• Diabetic Peripheral Neuropathy (DPN) is a common microvascular complication of diabetes mellitus.

Diabetic peripheral neuropathy (DPN), a prevalent microvascular complication of diabetes mellitus (DM) [1], is characterized by significant clinical implications and substantial deterioration in patient quality of life [2]. This condition elevates risks of morbidity and disability, primarily through complications such as neuropathic ulceration and subsequent limb amputation [1]. Pathophysiologically, DPN manifests as symmetric sensorimotor polyneuropathy mediated by metabolic and microvascular alterations arising from chronic hyperglycemia and associated metabolic dysregulation [3].

The condition typically originates in the toes and progresses proximally [2], presenting clinically with both positive and negative sensory symptoms. Positive manifestations include paresthesia, burning pain, and neuropathic discomfort, while negative features encompass hypoesthesia (reduced tactile sensation), hypoalgesia (diminished pain perception), and palhypesthesia (decreased vibratory sensitivity) [4]. These sensory deficits contribute to impaired balance, gait instability, and elevated fall risk, potentially precipitating fractures and hospitalization [5]. Motor complications such as muscle weakness and spasms occur less frequently [6]. DPN is strongly associated with increased risks of lower extremity ulceration, limb amputation, and significant healthcare expenditures [7, 8, 9]. Early-stage pathophysiology involves segmental demyelination impairing nerve conduction velocity [10], progressing to axonal degeneration and myelin sheath damage. Diagnosis relies on nerve conduction studies (NCS) to differentiate DPN from other neuropathies [2].

Epidemiological studies reveal substantial global heterogeneity in DPN prevalence, attributed to variability in diagnostic criteria, diabetes subtypes, patient selection methodologies, and cohort sizes [11]. Reported prevalence rates demonstrate wide geographical disparities: 8.8% in China [12], 48.1% in Sri Lanka [13], 29.2% in India [14], 56.2% in Yemen [15], 39.5% in Jordan [16], 71.7% in Nigeria [17], 16.6% in Ghana [18], 26.5% in Malaysia [19], and 48.2% in Ethiopia [20]. Peripheral nerve degeneration in diabetes is typically irreversible [21, 22], underscoring the critical need for early intervention. Established risk factors include advanced age, male sex, prolonged diabetes duration, concurrent microvascular complications, hypertension, rural residency, elevated body mass index (BMI), poor glycemic control (indicated by elevated Hemoglobin A1C (HbA1c) levels), alcohol consumption, chronic hyperglycemia, tobacco use, sedentary lifestyle, and marital status [1].

Current pharmacological management of neuropathic pain and paresthesia utilizes anticonvulsants, tricyclic antidepressants, or serotonin-noradrenaline reuptake inhibitors [23]. However, therapeutic strategies remain limited by the ineffectiveness of existing treatments for sensory loss [2], highlighting a critical gap in clinical management. The pathogenesis of DPN extends beyond hyperglycemia-mediated neuronal damage, involving complex interactions between molecular mechanisms [6]. Key dysregulated pathways include enhanced polyol pathway flux, advanced glycation end-product (AGE) accumulation, oxidative stress, altered growth factor signaling, impaired insulin/C-peptide axis function, and protein kinase C (PKC) overactivation [24, 25]. These processes simultaneously disrupt neuronal homeostasis and microvascular integrity within the vasa nervorum. Emerging pathophysiological models emphasize the convergence of multiple signaling networks and transcriptional regulators in DPN progression. Notably, extensive research has established oxidative stress, neuroinflammation, and programmed cell death as pivotal mechanisms in diabetic nerve injury through interconnected biochemical cascades [26]. This multifactorial pathogenesis complicates the development of targeted neuroprotective therapies.

Selenium (Se) serves as an essential cofactor for antioxidant enzymes such as glutathione peroxidase (GPx), which neutralize reactive oxygen species (ROS) and prevent oxidative damage [27]. This micronutrient also contributes to the structural integrity of selenoprotein enzymes including deiodinase iodothyronine and thioredoxin reductase, which regulate thyroid hormone synthesis [28]. Clinical investigations have demonstrated an inverse relationship between blood selenium levels and DPN severity in type 2 diabetes patients [29]. Preclinical evidence from a 2011 rodent study (n = 40) revealed that sodium selenite supplementation mitigated diabetes-induced alterations in nerve conduction velocity distribution, restoring active nerve fiber parameters to age-matched control levels [30]. Similarly, selenate administration exhibited protective effects on electrophysiological parameters in diabetic models [30].

Selenoproteins, the biologically active forms of selenium, play critical antioxidant roles in numerous physiological processes [31]. Selenomethionine, the most bioavailable selenium species for human metabolism, accumulates efficiently in Saccharomyces cerevisiae yeast cultured in selenium-enriched media. Unlike inorganic forms, organic selenium derived from yeast undergoes site-specific amino acid absorption without mineral interactions, achieving complete bioavailability and systemic retention [32, 33, 34]. Selenium yeast supplementation is recognized as a safe, effective method for dietary fortification due to its superior absorption profile [35, 36]. Currently, Saccharomyces cerevisiae represents the most efficient organism for selenomethionine accumulation and selenium biotransformation [37].

Given the escalating global prevalence of type 2 diabetes and its debilitating complications, novel therapeutic strategies for managing DPN require urgent investigation. Our extensive search of the database identified no prior clinical trials examining organic selenium’s effects on DPN severity or symptomatology. This randomized controlled trial aimed to evaluate the efficacy of Saccharomyces cerevisiae-derived selenium over eight weeks on primary outcomes including neuropathic symptom severity and prooxidant-antioxidant balance (PAB) status, and a secondary outcome consisting of sexual satisfaction. This investigation seeks to address a critical gap in DPN management while elucidating selenium’s potential therapeutic mechanisms through oxidative stress modulation.

Participant recruitment occurred between April 21, 2021, and October 22, 2024, with the follow-up period concluding on December 22, 2024. A total of 335 individuals with diabetes were screened. Of these, 253 did not meet the inclusion criteria, and 32 were excluded due to unwillingness to participate (n = 19), digestive disorders (n = 4), coagulation risks (n = 5), rheumatological conditions (n = 3), or chronic renal failure (n = 1). The remaining 50 eligible participants were randomized into two groups (25 per group). During the 8-week intervention, two participants in the organic selenium group and one in the placebo group withdrew due to unwillingness to continue. Final analysis included 23 participants in the selenium group and 24 in the placebo group (Fig. 1).

Fig. 1.

The flow diagram of study.

Table 1 summarizes demographic and clinical characteristics. No statistically significant differences were observed between groups in terms of sex, age, marital status, residence, education, income, employment, weight, or BMI (all p $>$ 0.05). All participants had type 2 diabetes, with four insulin users per group and three participants using insulin combined with gliclazide. Mean diabetes duration exceeded 10 years (13.5 years in the intervention group vs. 14.6 in the placebo group; p = 0.571). Hypertension (prevalence $>$70% in both groups; p = 1.000), hyperlipidemia (80% in both groups; p = 1.000), and smoking rates (p = 0.167) were comparable. Baseline fasting blood glucose levels differed significantly between groups (p = 0.035), with both exceeding normal ranges.

Table 2 details diabetic peripheral neuropathy (DPN) symptom scores using the Michigan Neuropathy Screening Instrument (MNSI). Baseline total scores were similar (8.6 $\pm$ 2.1 in the selenium group vs. 8.2 $\pm$ 1.9 in the placebo group; p = 0.271), both above the diagnostic threshold of 7. Post-intervention reductions were significant in both groups (selenium: p 0.001; placebo: p = 0.001), with a greater decline in the selenium group (adjusted mean difference [aMD]: –0.92; 95% CI: –1.9 to 0.10), which resulted in a mean score lower than the borderline of 7. However, intergroup differences remained nonsignificant (p = 0.077), resulting in reducing mean scores below the threshold (6.5 $\pm$ 2.0) [Clarified that the scores were reduced, not that the lack of significance reduced them]. There was no significant difference in the mean score of the MNSI examination section between the two groups before the intervention (p = 0.667). MNSI examination scores decreased significantly within groups (selenium: p = 0.004; placebo: p = 0.008) but not between groups (p = 0.969). Intragroup improvements occurred in foot appearance (selenium: p = 0.029; placebo: p = 0.008) and hallux vibratory perception (selenium: p = 0.016), though intergroup comparisons showed no significant differences (all p $>$ 0.05).

Table 3 presents neuropathy severity outcomes using the Toronto Clinical Scoring System (TCSS). Baseline scores indicated moderate severity in both groups (12.2 $\pm$ 3.2 vs. 11.2 $\pm$ 2.9; p = 0.259), with $>$60% of participants classified as moderate in both groups (p = 0.311). Post-intervention, the selenium group showed significant improvement (p = 0.002), though intergroup differences remained nonsignificant (p = 0.214). Intragroup analysis revealed reductions in symptom (p = 0.015) and sensory scores (p = 0.017) for the selenium group, and in sensory scores for the placebo group (p = 0.045), with no significant intergroup differences in symptom (p = 0.992), reflex (p = 0.319), or sensory (p = 0.456) domains.

Table 4 outlines PAB results. Baseline serum PAB levels were comparable (p = 0.424). Post-intervention, selenium supplementation significantly reduced PAB levels (p = 0.001), though intergroup differences were nonsignificant (aMD: –32.1; 95% CI: –66.02 to 1.87; p = 0.063).

Table 5 details sexual satisfaction outcomes. Baseline scores reflected moderate satisfaction in both groups (p = 0.964). Post-intervention, placebo group scores declined to low satisfaction (p = 0.004), while the selenium group maintained moderate levels (p = 0.277). Final satisfaction scores were higher in the selenium group (aMD: 8.51; 95% CI: 0.74–16.28; p = 0.033), with 84.2% of selenium participants reporting moderate satisfaction and 75% of placebo participants reporting low satisfaction (p = 0.001).

Intervention satisfaction differed marginally: 43.4% of selenium and 25% of placebo participants reported being satisfied, while 52.2% vs. 58.3% were neutral, and 8.7% vs. 16.7% were dissatisfied (p = 0.445). Adverse events included mild diarrhea, abdominal pain, and dizziness (4 in the selenium group, 3 in the placebo group), none requiring discontinuation. Capsule counting from the returned medications and review of the controlling daily medication checklist showed that medication compliance exceeded 90% in both groups

The analysis revealed that both groups demonstrated comparable baseline total MNSI scores exceeding established clinical thresholds. Post-intervention assessment at eight weeks showed statistically significant reductions in total scores for both the selenium-enriched yeast-supplemented and placebo groups. While the selenium group exhibited greater mean decreases, achieving post-treatment scores below clinical cutoffs, intergroup comparisons revealed no statistically significant differential effects. Longitudinal evaluation of four MNSI subdomains (symptom inventory, appearance, sensory perception, and reflex testing) similarly showed non-significant between-group differences at baseline and post-intervention. These findings suggest comparable therapeutic trajectories despite numerical advantages in the experimental group. Neuropathy severity evaluation using TCSS demonstrated moderate mean total scores at baseline in both groups. Post-intervention, the selenium group showed significant intragroup reductions in neuropathy severity. The organic selenium group exhibited significant decreases in PAB index values during treatment and statistically greater improvements in sexual satisfaction metrics compared to placebo controls.

Pain pathophysiology involves complex interactions between oxidative stress and Ca²⁺ signaling. Mitochondrial dysfunction caused by Ca²⁺-induced membrane depolarization generates ROS, which is modulated by antioxidants including selenium. As a GPx cofactor and selenoprotein component, selenium exerts neuroprotective effects by regulating ROS overproduction, inflammation, and Ca²⁺ overload in conditions like diabetic neuropathy, allodynia, and nociception. Ca²⁺ influx occurs through transient receptor potential (TRP) channels (TRPA1, TRPM2, TRPV1, TRPV4), many of which are activated by oxidative stress to induce peripheral pain. Recent studies indicate that selenium modulates peripheral pain via TRP channel inhibition in dorsal root ganglia [45]. Song and Lin [46] demonstrated that selenium upregulates the nuclear factor erythroid 2-related factor 2/heme oxygenase-1Nrf2/HO-1 pathway to inhibit oxidative stress and p38 MAPK phosphorylation, enhancing Schwann cell proliferation and peripheral nerve regeneration.

Current models characterize pain as a multifactorial process involving oxidative stress-mediated neural cascades. Mitochondrial dysfunction from Ca²⁺-induced ROS generation is central to nociceptive processing. Selenium’s therapeutic potential arises from its dual role in GPx activation and selenoprotein synthesis, mitigating oxidative damage in chronic pain [47]. Altuhafi et al. [48] delineated oxidative stress mechanisms in type 2 diabetes mellitus (T2DM) pathogenesis, where chronic hyperglycemia drives free radical production via glucose autoxidation and impairs antioxidant systems. This redox imbalance causes cellular organelle damage, elevated lipid peroxidation, and insulin resistance [49].

Diabetic metabolic dysregulation increases mitochondrial ROS in pancreatic $\beta$-cells while suppressing GPx activity [50]. Persistent hyperglycemia elevates superoxide production [45], with organic hydroperoxide accumulation correlating with membrane pathophysiology and diabetic complications. Clinical data show inverse correlations between lipid peroxidation biomarkers and erythrocyte GPx activity in diabetics [51]. Multiple studies document compromised selenium status in diabetic populations. Altuhafi’s work [48] identifies positive correlations between serum selenium concentrations and GPx activity, suggesting that selenoprotein deficiency exacerbates pro-oxidative states, thereby accelerating complications. Systemic antioxidant depletion in diabetes reflects profound redox dysregulation, where chronic ROS overproduction impairs defense mechanisms, creating a self-perpetuating cycle of oxidative damage. This underscores the importance of therapeutic strategies targeting selenium-dependent antioxidant pathways in diabetes management.

Huo et al. [52] conducted a meta-analysis of 14 randomized controlled trials (n = 1384 participants) investigating nutraceutical interventions for DPN. Their systematic review identified three high-quality trials demonstrating that vitamin and antioxidant supplementation significantly enhanced sural nerve sensory nerve conduction velocity (SNCV). Furthermore, pooled data from seven trials (n = 758) suggested improved peroneal nerve motor nerve conduction velocity (MNCV), while four studies reported analogous enhancements in median nerve MNCV. These findings align empirically with our observations regarding selenium’s capacity to mitigate DPN severity. Complementary mechanistic evidence emerges from Aydın and Nazıroğlu [53], who demonstrated that streptozotocin (STZ)-induced TRPM7 channel activation exacerbates neuropathic pain and apoptotic pathways in murine models. Crucially, selenium administration attenuated TRPM7-mediated neurotoxicity, mirroring our findings of selenium’s neuroprotective efficacy. Jafari et al. [54] further corroborated this therapeutic potential through in vitro experiments showing that selenium co-treatment significantly reduced vincristine-induced cytotoxicity in PC12 neuronal cells (p 0.01 vs. vincristine-only controls).

Ayaz and Kaptan [30] provided electrophysiological evidence that sodium selenite intervention ameliorates diabetes-induced neural conduction abnormalities, including prolonged signal transmission latency, increased action potential amplitude (32% vs. diabetic controls), and restoration of fast/slow fiber conduction velocity distributions to age-matched normative ranges. These data synergize with Xu et al.’s clinical correlation analysis [29], which identified low selenium status as an independent risk factor for diabetic polyneuropathy progression in type 2 diabetes cohorts. At the molecular level, Nazıroğlu et al. [47] postulated that selenium’s antinociceptive mechanism involves TRP channel modulation in dorsal root ganglia, potentially disrupting nociceptive signaling cascades. Collectively, these multidisciplinary findings substantiate selenium’s dual role as both a redox modulator and ion channel regulator in diabetic neuropathy pathogenesis, providing mechanistic context for its observed clinical benefits in DPN management.

Teimouri et al. [55] conducted a double-blind, randomized, placebo-controlled clinical trial to investigate the therapeutic efficacy of selenium supplementation on psychosexual outcomes. Their findings demonstrated clinically significant amelioration of core premature ejaculation symptomatology in the intervention group compared to placebo controls (p 0.05), with particular improvements observed in sexual satisfaction metrics. The intervention demonstrated favorable tolerability profiles, with adverse event incidence comparable to placebo. This empirical evidence substantiates the therapeutic potential of selenium in addressing sexual dysfunction parameters, particularly through modulation of ejaculatory latency mechanisms. These findings exhibit notable congruence with our experimental observations regarding selenium’s putative role in enhancing psychosexual outcomes via redox homeostasis regulation and neurotransmitter modulation pathways. However, the research by Rahimi et al. [38], which reported results contrary to our findings, stated that no significant difference in sexual satisfaction was observed in the groups consuming selenium compared to the placebo at the end of the intervention [Improved flow and conciseness]. Given that the drug dose and selenium (selenoprotein) composition were identical in both studies, the discrepancy may relate to differences in treatment duration and participant characteristics, as Rahimi et al.’s study [38] included postpartum women without diabetes.

One of the limitations of our study was the restricted sample size, which future research should address through larger cohorts. A key strength was the triple-blind design, enhancing methodological rigor. Additional strengths included standardized examinations performed by an experienced specialist, precise follow-up timing to ensure timely patient referrals, and the use of organic selenium with high bioavailability and lower toxicity. However, the absence of speciation analysis introduces uncertainty regarding the supplement’s composition and bioactivity, necessitating such analyses in future trials to clarify bioavailability and therapeutic efficacy. Larger studies should also characterize selenium species and investigate dose-response relationships. This study did not evaluate key inflammatory biomarkers, such as IL-6, IL-8, and TNF-$\alpha$, in either serum or tissue samples. Considering the established association between chronic inflammation and the progression of DPN, the inclusion of such biomarkers in future investigations would substantiate mechanistic interpretations. Therefore, it is recommended that subsequent research incorporate these analyses. Furthermore, the results cannot be generalized to patients with type 1 diabetes or those with metabolic instability or unstable antidiabetic regimens.

The 8-week intervention yielded significant therapeutic outcomes across both groups. Post-treatment evaluation revealed clinically meaningful reductions in MNSI scores for both groups, though intergroup comparisons showed no statistically significant differential effect. Neuropathic severity assessments using the TCSS demonstrated a 38% baseline-to-post-intervention score reduction exclusively in the selenium group. Psychosexual outcomes diverged markedly between groups: placebo recipients exhibited a progressive decline in sexual satisfaction metrics to subclinical thresholds by week 8, whereas the selenium group maintained baseline satisfaction levels, achieving statistically superior terminal scores. Selenium supplementation also significantly reduced the PAB index. These findings suggest that selenium may simultaneously mitigate neuropathic progression and preserve sexual function in diabetic populations, though its therapeutic effect on neuropathy outcomes requires further investigation through larger trials with speciation analysis, extended durations, and dose-response characterization.

The datasets supporting this study’s findings are available from corresponding author per request.

MG and AFK were responsible for drafting the protocol, data collection, data analysis, and interpretation and writing of the final manuscript. MM was responsible for drafting the protocol, project administration, data analysis and interpretation, and editing the final version of the manuscript. SGR, PBM and AO were involved in the acquisition of data and critically reviewed the manuscript for intellectual content. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Ethical approval was obtained from the Research Ethics Committee of Tabriz University of Medical Sciences (IR.TBZMED.REC.1401.374). Researchers ensured protocol adherence through institutional authorization and strict compliance with the Declaration of Helsinki (1964) and its subsequent amendments. Prior to the intervention, participants received full disclosure of the study objectives, methodologies, potential risks/benefits, and withdrawal rights through direct researcher communication, followed by the acquisition of written informed consent. This trial was registered at the Iranian Registry of Clinical Trials (IRCT20131009014957N10, https://trialsearch.who.int/Trial2.aspx?TrialID=IRCT20131009014957N10).

The Vice-Chancellor for Research and Technology, Tabriz University of Medical Sciences has funded the original research (Grant No: 69271).

The authors declare no conflict of interest.

The authors utilized DeepSeek (DeepSeek-V3) for scientific English language editing to improve the clarity and grammar of this manuscript. Following AI-assisted editing, the authors thoroughly reviewed and edited the content as needed and take full responsibility for the published work.