Chronic hyperglycemia and insulin resistance lead to systemic immune dysregulation and sustained inflammation within the male reproductive tract (23). This state of inflammation, characterized by abnormal activation of leukocytes, leads to an overproduction of reactive oxygen species (ROS). These ROS oxidize protamines, crucial for the correct condensation of sperm nuclei, leading to the disruption of disulfide bond formation. Consequently, incomplete chromatin packaging occurs, leading to heightened DNA fragility and genomic instability (24). These nuclear abnormalities are closely associated with morphological defects, particularly affecting the sperm head (25). Additionally, elevated levels of advanced glycation end products (AGEs) and DNA fragmentation markers have been consistently detected in the sperm of diabetic men, indicating substantial nuclear instability and chromatin disruption (26). Prolonged hyperglycemia disrupts normal spermatogenesis by interfering with the development of key structural components, including the sperm head, midpiece, and tail, leading to a significant increase in morphologically abnormal sperm (27).

DM, particularly T2DM, significantly reduces sperm count through multiple interrelated mechanisms. It disrupts the hypothalamic-pituitary-gonadal (HPG) axis, resulting in decreased levels of testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) (28). The reduction in hormone levels directly impairs critical stages of spermatogenesis, particularly the primary meiotic division, and disrupts the function of both SC and Leydig cell(LC). A reduction in the number of SC, combined with impaired lactate production, leads to an inadequate energy supply for germ cells, thereby promoting germ cell death (29, 30). Furthermore, oxidative stress activates apoptotic signaling pathways—such as the MAPK/p38 pathway— upregulating the expression of the pro-apoptotic protein Bax while downregulating the anti-apoptotic protein Bcl-2. This dysregulation ultimately triggers extensive programmed cell death among spermatogenic cells, including SC and LC (24). Structural and functional defects in the sperm tail further impair sperm motility and viability. Ultimately, hormonal imbalances, SC dysfunction, oxidative stress, defective chromatin maturation, excessive activation of apoptotic pathways, and abnormalities in sperm structure and function collectively lead to severe disruption of spermatogenesis. This results in a substantial decline in daily sperm production, sperm reserve quantity, and impaired overall testicular spermatogenic function (27, 31).

DM impairs sperm motility through a complex interplay of hormonal imbalance, oxidative stress, metabolic dysfunction, and inflammation (23, 27, 32). It compromises testicular antioxidant capacity and promotes germ cell apoptosis, leading to reduced testosterone levels. This testosterone deficiency disrupts epididymal function, weakens reproductive antioxidant defenses, and alters the expression of proteins critical for sperm flagellar movement and acrosome integrity, ultimately diminishing sperm motility (27, 33).

Trace element imbalances also contribute to diabetic testicular dysfunction. Ghasemi et al. observed significantly reduced concentrations of zinc and magnesium in the seminal plasma of diabetic individuals. Zinc levels exhibited a strong positive correlation with sperm motility and morphology, whereas magnesium was significantly associated with parameters of sperm motility (34).

Inflammation is another important factor. The accumulation of AGEs activates macrophages through the receptor for AGEs (RAGE), triggering the release of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α). In vitro studies have demonstrated that TNF-α can directly suppress sperm motility by 40%–60% (35, 36).

Furthermore, sperm motility is highly dependent on energy derived from glucose metabolism. Insulin deficiency or resistance interferes with glucose utilization, limiting energy availability for sperm motility (29).

Mitochondria play a pivotal role in regulating sperm function by modulating essential processes, including metabolism, signal transduction, energy production, and responses to oxidative stress. The midpiece of sperm is rich in mitochondria, which generate ATP through the electron transport chain (ETC), providing the energy required for sperm motility, capacitation, and overall functional capability (37). Additionally, mitochondria are essential for maintaining DNA integrity, regulating calcium homeostasis, mediating apoptotic signaling, and supporting the differentiation and maturation of spermatogenic cells (38). As the primary cellular energy generators, mitochondria are also the main source of ROS within the cell. Physiological levels of ROS are essential for sperm capacitation and fertilization. The antioxidant defense systems in semen generally maintain redox homeostasis under normal conditions. However, excessive ROS production can inhibit the activity of key antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx), leading to oxidative stress and mitochondrial dysfunction. Therefore, maintaining mitochondrial integrity is crucial for preserving sperm quality, and its impairment is widely recognized as a major cause of male infertility (39–41).

Insulin regulates reproductive function in both males and females by modulating the HPG axis. This effect is probably mediated by the MAPK/Erk1/2 pathway, whereby insulin stimulates the hypothalamus to secrete gonadotropin-releasing hormone (GnRH) (42). GnRH subsequently acts on the pituitary gland to promote the synthesis and release of LH and FSH, which in turn facilitate the maturation of seminiferous tubules and LC (2). Insulin resistance disrupts the function of the HPG axis, directly leading to decreased secretion of LH and FSH, reduced testosterone levels, and an imbalance in the androgen-to-estrogen ratio (43, 44). Meanwhile, persistent hyperglycemia further exacerbates reproductive dysfunction by impairing the pulsatile release of GnRH from the hypothalamus and suppressing LH and FSH synthesis in the pituitary. These disturbances ultimately impair testosterone production by LC and compromise the supportive function of SC in spermatogenesis, resulting in impaired spermatogenic function (2).

AGEs can severely impair sperm function through multiple mechanisms. Upon binding to RAGE, AGEs not only activate inflammatory signaling pathways but also directly disrupt key cellular processes and structural components of sperm. Notably, AGEs exposure significantly reduces sperm motility, particularly progressive motility (45, 46). This decline may result from AGEs-induced mitochondrial dysfunction, crosslinking with membrane proteins or flagellar components, and the induction of DNA damage and activation of apoptotic pathways. In addition, AGEs–RAGE interactions may interfere with essential fertilization-related processes such as capacitation and the acrosome reaction, further compromising the fertilizing potential of sperm (35, 37).

The number of SC in the adult testis determines daily sperm production, as each SC can maintain a limited number of germ cells (47). SC play a critical role in forming the BTB and providing nutrients essential for spermatogenesis. SC can metabolize a variety of substances, including glucose, lactic acid, fatty acids, and amino acids, and possess specific glucose sensing mechanisms that are highly sensitive to extracellular glucose levels (48). The glucose transporters GLUT1 and GLUT3 work synergistically in SC to maintain glucose uptake and ensure lactate production. Under diabetic conditions, the metabolic homeostasis of SC is disrupted, potentially leading to structural and functional impairment of the BTB in patients with T2DM (49). Both in vivo and in vitro studies have demonstrated that high glucose levels upregulate Apelin (APLN) in SC, which subsequently downregulates cell junction–related genes such as connexin 43 (Cx43) and zonula occludens-1 (ZO-1), ultimately compromising the integrity of the BTB (50).

The blood–testis barrier (BTB), also referred to as the SC barrier, is a critical structural and functional component of the seminiferous tubules. Located at the basal compartment of the seminiferous epithelium, the BTB is primarily formed by junctional complexes between SC, including tight junctions, gap junctions, and basal ectoplasmic specializations (51). The primary function of the BTB is to segregate the lumen of the seminiferous tubules from the systemic circulation, thereby establishing an immune-privileged microenvironment that protects developing germ cells from harmful substances and maintains the sterile conditions essential for spermatogenesis (52, 53).

During spermatogenesis, spermatogonia migrate across the BTB within the seminiferous tubules, the functional units of the mammalian testis. To facilitate this translocation, cell junctions are dynamically disassembled and reassembled, enabling the movement of immature germ cells from the basal compartment to the luminal compartment as they undergo meiosis and subsequent differentiation, ultimately culminating in the release of mature spermatozoa (54, 55). This process involves proteases, protease inhibitors, and cell-junction components (56).

The interaction between Cx43 and ZO-1 is crucial for the maintenance of BTB integrity. Hyperglycemia and AGEs have been shown to impair the expression and function of junctional proteins such as Cx43 and ZO-1 in SC by inducing oxidative stress, inflammation, and hormonal disturbances, ultimately compromising BTB function. Genetic deletion of Cx43 leads to BTB disruption and subsequent failure of spermatogenesis (11). Ke Song’s STRT-seq analysis of testicular tissue from diabetic patients at single-cell resolution revealed significant alterations in SC gene expression profiles and disruption of the BTB structure. In vivo biotin tracer assays in hyperglycemic (HGM) mice demonstrated a substantial increase in biotin-positive seminiferous tubules and deeper biotin penetration, indicating a loss of BTB integrity induced by hyperglycemia (50).

Basel A. Abdel-Wahab et al. reported histopathological changes in diabetic rat testes, including seminiferous tubule atrophy and significant degeneration and necrosis of LC (57).LC located in the testicular stroma, are regulated by LH to produce testosterone, essential for maintaining spermatogenesis. Androgens have a bidirectional relationship with glucose regulation (58). Androgen deficiency is a risk factor for T2DM, while hyperglycemia promotes the formation of AGEs through non-enzymatic glycation. These AGEs bind to receptors such as RAGE in the testes, triggering overactivation of downstream signaling pathways that downregulate key steroidogenic enzymes, ultimately impairing testosterone secretion (59, 60). Furthermore, chronic hyperglycemia itself induces ER stress within LC. This ER stress disrupts LC function, causing cell cycle arrest, apoptosis, and further suppression of testosterone synthesis. Collectively, these mechanisms disrupt the testicular reproductive environment and impair sperm production, contributing to male reproductive dysfunction in diabetes (59, 61, 62). Insulin resistance further exacerbates this by reducing insulin sensitivity and triggering compensatory hyperinsulinemia, which promotes facilitates the conversion of testosterone to dihydrotestosterone (DHT) and suppresses LH and FSH secretion, thereby disrupting the synthesis and regulation of reproductive hormones (63, 64). Consequently, men with T2DM frequently present with hypogonadism, which is closely associated with early LC dysfunction.

Current therapeutic strategies for diabetes-associated testicular dysfunction remain limited, with a predominant emphasis on glycemic control ( Table 2 ). Studies have demonstrated that metformin can improve sperm quality, an effect attributed to its ability to elevate testosterone levels and support spermatogenesis. This beneficial action is closely linked to the restoration of gonadotropic hormone and leptin system function within the testes. These effects are largely attributed to improved insulin sensitivity, which contributes to hormonal balance and promotes testicular function and integrity (65, 66). Conversely, evidence suggests that the use of sulfonylureas and thiazolidinediones may be associated with impaired sperm quality, exerting detrimental effects on motility and vitality (67). Emerging evidence suggests that semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), may offer a more comprehensive therapeutic approach for male infertility associated with diabetes and obesity. In diabetic rat models, semaglutide has been shown to restore redox homeostasis, modulate androgen levels, attenuate testicular inflammation, and alleviate diabetes-induced testicular damage by regulating the ferroptosis pathway (68). Furthermore, semaglutide improves the expression of key genes and proteins involved in spermatogenesis through multiple molecular mechanisms, thereby preventing testicular and sexual dysfunction induced by diabetes (69). In a 24-week clinical trial, semaglutide significantly improved sperm morphology in men with type 2 diabetes, obesity, and functional hypogonadism. Notably, its effects on sperm concentration and total sperm count were superior to those achieved with testosterone replacement therapy (TRT), offering a novel therapeutic option for this patient population (30). Liraglutide improves energy homeostasis by promoting fatty acid utilization in spermatogonia, thereby enhancing the energetic state of seminiferous tubules. Additionally, it exerts anti-inflammatory and antioxidant effects, contributing to the improvement of sperm quality and hormonal profiles (70, 71). A 16-week study demonstrated that liraglutide effectively facilitates weight loss, ameliorates sexual function, elevates testosterone levels, and restores HPT axis function. Furthermore, liraglutide positively impacts metabolic health by improving glycemic control, reducing HbA1c, alleviating insulin resistance, and mitigating metabolic syndrome (72). Simultaneously, another study investigating liraglutide treatment in obese men with metabolic hypogonadism reported significant improvements in sperm motility, semen parameters, and sexual function after four months of therapy, compared to both gonadotropin and transdermal testosterone groups. Moreover, increases in testosterone, sex hormone-binding globulin (SHBG), and gonadotropin levels were also observed (73). The GLP-1 peptide-based agents discussed above have demonstrated the potential to enhance spermatogenesis and testosterone synthesis in both preclinical and clinical studies, offering valuable insights for the development of therapeutic strategies in clinical practice. Consequently, addressing testicular dysfunction and abnormalities in spermatogenesis continues to represent a meaningful and promising direction for future research.

Bifidobacterium longum exerts multifaceted anti-diabetic effects, with its antioxidant and anti-apoptotic properties contributing to improvements in reproductive function and the regulation of hormone levels (74). Soy milk fortified with Lactobacillus casei and omega-3 inhibits the infertility phenotype in a rat model of type 1 diabetes, increasing the number of SC and LC and enhancing sperm quality (75). The combination of Lactobacillus, montelukast, and metformin synergistically mitigates diabetes-induced testicular damage by modulating the intestinal microbiome and reducing oxidative stress (76).Multiple randomized controlled trials (RCTs) have demonstrated that probiotic supplementation significantly improves sperm parameters in infertile men, including sperm concentration, motility, and morphology. In addition, a marked reduction in oxidative stress biomarkers has been reported, suggesting that probiotics help restore redox homeostasis within the seminal microenvironment (77–79). Probiotics may also influence male hormonal profiles. Several studies have reported a mild increase in serum testosterone levels and improved hormonal balance following probiotic supplementation, which may support spermatogenesis. Furthermore, synbiotic therapy (a combination of probiotics and prebiotics) has shown beneficial effects in certain trials, including improvements in sperm DNA integrity and chromatin quality (80). Lactobacillus and Bifidobacterium species are among the most commonly used and well-studied probiotic strains. These bacteria can lower intestinal pH and significantly enhance sperm quality through antioxidant, anti-inflammatory, and gut microbiota-modulating mechanisms. Clinically, probiotic-based treatments are low-cost, safe, and offer promising potential as adjunctive therapies for improving sperm quality in men with diabetes. Nevertheless, large-scale clinical studies are still needed to determine the most effective strain combinations and to validate their long-term efficacy (77).

A variety of plant-derived compounds, including stevioside, tripterine, silymarin, phloridzin, icariin, dognoside, Aucubin, dendrobium polysaccharides, and propolis, have demonstrated protective effects against testicular damage induced by diabetes or inflammation (11, 12, 14, 62, 81–87). The core mechanisms underlying these protective effects involve inhibition of oxidative stress and inflammatory pathways (e.g., regulation of NF-κB, Nrf2, AGEs/RAGE/Nox4), reduction of apoptosis and necrosis, enhancement of endogenous antioxidant defenses (e.g., increased antioxidant enzyme activity and Hsp70/90 expression), and improvement of BTB integrity (61, 88). In some cases, the protective effects are associated with the regulation of intestinal microbiota, as observed with phloridzin and dognoside (89). Ultimately, these interventions help restore testosterone levels, promote spermatogenesis, and improve testicular tissue structure.

Selenium plays a critical role in healthy spermatogenesis, testicular development, and sperm motility. Selenium nanoparticles (SeNPs), functionalized with active targeting ligands, exhibit excellent biocompatibility and enable efficient, targeted delivery of therapeutic agents (90). Recent studies have demonstrated that the combined administration of SeNPs and metformin confers protective effects against streptozotocin-induced testicular oxidative damage in diabetic rats. This protective mechanism involves the suppression of redox imbalance, improvement of sperm quality, and upregulation of nuclear factor erythroid 2–related factor 2 (Nrf2) expression (91). Similarly, zinc oxide nanoparticles (ZnO NPs) have been shown to exert protective effects against diabetes-induced testicular damage. These effects are attributed not only to the potent antioxidant and hypoglycemic properties of ZnO NPs, but also to their ability to downregulate pro-apoptotic gene expression and upregulate the expression of steroidogenesis-related regulatory genes within testicular tissue (92, 93). Collectively, selenium and zinc oxide nanoparticles demonstrate promising protective effects against diabetes-induced testicular oxidative damage and sperm dysfunction. Experimental evidence supports the role of these nanoparticles in improving sperm quality, highlighting their value as adjunctive agents in the management of male reproductive disorders associated with diabetes.

Montelukast, a cysteinyl leukotriene receptor 1 antagonist, has been shown to attenuate testicular injury through its anti-inflammatory, antioxidant, and autophagy-inducing properties (94). Similarly, bezafibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, has been shown to suppress inflammation and oxidative stress, thereby alleviating diabetic spermatogenesis disorder (95). Tropisetron, an antagonist of 5-Hydroxytryptamine (5-HT) type 3 receptor, has been demonstrated to reduce testicular inflammation induced by streptozotocin in diabetic rats. Furthermore, the late sodium current inhibitor ranolazine, as well as the mechanistic target of rapamycin (mTOR) inhibitor rapamycin and the chromium-based compound chromium picolinate, have demonstrated protective trends against diabetic testicular injury by inducing autophagy, inhibiting ER stress, oxidative damage, and apoptosis (96–99). Islet transplantation may also serve as an therapeutic strategy for diabetic complications in men by delaying diabetic testicular interstitial fibrosis (100, 101).

Zinc combined with metformin restores zinc homeostasis by activating the PI3K/AKT/mTOR pathway, thereby enhancing steroidogenesis and improving semen quality in male mice with T2DM (102). Vitamin D enhances the efficacy of metformin in alleviating testicular dysfunction associated with T2DM (103). Co-administration of chrysin with MIRET significantly ameliorates diabetic testicular histopathological testicular histopathological and biochemical damage and diminishes pro-apoptotic effects (104). Cilostazol and sildenafil alleviate testicular damage in diabetes by exerting anti-inflammatory and antioxidant effects (105). The combination of sitagliptin and L-theanine demonstrates potential to significantly reduce diabetic testicular dysfunction, indicating a promising therapeutic approach (106).

Although the aforementioned studies provide several potential therapeutic strategies for alleviating diabetic testicular dysfunction and impaired spermatogenesis, most of the current evidence is derived from animal models, with clinical data remaining relatively limited. Therefore, future research should focus on optimizing these interventions to enhance their clinical efficacy while minimizing potential side effects and safety concerns. Such efforts may contribute to the development of more personalized and targeted therapeutic approaches for diabetes-related complications, ultimately facilitating the clinical translation of these emerging treatments.