These enzymes break down complex carbs into glucose, inhibiting their function and lowering hyperglycemia after meals. Prolonged hyperglycemia encourages oxidative stress and glycation end products (AGEs), which harm the seminiferous epithelium, disrupt the function of Leydig and Sertoli cells, and fragment sperm DNA (51).

Sertoli and Leydig cells have receptors for insulin and insulin-like growth factor-1 (IGF-1). Insulin resistance impairs testosterone synthesis, breaks down the blood-testis barrier, and decreases spermatogenesis, all of which decrease these cells’ responsiveness. This is partially mediated by the MAPK and PI3K/Akt pathways, which are implicated in cell survival and glucose uptake (52).

Spermatogenesis depends on Sertoli cells’ uptake of glucose (via the GLUT1 and GLUT3 transporters). The expression of the glucose transporter is dysregulated in diabetic conditions, which causes seminiferous tubules to lose energy. The maturation of germ cells is restricted, and apoptosis is increased (53).

Prolonged hyperglycemia weakens antioxidant defenses and produces excessive ROS. This oxidative imbalance results in decreased sperm motility, mitochondrial failure, and lipid peroxidation in sperm membranes. Inflammatory cytokines, such as TNF-α and IL-6, also affect the endocrine and exocrine processes of the testicles (54).

Hypogonadotropic hypogonadism is linked to insulin resistance. It inhibits testosterone synthesis and Sertoli cell support for growing germ cells by decreasing LH and FSH signaling (55).

The activation of a transcription factor, peroxisome proliferator-activated receptor (PPAR), is the mechanism by which TZDs exert their anti-diabetic action. This factor affects the transcription of various genes involved in glucose and lipid metabolism and energy balance, such as fatty acyl-CoA synthase, malic enzyme, glucokinase, and glucose transporter 4 (GLUT4), among others. As a result, TZDs decrease insulin resistance (IR) in adipose tissue, muscle, and the liver (70, 71).

One of the main adverse effects associated with PPAR receptor activation is the enhanced proliferation of peripheral adipocytes, which leads to increased uptake of free fatty acids. This process can ultimately result in weight gain and an increase in peripheral fat mass (72, 73). Several recent studies and analyses have indicated the potential role of TZD in cardiovascular events in type 2 diabetic patients. In this way, meta-analyses of adverse outcomes from controlled studies have revealed a possible link between thiazolidinedione use and an elevated risk of ischemic myocardial events in diabetes patients (74, 75). Fluid retention is another known side effect associated with the use of thiazolidinediones (TZDs). It is hypothesized that TZD-induced renal edema results from the activation of sodium-coupled bicarbonate reabsorption in the renal proximal tubules. This leads to increased salt and water reabsorption, ultimately causing an expansion in kidney volume (76). The outcomes of these studies caused disagreement as well as confusion about the use of TZDs in diabetic treatment methods (68, 71).

Symptoms of the gastrointestinal tract (e.g., nausea, vomiting, diarrhea, and abdominal discomfort) are among the side effects linked with the therapeutic use of all biguanides (78, 91). Metformin is seldom associated with acute hepatitis and cholestasis (81, 92–100) Metformin has been linked to malabsorption syndromes, which can result in electrolyte imbalances and vitamin B12 insufficiency (13, 81, 84–86, 90, 101–112) Diarrhea is associated with hypomagnesaemia, hypocalcemia, and hypokalemia (85, 104, 105, 113). Vitamin B12 deficiency can lead to megaloblastic anemia and various neuropathies. The underlying causes of this deficiency are not fully understood but appear to be multifactorial. Contributing factors may include alterations in gut microbiota, reduced gastrointestinal motility, competitive inhibition of B12 absorption, and disruptions in calcium-dependent membrane transport mechanisms in the terminal ileum (106, 113).

Lactic acidosis is an uncommon but possibly hazardous metformin adverse effect. The occurrence of this consequence is quite low: one case per 100,000 individuals receiving treatment (114–119). Lactic acidosis can be produced by very high metformin levels in blood vessels or by any circumstance that causes hypoxia or hepatic insufficiency, restricting the capacity of the body to break down lactate (120). Lactic acidosis usually arises in patients who have persisted in using metformin despite risks (114, 120). Renal insufficiency, indicated by serum creatinine levels of 1.5 mg/dL or higher in men and 1.4 mg/dL or higher in women, is a contraindication for metformin therapy. Additionally, conditions such as severe cardiac or pulmonary insufficiency that lead to reduced peripheral perfusion, lactic acidosis, liver disease, alcohol dependence, or the use of intramuscular contrast agents for radiographic imaging also represent exclusion criteria due to the increased risk of adverse effects, particularly lactic acidosis (80, 121).

Sulfonylureas act by inhibiting the ATP-sensitive K channel (KATP), causing the release of insulin from the cells of the pancreas and therefore lowering blood glucose levels (128–131). Over 90 percent of sulfonylureas in the blood are linked to plasma proteins, causing interactions between drugs with salicylates, sulfonamides, and warfarin (123, 132). While the effectiveness of sulfonylureas varies, they tend to reduce A1C to a comparable extent as metformin, by 1.5 percentage points (117, 133).

The primary adverse effect associated with sulfonylureas is hypoglycemia. Due to variations in the pharmacotherapeutic properties of different sulfonylurea agents, the risk of hypoglycemic episodes can vary significantly among them (120, 134). The possibility of gaining weight is yet another drawback of sulfonylureas. Many people see an increase of at least 2 kg when taking these drugs (117, 135). It is also to be noted that certain people with sulfonamide allergies show cross reactivity with sulfonylureas; thus, these treatments shouldn’t be used in patients with sulfa allergies. Cross-reactivity with other medicines, such as carbonic anhydrase inhibitors, loop diuretics, and thiazide diuretics, is also possible (120, 136). Sulfonylureas are also linked to an increased risk of cardiovascular disease (68, 137). According to research, while promoting the closure of pancreatic-cell KATP channels to boost insulin secretion, this medicine may also lead to the closure of cardiac KATP channels, resulting in a higher cardiac risk in those people (138, 139).

Meglitinides attach themselves to Sulfonylurea Receptor 1 (SUR1’s) benzamido site on β cells (123, 147). The first meglitinide analogue approved for clinical use in adults with T2DM was repaglinide. The insulinotropic effect of repaglinide, similar to that of sulfonylureas, operates through ATP-dependent potassium (KATP) channels. Repaglinide stimulates insulin secretion by inhibiting KATP channels in pancreatic β-cells, leading to membrane depolarization and the opening of voltage-gated calcium channels. The resulting influx of calcium increases intracellular calcium levels, triggering the exocytosis of insulin-containing granules (148, 149). Nateglinide, like repaglinide, binds to SURs, blocking KATP channels and promoting insulin secretion, but its pharmacodynamic effects are distinct in several important respects (150, 151).

Repaglinide and nateglinide studies have revealed different levels of hypoglycemia and, overall, lesser weight gain than sulfonylureas (149, 152–163). Although a topical test-positive delayed-type hypersensitivity reaction to repaglinide has been documented, cutaneous reactions to meglitinides seem to be uncommon. In this case, the fifth day after starting repaglinide, a maculopapular rash developed. Repaglinide was stopped, and systemic corticosteroids and antihistamines were administered instead (158, 164). Six people in a post-marketing monitoring study of nateglinide reported seven cutaneous side effects associated with treatment, including two occurrences of allergic dermatitis and one non-specific rash. There were 892 patients in the study overall (153, 165).

In the brush border of enterocytes lining the intestinal villi, α-glucoside inhibitors (AGIs) competitively inhibit α-glucosidase enzymes, preventing the enzymes from cleaving disaccharides and oligosaccharides into monosaccharides (167–170). This process helps to reduce fluctuations in blood glucose levels and decrease the amount of insulin required during meals by slowing down the digestion and absorption of carbohydrates in the lower part of the digestive system (148, 167). Compared to controls, AGI therapy reduces Glucagon-like Peptide (GIP) secretion and increases postprandial Glucose-dependent Insulinotropic Polypeptide (GLP-1) secretion (171–173). Varying α-glucosidase enzymes have distinct affinities for AGIs, resulting in unique activity profiles. For example, acarbose shows a higher affinity for glucoamylase while miglitol is a more effective sucrase inhibitor (167, 174).

The common gastrointestinal side effects caused by AGIs, such as flatulence, stomach pain, and diarrhea, may lead patients to discontinue their medication (123, 175).

DPP-4 inhibitors increase levels of incretin hormones in circulation, notably GLP-1 and GIP. The “incretin effect” refers to the ability of intestinal variables to increase insulin responses by 50-70% in healthy individuals following a diet (182–184). In T2DM, this effect is significantly reduced. When lipids and carbohydrates are consumed, K cells in the duodenum and jejunum release glucose-dependent insulinotropic polypeptide (GIP) (185–190). Apart from its incretin action, GIP also plays roles in adipogenesis and potentially β-cell proliferation, and reduces stomach acid output (188, 190–198).

There is an uncertain safety concern over the long run, which may raise the possibility of pancreatitis and an increased risk of liver dysfunction associated with Vildagliptin (123).

Using green synthesis techniques, plant extracts serve as both capping and reducing agents in the synthesis of plant-based metallic nanoparticles (NPs). The extracts, which are high in alkaloids, terpenoids, phenolics, and flavonoids, are combined with metal precursors such as gold chloride (HAuCl₄), zinc sulfate (ZnSO₄), or silver nitrate (AgNO₃) (208). The pH, temperature, and reaction time are all regulated during the biosynthesis, which is usually shown by a color shift brought on by surface plasmon resonance (for example, AgNPs turning from pale yellow to dark brown) For example, the aqueous leaf extract of Musa paradisiaca is frequently utilized as a stabilizing and reducing agent in the synthesis of zinc oxide nanoparticles (ZnONPs). The plant extract’s bioactive components, including flavonoids, polyphenols, and reducing sugars, convert Zn²⁺ ions to ZnO nuclei when the zinc nitrate hexahydrate [Zn(NO3)2·6H2O]⁺ precursor is introduced under carefully monitored conditions (usually 60–80°C, pH ~9). These phytochemicals also cap the developing nanoparticles as the reaction goes on, limiting aggregation and encouraging size control. A color shift (such as a yellowish-white precipitate) usually signals the creation of ZnONPs, and UV-Vis spectroscopy, which shows a distinctive absorption peak at about 360–380 nm, confirms this (209).

Similarly, Argyria nervosa root extract is used to synthesize silver nanoparticles (AgNPs) by reducing Ag⁺ ions from silver nitrate (AgNO₃). The phytochemicals present, particularly phenolics and alkaloids, donate electrons to reduce Ag⁺ to metallic Ag⁰, initiating nanoparticle nucleation. Simultaneously, these compounds act as capping agents, forming a protective layer around each nanoparticle that improves colloidal stability and biocompatibility (210) ( Tables 2 , 3 ). In these green synthesis systems, plant-derived compounds become physically or chemically associated with the nanoparticle surface. For crude extracts, the nanoparticles serve as nano-carriers, embedding or adsorbing various phytochemicals in their matrix or on their surface. This makes it possible for several bioactives, like enzyme inhibitors, anti-inflammatory drugs, and antioxidants, to be delivered simultaneously in a single nanoformulation (239).

The production of gold nanoparticles (AuNPs) using extract from Typha capensis, which includes bioactive flavonoids and glycosides, is another well-researched example. The gold ion precursor in this method is chloroauric acid (HAuCl₄). When the phytochemicals are combined with the plant extract and heated to about 70°C, they convert Au³⁺ to elemental Au⁰, which starts the nucleation of nanoparticles. The extract’s flavonoids stabilize the suspended nanoparticles by attaching to the gold surface and acting as capping ligands in addition to reducing agents (240). Additionally, certain bioactive substances, like naringenin, can be added to these AuNPs either post-synthesis or from the same extract. Naringenin finds adsorption sites on the surface of the nanoparticles through π-π stacking interactions or hydrogen bonding. Consequently, the plant-derived substance with enhanced cellular absorption and prolonged release is delivered by the nanocarrier system along with the metallic therapeutic activity (e.g., antioxidant, anti-inflammatory from AuNPs) (241).

Analyzing the composition and functionality of synthesized NPs using key approaches includes:

From the reference to tables (2–6), plant-based metallic NPs in this review utilize:

In the preclinical studies reviewed, the following administration routes were commonly reported:

Plant-mediated metal nanoparticles have synergistic therapeutic effects that result from the interaction of metal cores (such as Au, Ag, Zn, and Mn) with bioactive phytochemicals (like flavonoids, alkaloids, and phenolics) (208). In addition to improving the solubility and bioavailability of encapsulated plant components, metallic nanoparticles shield them against early degradation. To replicate natural pharmacokinetics, this permits sustained release. In diabetic and cancer animals, for example, AuNPs loaded with naringenin from Typha capensis demonstrated enhanced delivery. Metal nanoparticles (NPs) such as ZnO or AgNPs may reduce oxidative stress by upregulating endogenous antioxidant enzymes (e.g., SOD, CAT, GPx), while plant components frequently scavenge free radicals. By doing so, oxidative damage to cells decreases (240).

For example, in diabetic mice, SeNPs derived from Withania somnifera increased antioxidant defense and decreased ROS, improving sperm quality (250). The inhibition of important enzymes in glucose metabolism (α-amylase, α-glucosidase, and DPP-IV) by both phytochemicals and metal nanoparticles can result in additive or synergistic hypoglycemic effects. The metal ion activity and polyphenolic stabilization of Moringa oleifera-ZnONPs were responsible for the 90% and 96% inhibition of α-amylase and α-glucosidase, respectively. Furthermore, phytochemicals facilitate receptor-mediated endocytosis of NPs by acting as biocompatible capping agents. This improves insulin signaling and tissue regeneration by increasing NP uptake into target cells (such as pancreatic β-cells and Sertoli cells) (256). For instance, male rats’ levels of LH, FSH, and testosterone were raised by Costus after-derived AgNPs. This was probably because of increased bioavailability and hormonal signaling through NP absorption (257).

The structure and functional characteristics of many active chemicals originating from plants are comparable to those of commercially marketed medications. For instance, thiazolidinediones and flavonoids like quercetin and kaempferol have structural similarities and can bind to PPAR-γ to increase insulin sensitivity (258). The same mechanism that metformin targets, AMPK, is also activated by berberine, and silybin from Silybum marianum has antioxidant and insulin-sensitizing properties similar to those of hepatoprotective drugs (259). In addition to sharing structural similarities with synthetic pharmaceuticals, these substances also modulate insulin signaling, glucose metabolism enzymes (including α-glucosidase and α-amylase), and reproductive hormone pathways.

Due to the synergistic effects of several phytochemicals acting on various targets at once, crude plant extracts frequently exhibit efficacy that is about equal to or even better than isolated substances. For example, formulations using extracts of Azadirachta indica and Moringa oleifera for ZnONPs showed over 85% inhibition of important enzymes involved in the digestion of glucose, which is comparable to that of common medications such as acarbose (260) ( Table 3 ), whereas the extract from Eysenhardtia polystachya increased the release of insulin via INS-1 pancreatic cells ( Table 2 ). Improved bioavailability, wider therapeutic coverage, and natural excipients that promote stability and solubility are all advantages of these multi-component systems (221). However, there are drawbacks to crude extracts as well, including unpredictability, ambiguity in composition, and standardization issues. Curcumin and naringenin, on the other hand, are single-component phytochemicals that provide superior control over nanoparticle formulations, promoting regulatory compliance and reproducibility (261). In general, plant-based bioactives serve as natural substitutes for synthetic medications, and both isolated molecules and crude extracts offer special benefits that can be used strategically depending on the intended therapeutic outcome (262).

Delivering therapeutic agents to their target sites presents several challenges, including poor bioavailability, in vivo instability, low solubility, limited absorption, target-specific delivery difficulties, and suboptimal therapeutic efficacy. To address these limitations, advanced targeted drug delivery systems have been developed. Among these, nanotechnology has emerged as a promising interdisciplinary approach, offering cost-effective and innovative solutions for precise drug delivery (263). In particular, metal nanoparticles (NPs) have gained significant attention due to their wide-ranging applications in medicine, biology, and physics, making them valuable tools for enhancing the efficiency and specificity of therapeutic interventions (263, 264). The use of plant-based metallic NPs in diabetes treatment offers a promising approach for the precise delivery of therapeutic compounds ( Table 2 ). Derived from natural sources, these NPs are biocompatible and can be engineered to encapsulate insulin, antidiabetic medications, and plant-derived bioactive compounds. This allows for sustained and targeted delivery, mimicking the body’s insulin release patterns, regulating blood glucose levels, and potentially reducing the dosage needed. Additionally, these NPs can help mitigate diabetes-related inflammation and oxidative stress, protect against complications, and enhance the bioavailability of oral medications (265). These phytogenic nanoparticles offer various advantages compared to synthetic antidiabetic drug ( Table 5 ).

Utilizing Nigella sativa plant extract, Alkhalaf et al. (276) Assessed the green prepared Ag NPs for diabetic neuropathy. A comparison between diabetic neuropathy-induced and stable control groups revealed a significant increase in blood glucose levels, advanced glycation end products (AGEs), and aldose reductase activity, accompanied by a marked reduction in insulin levels. Additionally, inflammatory markers were significantly elevated in the diabetic neuropathy group. Notably, nitrotyrosine levels were substantially lower, suggesting a notable alteration in the oxidative state. Gene expression analysis further demonstrated a significant upregulation of nerve growth factor (NGF) and a downregulation of brain Tyrosine Kinase Receptor A (TrkA) in individuals with diabetic neuropathy compared to healthy controls. Various therapeutic interventions targeting diabetic neuropathy have shown significant improvements across all evaluated biomarkers (276).

Cheng et al. (277) conducted a study involving the manufacturing of Ramulus Mori extract loaded on polyacrylic Gold nanoparticles (AuNPs) as an antidiabetic agent, specifically gestational diabetes mellitus nursing (GDM). Microscopic examination of the livers in diabetic mother rats revealed characteristic alterations in cell layers. However, administering Au NPs at the maternal stage significantly improved. Biochemical analysis indicated that Au–PAA–NPs contributed to the amelioration of alterations in maternal serum glucose concentration. Govindan et al. (278) created eco-friendly Zn-doped Catharanthus Roseus plants, aiming to enhance anti-diabetic properties through inhibiting alpha amylase activity.

A recent study revealed that Allium cepa extract-prepared NPs effectively suppressed the activity of α-amylase and α-glucosidase enzymes. Since α-amylase plays a crucial role in carbohydrate metabolism, inhibiting its activity is considered a promising strategy to lower blood sugar levels. Additionally, these amylase inhibitors act to reduce the absorption of dietary starch in the body. Likewise, α-glucosidase is a key enzyme in carbohydrate metabolism, facilitating the breakdown of disaccharides and oligosaccharides into monosaccharides (279, 280). Furthermore, NPs derived from plants and coated with phytochemicals, and other vital bioactive compounds sourced from plant secondary metabolites may find application in treating foot or limb infections in individuals with diabetes (281, 282).

Silver NPs derived from Argyreia nervosa and Punica granatum (211, 283), and marine algae Colpomenia sinuosa (284, 285) Have been documented for their antidiabetic properties. They exhibited a dose-dependent inhibition of α-amylase and α-glucosidase activities, as compared to the crude plant extracts. Moreover, silver nanoparticles (AgNPs) derived from the stem section of Tephrosia tinctoria were found to inhibit the activities of α-amylase and α-glucosidase, while also enhancing glucose uptake in human red blood cells (286, 287).

Shanker et al. (288) Reported that Zinc oxide nanoparticles (ZnONPs) derived from different plant sources such as Momordica charantia, Azadirachta indica, Hibiscus rosa-sinensis, Murraya koenigii, Moringa oleifera, and Tamarindus indica have antidiabetic potential by significantly inhibiting the activities of α-amylase and α-glucosidase( Table 3 ). The anti-diabetic properties of ZnONPs prepared from the leaves of the insulin plant (Costus igneus), by diminished the activities of α-amylase and α-glucosidase, were reported by (282). Gold NPs (AuNPs) obtained from Cassia auriculata (289) And Sargassum swertzii (Dhas et al., 2016) demonstrated antihyperglycemic action in rats after induced diabetes. Gold NPs have been found the application biocompatible, nontoxic, and easily interact with a variety of biomolecules such as amino acids, proteins, enzymes, and DNA, also playing a vital role in their immobilization ( Table 6 ).

Plant-based metallic NPs have been found to heighten antimicrobial resistance in diabetic patients even at lower concentrations, exhibiting lower toxicity to the human body ( Table 7 ). These SNPs induce bacterial cell damage through two mechanisms. Firstly, they adhere to the bacterial cell wall, disrupting permeability and cellular respiration (298). Additionally, they cause damage by interacting with phosphorus- and sulfur-containing compounds like DNA and proteins (299). Based on the Streptomyces achromogenes bacterium, Streptozotocin (STZ) serves as a broad-spectrum antibiotic. Additionally, it functions as a pancreatic beta-cell–specific cytotoxin, making it a commonly used inducer of diabetes in rat models (280).

STZ elevates malondialdehyde (MDA) and nitric oxide (NO) levels while reducing the antioxidant capabilities of catalase (CAT), superoxide dismutase (SOD), GR, and glutathione peroxidase (GPx) in rodents. It utilizes specific receptors such as glucose transporter-2 (GLUT 2) receptors, competing with glucose molecules and leading to AKt phosphorylation, also referred to as protein kinase B. Moreover, STZ triggers apoptosis and cytotoxicity by elevating reactive oxygen species (ROS) and nitric oxide synthase production. It instigates oxidative stress, resulting in lowers testosterone levels, mitochondrial breakage, and DNA destruction through diminishing the antioxidant capacity of CAT, SOD, and other factors. Eventually resulting in the demise of cells. Through the utilization of receptor-mediated endocytosis for internalization, phyto-fabricated metallic NPs reduce the generation of ROS and nitric oxide synthase by boosting the antioxidant capacity of CAT, POD, serum testosterone, and lipid levels in STZ-treated rodents (305).

Furthermore, the synthesis of metallic NPs from plant extracts adds another dimension to the therapeutic potential of these natural remedies. NPs exhibit diverse shapes and sizes, which can influence their pharmacokinetics, biodistribution, and interactions with biological systems. For instance, NPs with smaller sizes may have enhanced cellular uptake and bioavailability compared to larger particles. Additionally, their unique shapes can affect their stability, surface area, and binding affinity to target molecules.

When metallic NPs derived from plant extracts are used as antidiabetic agents, their distinct properties contribute to their efficacy through multiple mechanisms. These mechanisms may include modulating insulin sensitivity, enhancing glucose uptake by cells, inhibiting carbohydrate-digesting enzymes, and protecting pancreatic beta cells from oxidative stress. The specific combination of phytochemicals encapsulated within NPs, along with their size and shape characteristics, determines their overall impact on different regulatory pathways involved in diabetes management ( Figure 3 ).