduced insulin resistance and alleviated symptoms of metabolic syndrome, indicating its potential for therapeutic intervention in obesity-related metabolic dysfunctions [63].

3.1.3 In Vitro and in Vivo Antidiabetic Activity of Isolated Compounds

The bioactive derivatives such as bilobalide, quercetin, rutin, and ginkgolide C demonstrated lower blood glucose levels, improving the body’s sensitivity to insulin. The subsequent effect of lowered insulin resistance by rutin and ginkgolic acid was potentiated through slow release of glucose to blood after a meal by potent and mild inhibition of digestive enzymes such as alpha-glucosidase and alpha-amylase, respectively. Kaempferol from G. biloba protected beta cell damage by expressing antiapoptotic protein and improved insulin function by enhancing insulin signalling by cAMP. The bioactive derivatives 2-hydroxy-6-(10^′-hydroxypentadec-11^′(E)-en-1-yl) benzoic acid (2), 2-hydroxy-6-(11^′-hydroxypentadec-9^′(E)-en-1-yl) benzoic acid, 2-hydroxy-6-tridecylbenzoic acid, 2-hydroxy 6-pentadecylbenzoic demonstrated inhibition of multiple protein tyrosine phosphatases (PTPs) involved in insulin resistance such as PTPN11, PTPN2, PTPN9, PTP1B, and DUSP9. Ginkgolides A, B, C, and bilobalide derivatives, especially ginkgolide B, lowered hyperglycemic states, total cholesterol, triglyceride serum levels, and lipid accumulation associated with diabetes, thus maintaining adipose tissue. Amentoflavone, bilobetin, sequoiaflavone, ginkgetin, sciadopitysin, and isoginkgetin exerted hypolipidemic effects by reducing lipolysis and inhibiting the enzyme cAMP phosphodiesterase. A mechanism of action of G. biloba on glucose is given in Fig. 3.

Bilobalide, when administered to male Wistar rats at a dose of 10 mg/kg intraperitoneally, demonstrated a remarkable reduction in blood glucose levels, activation of insulin secretion, and alleviation of liver damage caused by streptozotocin (STZ)-induced diabetes. These findings suggest potential therapeutic effects on diabetes-related complications [64]. In vitro, bilobalide has been shown to inhibit adipogenesis and promote lipolysis in 3T3-L1 preadipocytes by activating the AMPK signaling pathway, further supporting its role in modulating metabolic processes [65]. In female NMRI mice subjected to alloxan-induced diabetes, bilobalide administered orally at doses of 100 and 200 mg/kg by gavage, in conjunction with EGb 761, enhanced the activity of beta cells in the presence of glucose, indicating its synergistic effect on glucose regulation and insulin sensitivity [66]. Additionally, bilobalide exhibited protective properties in 3T3-L1 preadipocytes against hypoxia-induced inflammation and insulin resistance. This was achieved by reducing inflammatory adipokine secretion, enhancing adiponectin release, modulating the NF-\kappaB/JNK pathway, and inhibiting serine phosphorylation of IRS-1 receptors, thereby improving insulin signaling [67]. Fig. 4 illustrates the chemical structures of the isolated compounds.

Furthermore, bilobalide provided significant protection to adipocytes from the adverse effects of hypoxia in a dose-dependent manner, inflammation, mitochondrial damage, and attenuating oxidative stress. The treatment significantly reduced cell death, with the highest dose (50 µM) showing a 10% reduction, highlighting its potential in mitigating cellular damage associated with metabolic disorders [68]. In another study, bilobalide induced apoptosis in mature 3T3-L1 adipocytes through a ROS-mediated mitochondrial pathway, offering promising therapeutic avenues for obesity management [69]. Moreover, in vivo studies in male Wistar rats treated with bilobalide at a dose of 2 mg/kg/day revealed increased glycogen content in the liver and muscle, in normal and STZ-induced diabetic rats This effect suggests that bilobalide may help mitigate impaired glucose utilization, possibly through its antioxidant properties or by enhancing glucose uptake, further supporting its role in managing diabetes [70]. The compounds 2-hydroxy-6-(10^′-hydroxypentadec-11^′(E)-en-1-yl) benzoic acid (2), 2-hydroxy-6-(11^′-hydroxypentadec-9^′(E)-en-1-yl) benzoic acid (3), 2-hydroxy-6-tridecylbenzoic acid (4), 2-hydroxy-6-pentadecylbenzoic acid (5), 2-hydroxy-6-(12^′-hydroxyheptadec-13^′(E)-en-1-yl) benzoic acid (6), and 2-hydroxy-6-(11-hydroxyundecyl) benzoic acid (7) were tested for their inhibitory effects on protein tyrosine phosphatases (PTPs) relevant to insulin resistance. These compounds exhibited potent enzyme inhibition, with 4–6 showing over 90% inhibition against PTPN11, PTPN2, PTP1B, DUSP9, PTPRS, and PTPN9. Compounds 2 and 3 also displayed significant inhibitory activity against several PTPs, including PTPN11, PTPN2, PTP1B, and DUSP9. These findings underscore the importance of the side chain length and substitutions within the side chain of ginkgolic acid derivatives in determining their inhibitory potency. These derivatives from G. biloba leaves may serve as promising therapeutic candidates for managing Type 2 diabetes mellitus (T2DM) due to their potential to inhibit PTPs involved in insulin resistance [71]. Quercetin (8) and rutin (9), both derived from the leaves, exhibited potent \alpha-glucosidase inhibition and mild \alpha-amylase inhibition at concentrations of 0.061 µM and 0.038 µM for quercetin, and 0.043 µM and 0.037 µM for rutin. Their activity makes them suitable candidates as nutraceuticals for managing non-insulin-dependent diabetes mellitus (NIDDM) [72]. In studies with 3T3-L1 cells, Ginkgolide C (10) demonstrated significant inhibition of transcription factors and enzymes associated with adipogenesis, while promoting Sirt1/AMPK activity to enhance lipolysis in differentiated adipocytes. This suggests that ginkgolide C may improve metabolic syndrome and insulin resistance [73]. Kaempferol (11), when tested on INS-1E cells and human islets, enhanced \beta-cell survival and function. It improved cAMP signaling and upregulated antiapoptotic protein expression, highlighting its potential in supporting pancreatic \beta-cell health and insulin production [74]. Table 1C (Ref. [64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85]) provides an overview of the in vitro and in vivo Antidiabetic Activity of isolated Compounds of G. biloba.

Ginkgetin (12), a compound derived from G. biloba leaves, was found to inhibit the expression of PPAR\gamma and C/EBP\alpha in 3T3-L1 cells, a key event in the initiation of adipogenesis. This inhibition prevents STAT5 activation during the early stages of adipocyte differentiation. This suggests that ginkgetin may serve as a potent modulator of adipogenesis and could be developed as an anti-obesity agent. In vivo studies on C57BL/6 male mice further support this notion, as ginkgetin exhibited inhibitory effects on the hypertrophy of white adipose tissue when administered intraperitoneally at doses of 5 mg/kg and 10 mg/kg per day. These findings highlight ginkgetin’s potential as an anti-adipogenesis and anti-obesity drug [75]. The compounds isoginkgetin (13), bilobetin (14), ginkgetin (12), and sciadopitysin (15), also derived from G. biloba leaves, were evaluated for their inhibitory effects on pancreatic lipase (PL) activity. At concentrations of 1 µM, 10 µM, and 100 µM, these compounds exhibited significant inhibitory activity, providing new evidence for the hypolipidemic effects of G. biloba. These findings suggest that these biflavonoids could serve as lead compounds for developing pancreatic lipase inhibitors, offering potential therapeutic benefits for managing lipid metabolism disorders [76]. Isoginkgetin (13) was further investigated in 3T3-L1 mouse fibroblasts, where it was shown to enhance adiponectin production in adipocytes through a novel mechanism involving the AMPK pathway. This mechanism differs from that of rosiglitazone, a known regulator of adiponectin. Isoginkgetin’s ability to elevate adiponectin levels could provide new insights into treating metabolic diseases and developing agents that increase plasma adiponectin levels, a biomarker associated with improved metabolic health [77]. Ginkgolide B (16), tested in human umbilical vein endothelial cells (HUVECs), demonstrated protective effects against high glucose-induced endothelial dysfunction. At concentrations of 0.2, 0.4, and 0.6 mg/mL, ginkgolide B inhibited the TLR4-mediated inflammatory response, which is crucial in the pathogenesis of diabetic vascular complications. The underlying mechanism was linked to the inhibition of JAK2/STAT3 and p38 MAPK phosphorylation, highlighting ginkgolide B’s potential as an anti-inflammatory agent for vascular protection in diabetes [78]. Additionally, in mouse renal podocytes (MPC5), ginkgolide B reduced hyperglycemia-induced lipid accumulation and lowered serum levels of total cholesterol and triglycerides at doses ranging from 5 to 200 µM. This effect suggests that ginkgolide B may play a role in managing lipid metabolism disorders in diabetes [79]. In vivo studies in streptozotocin-induced diabetic ICR mice further demonstrated that G. biloba (GB) protects against endothelial dysfunction in the aorta by increasing superoxide dismutase 1 (SOD1) activity and enhancing nitric oxide (NO) bioavailability in endothelial cells, which may contribute to improved vascular health in diabetic conditions [80]. Ginkgolic acid (36), derived from G. biloba leaves, exhibited the highest \alpha-glucosidase inhibitory activity. This study, which represents the first to isolate ginkgolic acids as \alpha-glucosidase inhibitors, suggests that these compounds could manage blood glucose levels, particularly in type 2 diabetes [81]. Amentoflavone (36), bilobetin (14), sequoiaflavone (37), ginkgetin (12), sciadopitysin (15), and isoginkgetin (13) were tested for their effects on lipolysis in 3T3-L1 preadipocytes. These biflavonoids stimulated lipolysis by inhibiting cAMP phosphodiesterase, which could potentially contribute to the management of obesity by promoting fat breakdown [82]. A variety of compounds, including (2E,4E,1^′R,3^′S,5^′R,8^′S)-dihydrophaseic acid 3^′-O-\beta-D-glucopyranoside (38), 7,8-dihydro-(R)-7-methoxyconiferyl alcohol (39), and ginkgolides A, B, and C (52), were found to inhibit TNF\alpha-induced NF-\kappaB transcriptional activity in human hepatocarcinoma HepG2 cells. This inhibition led to reduced COX-2 and iNOS gene expression, indicating the potential of these compounds in the prevention and treatment of inflammatory and metabolic diseases [83]. In an in vivo study with high-fat diet-induced obese male Wistar rats, a combination of flavone glycosides, terpenoids, and ginkgolides from G. biloba led to a reduction in adipocyte size and acetate accumulation, suggesting a potential anti-obesogenic effect that could be beneficial for long-term therapies aimed at obesity management [84]. Rutin (9) and quercetin (20) were tested in adult Sprague-Dawley rats with streptozotocin-induced diabetes. At a 90 mg/kg dose, these flavonoids inhibited aldose reductase activity, stimulated glutathione production, and decreased malondialdehyde (MDA) and advanced glycosylation end products (AGEs). These effects highlight the potential of rutin and quercetin in managing oxidative stress and diabetic complications [85].

4. Clinical Studies and Safety Profile of Ginkgo biloba in Diabetes Management

The clinical trials conducted to date with G. biloba have primarily targeted its antidiabetic effects and improve lipid profiles, and mitigate diabetes-related complications (Table 2, Ref. [86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100]).

A randomized, placebo-controlled, double-blinded study conducted on 60 patients with type 2 diabetes mellitus (T2DM) over 90 days demonstrated that administering 120 mg/day of GKB extract significantly reduced blood HbA1c and fasting serum glucose levels [86]. Similarly, another randomized, placebo-controlled, double-blinded study involving 24 T2DM patients found that the exact dosage of GKB extract effectively inhibited insulin resistance [87]. In a randomized, double-blind, placebo-controlled crossover study conducted on 10 T2DM patients, G. biloba extract (EGb 761) at a dosage of 120 mg/day resulted in a reduction in glycosylated hemoglobin A1c (1c) levels [88]. Additionally, a control treatment study using G. biloba extract injection in 60 diabetic nephropathy (DN) patients revealed that administering 20 mL (5 mL per ampule) led to a decrease in urinary albumin excretion rate, regulation of blood lipids, and improvement in renal function and hemorheology [89]. A randomized controlled study with 80 non-proliferative diabetic retinopathy (NPDR) patients over a six-month duration showed that oral administration of 2 mL of GKB extract three times daily significantly decreased the number of retinal microaneurysms and areas of retinal hemorrhage, along with lowering serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol while increasing high-density lipoprotein cholesterol. Furthermore, platelet aggregation and adhesion rates were also reduced [90]. A large-scale, randomized, double-blind, multicenter controlled trial involving 600 type 2 diabetes patients over 24 months indicated that daily intake of 24 mg of G. biloba tablets helped attenuate the deterioration of albuminuria in diabetic patients [91]. Similarly, a randomized controlled trial with 68 DN patients over three months showed that an oral dosage of 9.6 mg of G. biloba extract (EGB) taken three times daily led to significant reductions in urinary microalbumin (mALB), alpha1-microglobulin (alpha1-MG), immunoglobulin (IgG), transferrin (TF), retinal binding protein (RBP), and N-acetyl-beta-D-glycosaminidase (NAG) levels [92]. A long-term, randomized, double-blind, placebo-controlled study on 210 T2DM patients conducted over three years found that consuming 24 mg of GKB extract three times daily resulted in a lower albumin-to-creatinine ratio (ACR) increase [93]. Another randomized, double-blind, placebo-controlled trial on 250 T2DM patients over 27 months revealed that administering 80 mg of GKB extract capsules twice daily for the first nine months and thrice daily for the following nine months demonstrated moderate improvements in psychological states and significantly enhanced glycemic control [94]. A study on 20 patients with standard glucose tolerance over three months showed that taking 120 mg of G. biloba extract daily reduced blood pressure and increased insulin metabolic clearance rate [95]. Furthermore, research on 20 patients with non-insulin-dependent diabetes mellitus (NIDDM) with hyperinsulinemia or pancreatic exhaustion over three months found that daily intake of 120 mg of G. biloba extract reduced insulin-mediated glucose metabolism while elevating blood glucose levels [96]. A six-month study involving 120 T2DM patients revealed that consuming 240 mg/day of G. biloba (EGb 761®) positively affected insulin resistance-related factors in the brain, improving overall brain function and enhancing quality of life indicators [97]. A randomized, double-blind, placebo-controlled trial on 12 participants over 58 weeks assessed the impact of G. biloba pills, taken three times a day in groups of five, in controlling impaired glucose regulation, slowing diabetes progression, and reducing the incidence and mortality of cardiovascular diseases [98]. A randomized, double-blind, placebo-controlled crossover study on 30 healthy, glucose-tolerant volunteers over three months reported that administering 120 mg of G. biloba extract as a single dose affected the hypothalamic-pituitary-adrenal axis by reducing basal cortisol levels and cortisol production in response to acute hyperglycemic challenges [99]. Lastly, a double-blind, randomized, placebo-controlled trial on 60 T2DM patients over 90 days found that consuming 120 mg of G. biloba capsules significantly decreased inflammatory mediators and leptin levels while improving antioxidant status and lipid profiles [100].

G. biloba demonstrates a strong safety profile, with multiple animal and human studies reporting no significant toxicity or adverse effects, supporting its use as a safe natural therapeutic agent. In clinical trials, administration of G. biloba extract at a dose of 120 mg/day showed no adverse effects on treated individuals’ liver, kidney, or hematopoietic functions [86]. Similarly, another study using EGb 761 at the same dose for three months reported it to be safe and well-tolerated in both healthy and diabetic participants, with only minor, non-life-threatening side effects such as changes in appetite, mild headaches, and menstrual bleeding [88]. In animal studies, acute toxicity assessments revealed no toxic effects even at higher doses; for example, oral administration of GKB at 400 mg/kg showed no signs of toxicity [63]. Further supporting its safety, no adverse effects were noted after administering 200 mg/kg body weight over 60 days [61]. In experimental models, to further mitigate any risk of toxicity, high doses of GKB (500 mg/kg) were diluted in normal saline (0.9%) before administration, and no toxicological effects were reported [48]. Similarly, in another study, high doses of G. biloba extract, such as 400 mg/kg, were dissolved and delivered in normal saline to minimize potential toxicity [56]. While adverse events—including coronary artery disease, cerebrovascular accidents, and cancer have been reported, no direct causal relationship to G. biloba alone has been established. In combination therapy trials, such as those involving G. biloba and Liuwei Dihuang (LWDH), the absence of detailed subgroup analyses limits the ability to attribute these events to any single component [91]. These findings are consistent across different formulations and dosages, emphasizing G. biloba’s tolerability at both therapeutic and elevated doses. Nonetheless, further investigations, particularly regarding long-term use and potential interactions, are recommended to confirm its safety for broader clinical applications.

5. Nutritional Value of Ginkgo biloba in Diabetes Management

There is growing commercialization of products that combine concentrated bioactive compounds from natural sources, known as nutraceuticals. The health benefits of these compounds have attracted significant interest from the scientific community, with some tested through experimental studies [101]. Plant-derived dietary supplements, including antioxidants, essential fatty acids, lipid metabolism enhancers, vitamins, and trace elements, are marketed and recommended to patients as beneficial additions to a diabetic diet and conventional treatments. These supplements aim to enhance glycemic control and minimize the effects of chronic complications [102]. G. biloba products were among the top-selling medicinal items in U.S. health food stores. Unlike the leaves, Ginkgo nuts have a long history of use as both food and medicine, with their first mention in herbals around 1350 AD [103]. G. biloba leaves and seeds are rich in vitamin, carbohydrates, riboflavin, proteins, amino acid, minerals and other essential nutrients (Table 3, Ref. [103, 104, 105, 106]). These nuts are believed to provide health benefits, including diabetes, cancer prevention and treatment for neurological diseases [107]. Carbohydrate compounds in plants, such as oligosaccharides and polysaccharides, have been found to significantly enhance glucose and insulin metabolism in both healthy and diabetic individuals. A study compared three diets in diabetic patients: low-starch (43% carbs, 22% protein, 34% fat), high-starch (55% carbs, 15% protein, 30% fat), and a typical American diet (40% carbs, 20% protein, 40% fat). The low-starch diet resulted in significantly lower plasma glucose and insulin levels. Another trial of over 3200 patients showed that high-fiber, low-fat diets could help prevent diabetic complications. A clinical study also found that high-carb, high-fiber meals improved glycemic control and reduced post-meal lipids in type 2 diabetes patients [108].

6. Limitations

The reviewed studies on the antidiabetic effects of Ginkgo biloba leaf extracts exhibited significant heterogeneity, particularly in dosage, administration routes, animal models, and outcome measures, thus making comparisons and generalizations challenging. The dosage range varies considerably for each bioactive derivative from G. biloba (Tables 1A,1B,1C (Ref. [19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85])). This discrepancy raises concerns about the feasibility and safety of translating these doses to human-equivalent doses (HEDs). For instance, a 200 mg/kg rat dose translates to approximately 32 mg/kg in humans, highlighting the need for further research into dose-response relationships and the therapeutic window for human applications. This lack of dose translation between animal models and humans restricts applying preclinical results to clinical practice. Moreover, the heterogeneity in administration routes (e.g., intraperitoneal injection, oral gavage, and oral administration) adds to the variability. For example, intraperitoneal administration of leaf extracts at doses ranging from 50–500 mg/kg showed significant antihyperglycemic, antioxidant, and hypolipidemic effects in STZ-induced diabetic rats (Table 1B). In contrast, 100 mg/kg/day of ethanolic leaf extract oral administration preserved pancreatic \beta-cell integrity and enhanced insulin expression in type 2 diabetic rats [37]. These discrepancies in administration routes may affect bioavailability, absorption, and efficacy; therefore, they should be carefully considered when interpreting the results. The variation in animal models used across studies, such as STZ-induced diabetes and high-fat diet models, also influences the observed outcomes. For example, STZ models primarily induce \beta-cell destruction, which may not fully represent insulin resistance in type 2 diabetes. This highlights the need to contextualize findings based on the model used, as the STZ-induced model may not adequately reflect the complex pathophysiology of T2DM (Table 1B). Furthermore, in vitro studies that examine \alpha-glucosidase inhibition and adipogenesis are not always validated in in vivo systems, weakening their translational potential. The lack of standardization in dosing protocols and extraction methods (e.g., water, ethanol, petroleum ether, and vinegar) complicates the comparison of efficacy across studies. For example, ethanolic extracts have demonstrated more substantial antidiabetic effects than aqueous or petroleum ether extracts, yet the underlying mechanisms remain poorly understood [19, 20]. The impact of different solvents on the pharmacological properties of G. biloba should be more thoroughly investigated to ensure consistency in therapeutic claims. Another limitation is that the safety data are poorly reported in most studies. Although G. biloba extracts demonstrate significant therapeutic potential, the safety profiles of compounds like ginkgolic acids, which have known allergenic and neurotoxic potential, often remain underreported. Long-term toxicity studies are especially lacking, with no precise monitoring of hepatic or renal function in most studies, raising concerns about the safety of these extracts, particularly in vulnerable populations such as cachectic patients or those with liver or kidney disorders. Mechanistic insights from in vitro experiments provide a possible rationale for G. biloba’s effects but also highlight a disconnect with clinical dosing. For example, certain Ginkgo constituents (such as ginkgolic acids) can activate AMPK signaling and inhibit protein tyrosine phosphatases at ~50 µM concentrations in cell-based models [81], Yet, these concentrations far exceed what is achieved during in vivo testing with a typical oral dose of 120 mg of EGb 761 that yields peak plasma levels of key terpene lactones, on the order of only tens of ng/mL (i.e., sub-micromolar) [97]. This disparity suggests that while the proposed molecular mechanisms (e.g., AMPK activation) are biologically plausible, their clinical relevance at standard doses remains unclear, underscoring the need for caution when extrapolating high-concentration in vitro findings to expected in vivo effects. While G. biloba shows promising antidiabetic potential, the current body of literature is hindered by significant heterogeneity in study design, inconsistent reporting, lack of standardization, and insufficient safety data. Future studies should address these limitations by standardizing experimental protocols, clearly defining dosage ranges, and providing detailed safety profiles to better evaluate the therapeutic potential and safety of G. biloba for diabetes management.

7. Future Perspectives and Conclusion

G. biloba as a potential alternative therapy for diabetes mellitus (DM) has garnered significant attention due to its promising pharmacological effects, including its antioxidant, anti-inflammatory, and insulin-sensitizing properties. However, the current research scenarios about the antidiabetic activity of the herb present several challenges and gaps that need to be addressed in future studies to understand its full therapeutic potential better. One central area requiring further investigation is the standardization of G. biloba dosage. While numerous studies have demonstrated its efficacy in reducing blood glucose levels and improving insulin sensitivity, there is considerable variation in the dosages and forms of G. biloba used across clinical trials. This inconsistency makes it difficult to determine an optimal, universally applicable dose for effective diabetes management. Future clinical studies should focus on selecting the most effective doses while considering factors such as the bioavailability of active compounds, patient age, comorbidities, and the duration of treatment. While preclinical studies have provided valuable insights into the mechanisms through which G. biloba exerts its effects, such as AMPK activation, GLUT4 translocation, and inhibition of protein tyrosine phosphatases, the detailed molecular pathways remain insufficiently explored. To further validate the therapeutic antidiabetic activity of G. biloba, future research must focus on uncovering the exact mechanisms of action behind its potency in managing diabetes. Investigations around molecular interactions of key bioactive compounds, such as bilobalide and flavonoids, will provide deeper insights into their role in regulating glucose metabolism and insulin secretion. These mechanistic studies could lead to more specific therapeutic regimens, which can be used as adjunct therapy alongside other antidiabetic agents. Another possible direction for future research could be to explore the long-term safety and efficacy of G. biloba in diabetic populations with comorbid conditions, such as cardiovascular disease, neuropathy, and nephropathy. Focus should be placed on chronic toxicity, herb-drug interactions, and use during pregnancy. While initial clinical studies have suggested that G. biloba may help mitigate diabetes-related complications, large-scale, multicenter clinical trials are necessary to establish its role in preventing and treating complications over extended periods. Additionally, the potential of G. biloba in managing gestational diabetes and its effects during pregnancy remains largely unexplored, which calls for further investigation.

In conclusion, G. biloba L. holds considerable promise as a complementary therapy for diabetes management. Its multifaceted pharmacological activities, such as enhanced glucose uptake, improved insulin secretion, and reduced oxidative stress, make G. biloba an ideal candidate for improving glycemic control, thus helping prevent diabetes-related complications. Preclinical and clinical studies have shown encouraging results, suggesting that G. biloba can reduce blood glucose levels, improve lipid profiles, and protect against diabetes-induced nephropathy and retinopathy. However, to fully establish its role as an effective adjunct in diabetes management, future research must address the gaps in clinical trials, optimise dosing regimens, and further elucidate the underlying mechanisms of action. With well-designed, large-scale clinical trials and a deeper understanding of its molecular effects, G. biloba could become integral to diabetes treatment strategies, offering a natural, safe alternative to conventional therapies.

References

[1] Ansari P, Tabasumma N, Snigdha NN, Siam NH, Panduru RV, Azam S, et al. Diabetic retinopathy: An overview on mechanisms, pathophysiology, and pharmacotherapy. Diabetology. 2022; 3: 159–175. https://doi.org/10.3390/diabetology3010011.

[2] Tomic D, Shaw JE, Magliano DJ. The burden and risks of emerging complications of diabetes mellitus. Nature Reviews. Endocrinology. 2022; 18: 525–539. https://doi.org/10.1038/s41574-022-00690-7.

[3] Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Research and Clinical Practice. 2022; 183: 109119. https://doi.org/10.1016/j.diabres.2021.109119.

[4] Siam NH, Snigdha NN, Tabasumma N, Parvin I. Diabetes Mellitus and Cardiovascular Disease: Exploring Epidemiology, Pathophysiology, and Treatment Strategies. Reviews in Cardiovascular Medicine. 2024; 25: 436. https://doi.org/10.31083/j.rcm2512436.

[5] Yedjou CG, Grigsby J, Mbemi A, Nelson D, Mildort B, Latinwo L, et al. The Management of Diabetes Mellitus Using Medicinal Plants and Vitamins. International Journal of Molecular Sciences. 2023; 24: 9085. https://doi.org/10.3390/ijms24109085.

[6] Bielka W, Przezak A, Molęda P, Pius-Sadowska E, Machaliński B. Double diabetes-when type 1 diabetes meets type 2 diabetes: definition, pathogenesis and recognition. Cardiovascular Diabetology. 2024; 23: 62. https://doi.org/10.1186/s12933-024-02145-x.

[7] Tan Y, Cheong MS, Cheang WS. Roles of Reactive Oxygen Species in Vascular Complications of Diabetes: Therapeutic Properties of Medicinal Plants and Food. Oxygen. 2022; 2: 246–268. https://doi.org/10.3390/oxygen2030018.

[8] Alam S, Hasan MK, Neaz S, Hussain N, Hossain MF, Rahman T. Diabetes Mellitus: Insights from Epidemiology, Biochemistry, Risk Factors, Diagnosis, Complications, and Comprehensive Management. Diabetology. 2021; 2: 36–50. https://doi.org/10.3390/diabetology2020004.

[9] Dahlén AD, Dashi G, Maslov I, Attwood MM, Jonsson J, Trukhan V, et al. Trends in Antidiabetic Drug Discovery: FDA Approved Drugs, New Drugs in Clinical Trials and Global Sales. Frontiers in Pharmacology. 2022; 12: 807548. https://doi.org/10.3389/fphar.2021.807548.

[10] Chawla A, Chawla R, Jaggi S. Microvasular and macrovascular complications in diabetes mellitus: Distinct or continuum? Indian Journal of Endocrinology and Metabolism. 2016; 20: 546–551. https://doi.org/10.4103/2230-8210.183480.

[11] Shabab S, Gholamnezhad Z, Mahmoudabady M. Protective effects of medicinal plant against diabetes induced cardiac disorder: A review. Journal of Ethnopharmacology. 2021; 265: 113328. https://doi.org/10.1016/j.jep.2020.113328.

[12] Kong M, Xie K, Lv M, Li J, Yao J, Yan K, et al. Anti-inflammatory phytochemicals for the treatment of diabetes and its complications: Lessons learned and future promise. Biomedicine & Pharmacotherapy. 2021; 133: 110975. https://doi.org/10.1016/j.biopha.2020.110975.

[13] Zou H, Fang J, Han Y, Hu X, Meng J, Huang F, et al. Effects and safety of Ginkgo biloba on blood metabolism in type 2 diabetes mellitus: a systematic review and meta-analysis. Frontiers in Endocrinology. 2024; 14: 1231053. https://doi.org/10.3389/fendo.2023.1231053.

[14] Forman V, Luo D, Geu-Flores F, Lemcke R, Nelson DR, Kampranis SC, et al. A gene cluster in Ginkgo biloba encodes unique multifunctional cytochrome P450s that initiate ginkgolide biosynthesis. Nature Communications. 2022; 13: 5143. https://doi.org/10.1038/s41467-022-32879-9.

[15] Achete de Souza G, de Marqui SV, Matias JN, Guiguer EL, Barbalho SM. Effects of Ginkgo biloba on Diseases Related to Oxidative Stress. Planta Medica. 2020; 86: 376–386. https://doi.org/10.1055/a-1109-3405.

[16] Tabrizi R, Nowrouzi-Sohrabi P, Hessami K, Rezaei S, Jalali M, Savardashtaki A, et al. Effects of Ginkgo biloba intake on cardiometabolic parameters in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of clinical trials. Phytotherapy Research. 2020; 10.1002/ptr.6822. https://doi.org/10.1002/ptr.6822.

[17] Biernacka P, Adamska I, Felisiak K. The Potential of Ginkgo biloba as a Source of Biologically Active Compounds-A Review of the Recent Literature and Patents. Molecules. 2023; 28: 3993. https://doi.org/10.3390/molecules28103993.

[18] Mahadevan S, Park Y. Multifaceted therapeutic benefits of Ginkgo biloba L.: chemistry, efficacy, safety, and uses. Journal of Food Science. 2008; 73: R14–R19. https://doi.org/10.1111/j.1750-3841.2007.00597.x.

[19] Pinto MDS, Kwon YI, Apostolidis E, Lajolo FM, Genovese MI, Shetty K. Potential of Ginkgo biloba L. leaves in the management of hyperglycemia and hypertension using in vitro models. Bioresource Technology. 2009; 100: 6599–6609. https://doi.org/10.1016/j.biortech.2009.07.021.

[20] Rusak G, Vujčić Bok V, Šola I, Nikša E, Maleš Ž. Effect of Protein, Carbohydrate, and Oil on Phytochemical Bioaccessibility and Bioactivities of the Ginkgo biloba L. Leaf Formulations After In Vitro Digestion. Molecules. 2024; 29: 5300. https://doi.org/10.3390/molecules29225300.

[21] Sun W, Wu C, Fan G, Hao G, Shi H, Zhang C. Preparation of a functional beverage with α-glucosidase inhibitory peptides obtained from ginkgo seeds. Journal of Food Science and Technology. 2021; 58: 4495–4503. https://doi.org/10.1007/s13197-020-04931-3.

[22] Li T, Lv Q, Liu C, Li C, Xie X, Zhang W. The Lipophilic Extract from Ginkgo biloba L. Leaves Promotes Glucose Uptake and Alleviates Palmitate-Induced Insulin Resistance in C2C12 Myotubes. Molecules. 2024; 29: 1605. https://doi.org/10.3390/molecules29071605.

[23] Kim SC, Han MY, Kim HJ, Jung KH. The effect of Ginkgo biloba Extract (GB) on Glucose Uptake in L6 Rat Skeletal Muscle Cells. The Korea Journal of Herbology. 2007; 22: 155–161.

[24] Bruel A, Gardette J, Berrou E, Droy-Lefaix MT, Picard J. Effects of Ginkgo biloba extract on glucose transport and glycogen synthesis of cultured smooth muscle cells from pig aorta. Pharmacological Research. 1989; 21: 421–429. https://doi.org/10.1016/1043-6618(89)90160-6.

[25] Ren M, Yang S, Li J, Hu Y, Ren Z, Ren S. Ginkgo biloba L. extract enhances the effectiveness of syngeneic bone marrow mesenchymal stem cells in lowering blood glucose levels and reversing oxidative stress. Endocrine. 2013; 43: 360–369. https://doi.org/10.1007/s12020-012-9745-5.

[26] Zhou L, Meng Q, Qian T, Yang Z. Ginkgo biloba extract enhances glucose tolerance in hyperinsulinism-induced hepatic cells. Journal of Natural Medicines. 2011; 65: 50–56. https://doi.org/10.1007/s11418-010-0456-z.

[27] Choi SE, Shin HC, Kim HE, Lee SJ, Jang HJ, Lee KW, et al. Involvement of Ca2+, CaMK II and PKA in EGb 761-induced insulin secretion in INS-1 cells. Journal of Ethnopharmacology. 2007; 110: 49–55. https://doi.org/10.1016/j.jep.2006.09.001.

[28] Thomaz FM, de Jesus Simão J, da Silva VS, Machado MMF, Oyama LM, Ribeiro EB, et al. Ginkgo biloba Extract Stimulates Adipogenesis in 3T3-L1 Preadipocytes. Pharmaceuticals. 2022; 15: 1294. https://doi.org/10.3390/ph15101294.

[29] Ji L, Yin XX, Wu ZM, Wang JY, Lu Q, Gao YY. Ginkgo biloba extract prevents glucose-induced accumulation of ECM in rat mesangial cells. Phytotherapy Research. 2009; 23: 477–485. https://doi.org/10.1002/ptr.2652.

[30] He YT, Xing SS, Gao L, Wang J, Xing QC, Zhang W. Ginkgo biloba attenuates oxidative DNA damage of human umbilical vein endothelial cells induced by intermittent high glucose. Die Pharmazie. 2014; 69: 203–207.

[31] Hosoda S, Kawazoe Y, Shiba T, Numazawa S, Manabe A. Anti-Obesity Effect of Ginkgo Vinegar, a Fermented Product of Ginkgo Seed Coat, in Mice Fed a High-Fat Diet and 3T3-L1 Preadipocyte Cells. Nutrients. 2020; 12: 230. https://doi.org/10.3390/nu12010230.

[32] Tsai HY, Huang PH, Lin FY, Chen JS, Lin SJ, Chen JW. Ginkgo biloba extract reduces high-glucose-induced endothelial reactive oxygen species generation and cell adhesion molecule expression by enhancing HO-1 expression via Akt/eNOS and p38 MAP kinase pathways. European Journal of Pharmaceutical Sciences. 2013; 48: 803–811. https://doi.org/10.1016/j.ejps.2013.01.002.

[33] Wu ZM, Yin XX, Ji L, Gao YY, Pan YM, Lu Q, et al. Ginkgo biloba extract prevents against apoptosis induced by high glucose in human lens epithelial cells. Acta Pharmacologica Sinica. 2008; 29: 1042–1050. https://doi.org/10.1111/j.1745-7254.2008.00837.x.

[34] Jiang Q, Yuan S, Wang K, Zhu X, Hu Y, Jiang Y, et al. Ginkgo biloba extract ameliorates hyperglycaemia-induced enteric glial cell injury via regulation of the TLR2-related pathway. The Journal of Pharmacy and Pharmacology. 2023; 75: 1430–1441. https://doi.org/10.1093/jpp/rgad075.

[35] Cheng D, Liang B, Li Y. Antihyperglycemic effect of Ginkgo biloba extract in streptozotocin-induced diabetes in rats. BioMed Research International. 2013; 2013: 162724. https://doi.org/10.1155/2013/162724.

[36] Kim J, Yokoyama K, Araki S. The effects of Ginkgo biloba extract (GBe) on axonal transport microvasculature and morphology of sciatic nerve in streptozotocin-induced diabetic rats. Environmental Health and Preventive Medicine. 2000; 5: 53–59. https://doi.org/10.1007/BF02932004.

[37] Saleh A, Anwar MM, Zayed AE, Ezz Eldeen MES, Afifi G, Alnashiri HM, et al. Impact of Ginkgo biloba extract and magnetized water on the survival rate and functional capabilities of pancreatic β-cells in type 2 diabetic rat model. Diabetes, Metabolic Syndrome and Obesity. 2019; 12: 1339–1347. https://doi.org/10.2147/DMSO.S209856.

[38] Naseem M, Ouguerram K, Nazih H, Rabbani I, Zaneb H, Rehman HU, et al. Synergistic Effect of Extracts of Ginkgo biloba Leaf and Panax Ginseng Root on Carbohydrate and Lipid Metabolism Gene Expression in Alloxan Induced Diabetic Rats. The Journal of Animal and Plant Sciences. 2020; 30. https://doi.org/10.36899/japs.2020.6.0158.

[39] Saini AS, Taliyan R, Sharma PL. Protective effect and mechanism of Ginkgo biloba extract-EGb 761 on STZ-induced diabetic cardiomyopathy in rats. Pharmacognosy Magazine. 2014; 10: 172–178. https://doi.org/10.4103/0973-1296.131031.

[40] Rudge MVC, Damasceno DC, Volpato GT, Almeida FCG, Calderon IMP, Lemonica IP. Effect of Ginkgo biloba on the reproductive outcome and oxidative stress biomarkers of streptozotocin-induced diabetic rats. Brazilian Journal of Medical and Biological Research. 2007; 40: 1095–1099. https://doi.org/10.1590/s0100-879x2006005000132.

[41] Zayed AE, Saleh A, Gomaa AMS, Abd-Elkareem M, Anwar MM, Hassanein KMA, et al. Protective Effect of Ginkgo biloba and Magnetized Water on Nephropathy in Induced Type 2 Diabetes in Rat. Oxidative Medicine and Cellular Longevity. 2018; 2018: 1785614. https://doi.org/10.1155/2018/1785614.

[42] Yu X, Su Q, Geng J, Liu H, Liu Y, Liu J, et al. Ginkgo biloba leaf extract prevents diabetic nephropathy through the suppression of tissue transglutaminase. Experimental and Therapeutic Medicine. 2021; 21: 333. https://doi.org/10.3892/etm.2021.9764.

[43] da Silva GGP, Zanoni JN, Buttow NC. Neuroprotective action of Ginkgo biloba on the enteric nervous system of diabetic rats. World Journal of Gastroenterology. 2011; 17: 898–905. https://doi.org/10.3748/wjg.v17.i7.898.

[44] Taki Y, Hagiwara E, Hirose C, Shinozuka K, Umegaki K, Yamada S. Effects of Ginkgo biloba extract on the pharmacokinetics and pharmacodynamics of tolbutamide in protein-restricted rats. The Journal of Pharmacy and Pharmacology. 2011; 63: 1238–1243. https://doi.org/10.1111/j.2042-7158.2011.01327.x.

[45] Punkt K, Adams V, Linke A, Welt K. The correlation of cytophotometrically and biochemically measured enzyme activities: changes in the myocardium of diabetic and hypoxic diabetic rats, with and without Ginkgo biloba extract treatment. Acta Histochemica. 1997; 99: 291–299. https://doi.org/10.1016/S0065-1281(97)80023-2.

[46] Tian J, Liu Y, Liu Y, Chen K, Lyu S. Ginkgo biloba Leaf Extract Protects against Myocardial Injury via Attenuation of Endoplasmic Reticulum Stress in Streptozotocin-Induced Diabetic ApoE^-⁣/- Mice. Oxidative Medicine and Cellular Longevity. 2018; 2018: 2370617. https://doi.org/10.1155/2018/2370617.

[47] Rhee KJ, Lee CG, Kim SW, Gim DH, Kim HC, Jung BD. Extract of Ginkgo Biloba Ameliorates Streptozotocin-Induced Type 1 Diabetes Mellitus and High-Fat Diet-Induced Type 2 Diabetes Mellitus in Mice. International Journal of Medical Sciences. 2015; 12: 987–994. https://doi.org/10.7150/ijms.13339.

[48] Banin RM, Hirata BKS, Andrade IS, Zemdegs JCS, Clemente APG, Dornellas APS, et al. Beneficial effects of Ginkgo biloba extract on insulin signaling cascade, dyslipidemia, and body adiposity of diet-induced obese rats. Brazilian Journal of Medical and Biological Research. 2014; 47: 780–788. https://doi.org/10.1590/1414-431x20142983.

[49] Omayma AR, Zaid A, Ali HA, El-Regaily AF. Biochemical effect of Ginko biloba extract on carbohydrate metabolism in (induced type two) diabetic rats. Medicamentul Veterinar/Veterinary Drug. 2016; 10.

[50] Kamel EO, Abd-Elrhman ASH. The effect of diabetes mellitus on the rat ventral prostate and the possible protective role of G. biloba extracts. Al-Azhar Assiut Medical Journal. 2018; 16: 300. https://doi.org/10.4103/azmj.azmj_114_18.

[51] Ismail R, Mahdy A, Attia M, Eskander F. Effects of Ginkgo biloba Extract and Troxerutin on the Hippocampus of Adult Albino Rats after Induction of Diabetes Mellitus. Journal of Advances in Medicine and Medical Research. 2020; 32: 122–138. https://doi.org/10.9734/jammr/2020/v32i330391.

[52] Shankar PK, Kumar V, Rao Namita. Evaluation of Antidiabetic Activity of G. biloba in Streptozotocin-Induced Diabetic Rats. Iranian Journal of Pharmacology and Therapeutics. 2005; 4: 16–19.

[53] Shalan HT. The Potential Therapeutic Role of G. biloba Extracts on The Prostate In A Rat Model Of Streptozotocin-Induced Diabetes: A Histomorphometric Study. Ain Shams Medical Journal. 2022; 73: 705–717. https://doi.org/10.21608/asmj.2022.285346.

[54] Chang TT, Chen YA, Li SY, Chen JW. Nrf-2 mediated heme oxygenase-1 activation contributes to the anti-inflammatory and renal protective effects of Ginkgo biloba extract in diabetic nephropathy. Journal of Ethnopharmacology. 2021; 266: 113474. https://doi.org/10.1016/j.jep.2020.113474.

[55] Lim S, Yoon JW, Kang SM, Choi SH, Cho BJ, Kim M, et al. EGb761, a Ginkgo biloba extract, is effective against atherosclerosis in vitro, and in a rat model of type 2 diabetes. PLoS ONE. 2011; 6: e20301. https://doi.org/10.1371/journal.pone.0020301.

[56] Tian J, Popal MS, Liu Y, Gao R, Lyu S, Chen K, et al. Ginkgo Biloba Leaf Extract Attenuates Atherosclerosis in Streptozotocin-Induced Diabetic ApoE^-⁣/- Mice by Inhibiting Endoplasmic Reticulum Stress via Restoration of Autophagy through the mTOR Signaling Pathway. Oxidative Medicine and Cellular Longevity. 2019; 2019: 8134678. https://doi.org/10.1155/2019/8134678.

[57] Naseem M, Zaman MQ, Nazih H, Ouguerram K, Rabbani I, Zaneb H, et al. The Effects of Ginkgo biloba Leaf Extract on Metabolic Disturbances Associated to Alloxan-Induced Diabetic Rats. The Journal of Animal & Plant Sciences. 2016; 26: 627–635.

[58] Nofal AE, AboShabaan HS, Fadda WA, Ereba RE, Elsharkawy SM, Hathout HM. L-carnitine and Ginkgo biloba Supplementation In Vivo Ameliorates HCD-Induced Steatohepatitis and Dyslipidemia by Regulating Hepatic Metabolism. Cells. 2024; 13: 732. https://doi.org/10.3390/cells13090732.

[59] Zhang Q, Wang GJ, A JY, Wu D, Zhu LL, Ma B, et al. Application of GC/MS-based metabonomic profiling in studying the lipid-regulating effects of Ginkgo biloba extract on diet-induced hyperlipidemia in rats. Acta Pharmacologica Sinica. 2009; 30: 1674–1687. https://doi.org/10.1038/aps.2009.173.

[60] Yan M, Li M, Gu S, Sun Z, Ma T, Ma X. Ginkgo biloba extract protects diabetic rats against cerebral ischemia reperfusion injury by suppressing oxidative stress and upregulating the expression of glutamate transporter 1. Molecular Medicine Reports. 2020; 21: 1809–1818. https://doi.org/10.3892/mmr.2020.10990.

[61] Awad A, El Araby E, Albaiomy R. The influence of G. biloba on hepatic gene expression of (PGC1-α, PPAR-α and GLUT-2), liver, kidney functions, hematological and lipid profile in type I diabetic rats. Zagazig Veterinary Journal. 2021; 49: 270–283. https://doi.org/10.21608/zvjz.2021.86000.1149.

[62] Zhang F, Li DX, Lu DY, Lu YF, Zhang R, Zhao LL, et al. Analysis of plasma free amino acids in diabetic rat and the intervention of Ginkgo biloba leaves extract using hydrophilic interaction liquid chromatography coupled with tandem mass-spectrometry. Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2022; 1196: 123230. https://doi.org/10.1016/j.jchromb.2022.123230.

[63] Cong WN, Tao RY, Tian JY, Zhao J, Liu Q, Ye F. EGb761, an extract of G. biloba leaves, reduces insulin resistance in a high-fat-fed mouse model. Acta Pharmaceutica Sinica B. 2011; 1: 14–20. https://doi.org/10.1016/j.apsb.2011.04.006.

[64] Zhao M, Qin J, Shen W, Wu A. Bilobalide Enhances AMPK Activity to Improve Liver Injury and Metabolic Disorders in STZ-Induced Diabetes in Immature Rats via Regulating HMGB1/TLR4/NF-κB Signaling Pathway. BioMed Research International. 2021; 2021: 8835408. https://doi.org/10.1155/2021/8835408.

[65] Bu S, Yuan CY, Xue Q, Chen Y, Cao F. Bilobalide Suppresses Adipogenesis in 3T3-L1 Adipocytes via the AMPK Signaling Pathway. Molecules. 2019; 24: 3503. https://doi.org/10.3390/molecules24193503.

[66] Vasseur M, Jean T, DeFeudis FV, Drieu K. Effects of repeated treatments with an extract of Ginkgo biloba (EGb 761), bilobalide and ginkgolide B on the electrical activity of pancreatic beta cells of normal or alloxan-diabetic mice: an ex vivo study with intracellular microelectrodes. General Pharmacology: The Vascular System. 1994; 25: 31–46. https://doi.org/10.1016/0306-3623(94)90007-8.

[67] Priyanka A, Sindhu G, Shyni GL, Preetha Rani MR, Nisha VM, Raghu KG. Bilobalide abates inflammation, insulin resistance and secretion of angiogenic factors induced by hypoxia in 3T3-L1 adipocytes by controlling NF-κB and JNK activation. International Immunopharmacology. 2017; 42: 209–217. https://doi.org/10.1016/j.intimp.2016.11.019.

[68] Priyanka A, Nisha VM, Anusree SS, Raghu KG. Bilobalide attenuates hypoxia induced oxidative stress, inflammation, and mitochondrial dysfunctions in 3T3-L1 adipocytes via its antioxidant potential. Free Radical Research. 2014; 48: 1206–1217. https://doi.org/10.3109/10715762.2014.945442.

[69] Bu S, Xiong A, Yang Z, Aissa-Brahim F, Chen Y, Zhang Y, et al. Bilobalide Induces Apoptosis in 3T3-L1 Mature Adipocytes through ROS-Mediated Mitochondria Pathway. Molecules. 2023; 28: 6410. https://doi.org/10.3390/molecules28176410.

[70] Rapin JR, Yoa RG, Bouvier C, Drieu K. Effects of repeated treatments with an extract of Ginkgo biloba (EGb 761) and bilobalide on liver and muscle glycogen contents in the non-insulin-dependent diabetic rat. Drug Development Research. 1997; 40: 68–74. https://doi.org/10.1002/(sici)1098-2299(199701)40:1%3C68::aid-ddr7%3E3.0.co;2-r.

[71] Jeong SY, Lee KH, Kim JK, Ahn D, Kim H, Chung SJ, et al. Ginkgolic Acid Derivatives from Ginkgo biloba Show Inhibitory Activity against Protein Tyrosine Phosphatases Associated with Insulin Resistance. Applied Sciences. 2023; 13: 13220–13220. https://doi.org/10.3390/app132413220.

[72] Oboh G, Ademosun AO, Ayeni PO, Omojokun OS, Bello F. Comparative effect of quercetin and rutin on α-amylase, α-glucosidase, and some pro-oxidant-induced lipid peroxidation in rat pancreas. Comparative Clinical Pathology. 2014; 24: 1103–1110. https://doi.org/10.1007/s00580-014-2040-5.

[73] Liou CJ, Lai XY, Chen YL, Wang CL, Wei CH, Huang WC. Ginkgolide C Suppresses Adipogenesis in 3T3-L1 Adipocytes via the AMPK Signaling Pathway. Evidence-Based Complementary and Alternative Medicine. 2015; 2015: 298635. https://doi.org/10.1155/2015/298635.

[74] Zhang Y, Zhen W, Maechler P, Liu D. Small molecule kaempferol modulates PDX-1 protein expression and subsequently promotes pancreatic β-cell survival and function via CREB. The Journal of Nutritional Biochemistry. 2013; 24: 638–646. https://doi.org/10.1016/j.jnutbio.2012.03.008.

[75] Cho YL, Park JG, Kang HJ, Kim W, Cho MJ, Jang JH, et al. Ginkgetin, a biflavone from Ginkgo biloba leaves, prevents adipogenesis through STAT5-mediated PPARγ and C/EBPα regulation. Pharmacological Research. 2019; 139: 325–336. https://doi.org/10.1016/j.phrs.2018.11.027.

[76] Liu PK, Weng ZM, Ge GB, Li HL, Ding LL, Dai ZR, et al. Biflavones from Ginkgo biloba as novel pancreatic lipase inhibitors: Inhibition potentials and mechanism. International Journal of Biological Macromolecules. 2018; 118: 2216–2223. https://doi.org/10.1016/j.ijbiomac.2018.07.085.

[77] Liu G, Grifman M, Macdonald J, Moller P, Wong-Staal F, Li QX. Isoginkgetin enhances adiponectin secretion from differentiated adiposarcoma cells via a novel pathway involving AMP-activated protein kinase. The Journal of Endocrinology. 2007; 194: 569–578. https://doi.org/10.1677/JOE-07-0200.

[78] Chen K, Sun W, Jiang Y, Chen B, Zhao Y, Sun J, et al. Ginkgolide B Suppresses TLR4-Mediated Inflammatory Response by Inhibiting the Phosphorylation of JAK2/STAT3 and p38 MAPK in High Glucose-Treated HUVECs. Oxidative Medicine and Cellular Longevity. 2017; 2017: 9371602. https://doi.org/10.1155/2017/9371602.

[79] Chen J, Ou Z, Gao T, Yang Y, Shu A, Xu H, et al. Ginkgolide B alleviates oxidative stress and ferroptosis by inhibiting GPX4 ubiquitination to improve diabetic nephropathy. Biomedicine & Pharmacotherapy. 2022; 156: 113953. https://doi.org/10.1016/j.biopha.2022.113953.

[80] Taguchi K, Okudaira K, Matsumoto T, Kobayashi T. Ginkgolide B caused the activation of the Akt/eNOS pathway through the antioxidant effect of SOD1 in the diabetic aorta. Pflugers Archiv: European Journal of Physiology. 2023; 475: 453–463. https://doi.org/10.1007/s00424-023-02790-3.

[81] Sukito A, Tachibana S. Potent α-glucosidase inhibitors isolated from Ginkgo biloba leaves. Pakistan Journal of Biological Sciences. 2014; 17: 1170–1178. https://doi.org/10.3923/pjbs.2014.1170.1178.

[82] Dell’Agli M, Bosisio E. Biflavones of Ginkgo biloba stimulate lipolysis in 3T3-L1 adipocytes. Planta Medica. 2002; 68: 76–79. https://doi.org/10.1055/s-2002-19876.

[83] Ngan NTT, Quang TH, Tai BH, Song SB, Lee D, Kim YH. Anti-inflammatory and PPAR transactivational effects of components from the stem bark of Ginkgo biloba. Journal of Agricultural and Food Chemistry. 2012; 60: 2815–2824. https://doi.org/10.1021/jf204768d.

[84] Hirata BKS, Cruz MM, de Sá RDCC, Farias TSM, Machado MMF, Bueno AA, et al. Potential Anti-obesogenic Effects of Ginkgo biloba Observed in Epididymal White Adipose Tissue of Obese Rats. Frontiers in Endocrinology. 2019; 10: 284. https://doi.org/10.3389/fendo.2019.00284.

[85] Lu Q, Hao M, Wu W, Zhang N, Isaac AT, Yin J, et al. Antidiabetic cataract effects of GbE, rutin and quercetin are mediated by the inhibition of oxidative stress and polyol pathway. Acta Biochimica Polonica. 2018; 65: 35–41. https://doi.org/10.18388/abp.2016_1387.

[86] Aziz TA, Hussain SA, Mahwi TO, Ahmed ZA, Rahman HS, Rasedee A. The efficacy and safety of Ginkgo biloba extract as an adjuvant in type 2 diabetes mellitus patients ineffectively managed with metformin: a double-blind, randomized, placebo-controlled trial. Drug Design, Development and Therapy. 2018; 12: 735–742. https://doi.org/10.2147/DDDT.S157113.

[87] Kudolo GB, Wang W, Elrod R, Barrientos J, Haase A, Blodgett J. Short-term ingestion of Ginkgo biloba extract does not alter whole body insulin sensitivity in non-diabetic, pre-diabetic or type 2 diabetic subjects–a randomized double-blind placebo-controlled crossover study. Clinical Nutrition. 2006; 25: 123–134. https://doi.org/10.1016/j.clnu.2005.10.001.

[88] Kudolo GB, Wang W, Javors M, Blodgett J. The effect of the ingestion of Ginkgo biloba extract (EGb 761) on the pharmacokinetics of metformin in non-diabetic and type 2 diabetic subjects–a double blind placebo-controlled, crossover study. Clinical Nutrition. 2006; 25: 606–616. https://doi.org/10.1016/j.clnu.2005.12.012.

[89] Lu J, He H. Clinical observation of Gingko biloba extract injection in treating early diabetic nephropathy. Chinese Journal of Integrative Medicine. 2005; 11: 226–228. https://doi.org/10.1007/BF02836510.

[90] Zhu CY, Yi Q, Ma JL, Wei QP. Clinical evaluation of Ginkgo biloba extract for diabetic retinopathy. International Eye Science. 2016; 16: 361–364. https://doi.org/10.3980/j.issn.1672-5123.2016.2.45. (In Chinese)

[91] Shi R, Wang Y, An X, Ma J, Wu T, Yu X, et al. Efficacy of Co-administration of Liuwei Dihuang Pills and Ginkgo Biloba Tablets on Albuminuria in Type 2 Diabetes: A 24-Month, Multicenter, Double-Blind, Placebo-Controlled, Randomized Clinical Trial. Frontiers in Endocrinology. 2019; 10: 100. https://doi.org/10.3389/fendo.2019.00100.

[92] Zhu HW, Shi ZF, Chen YY. Effect of extract of ginkgo bilboa leaf on early diabetic nephropathy. Chinese Journal of Integrated Traditional and Western Medicine. 2005; 25: 889–891.

[93] Wang Y, Sun Z, Yu J, et al. Effects of G. biloba extract on prevention of development of diabetic nephropathy in type 2 diabetic patients. Diabetologia. 2012; 55: 456. https://doi.org/10.1007/s00125-012-2688-9.

[94] Lasaite L, Spadiene A, Savickiene N, Skesters A, Silova A. The effect of Ginkgo biloba and Camellia sinensis extracts on psychological state and glycemic control in patients with type 2 diabetes mellitus. Natural Product Communications. 2014; 9: 1934578X1400900931. https://doi.org/10.1177/1934578x1400900931.

[95] Kudolo GB. The effect of 3-month ingestion of Ginkgo biloba extract on pancreatic beta-cell function in response to glucose loading in normal glucose tolerant individuals. Journal of Clinical Pharmacology. 2000; 40: 647–654. https://doi.org/10.1002/j.1552-4604.2000.tb05991.x.

[96] Kudolo GB. The effect of 3-month ingestion of Ginkgo biloba extract (EGb 761) on pancreatic beta-cell function in response to glucose loading in individuals with non-insulin-dependent diabetes mellitus. Journal of Clinical Pharmacology. 2001; 41: 600–611. https://doi.org/10.1177/00912700122010483.

[97] Esin R, Esin O, Khayrullin I. Influence of Standardized Extract G. biloba EGb761® Towards Quality-of-Life Indicators in Patients with Diabetes Mellitus Type 2. BioNanoScience. 2018; 8: 916–923. https://doi.org/10.1007/s12668-018-0550-3.

[98] Sun M, Chai L, Lu F, Zhao Y, Li Q, Cui B, et al. Efficacy and Safety of Ginkgo Biloba Pills for Coronary Heart Disease with Impaired Glucose Regulation: Study Protocol for a Series of N-of-1 Randomized, Double-Blind, Placebo-Controlled Trials. Evidence-Based Complementary and Alternative Medicine. 2018; 2018: 7571629. https://doi.org/10.1155/2018/7571629.

[99] Kudolo GB. Effect of Ginkgo biloba Extract Ingestion on Plasma Total Cortisol Levels during an Oral Glucose Tolerance Test in Normal Glucose Tolerant Individuals. Food and Nutrition Sciences. 2014; 5: 1561–1567. https://doi.org/10.4236/fns.2014.516169.

[100] Hussain SA, Aziz TA, Mahwi TO, Ahmed ZA. Gingko biloba extract improves the lipid profile, inflammatory markers, leptin level and the antioxidant status of T2DM patients poorly responding to metformin: A double- blind, randomized, placebo-controlled trial. Brazilian Journal of Pharmaceutical Sciences. 2022; 58: e19516. https://doi.org/10.1590/s2175-97902022e19516.

[101] Fernandes I, Oliveira J, Pinho A, Carvalho E. The Role of Nutraceutical Containing Polyphenols in Diabetes Prevention. Metabolites. 2022; 12: 184. https://doi.org/10.3390/metabo12020184.

[102] Triggiani V, Resta F, Guastamacchia E, Sabbà C, Licchelli B, Ghiyasaldin S, et al. Role of antioxidants, essential fatty acids, carnitine, vitamins, phytochemicals and trace elements in the treatment of diabetes mellitus and its chronic complications. Endocrine, Metabolic & Immune Disorders Drug Targets. 2006; 6: 77–93. https://doi.org/10.2174/187153006776056611.

[103] Noor-E-Tabassum, Das R, Lami MS, Chakraborty AJ, Mitra S, Tallei TE, et al. Ginkgo biloba: A Treasure of Functional Phytochemicals with Multimedicinal Applications. Evidence-based Complementary and Alternative Medicine. 2022; 2022: 8288818. https://doi.org/10.1155/2022/8288818.

[104] Ogbuewu IP, Mabelebele M, Mbajiorgu CA. Ginkgo Biloba L. And The Effect of Its Fermented Products on Production Physiology, Blood Chemistry and Histology of Livestock Species: A Review. Applied Ecology and Environmental Research. 2024; 22: 4563–4579. http://dx.doi.org/10.15666/aeer/2205_45634579.

[105] Saeed MA, Ain HB, Koser HN, Rizwan B, Tufail T, Abdullah M, et al. Bioactive Profile and Health Claims of Gingo biloba. Pakistan BioMedical Journal. 2022; 5: 06–11. https://doi.org/10.54393/pbmj.v5i5.460.

[106] Pereira E, Barros L, Ferreira IC. Chemical characterization of Ginkgo biloba L. and antioxidant properties of its extracts and dietary supplements. Industrial Crops and Products. 2013; 51: 244–248. https://doi.org/10.1016/j.indcrop.2013.09.011.

[107] Wang HY, Zhang YQ. The main active constituents and detoxification process of Ginkgo biloba seeds and their potential use in functional health foods. Journal of Food Composition and Analysis. 2019; 83: 103247. https://doi.org/10.1016/j.jfca.2019.103247.

[108] Sajadimajd S, Bahrami G, Daglia M, Nabavi SM, Naseri R, Farzaei MH. Plant-Derived Supplementary Carbohydrates, Polysaccharides and Oligosaccharides in Management of Diabetes Mellitus: A Comprehensive Review. Food Reviews International. 2019; 35: 563–586. https://doi.org/10.1080/87559129.2019.1584818.