**Background:** Type 2 diabetes mellitus (T2DM) is a growing global health burden, affecting 536.6 million people in 2021, projected to rise 46% by 2045. Chronic hyperglycaemia drives oxidative stress and macrovascular/microvascular complications (neuropathy, retinopathy, nephropathy, ulceration). Emerging evidence implicates gut microbiota dysbiosis — specifically a shift toward gram-negative bacteria and increased Firmicutes/Bacteroidetes ratio — in promoting inflammatory cascades, insulin resistance, and metabolic endotoxaemia via lipopolysaccharide (LPS) translocation. Functional foods with prebiotic and polyphenolic properties may simultaneously modulate inflammation, oxidative stress, and gut health. Date seeds (Phoenix dactylifera), a byproduct of date processing, are rich in polyphenols (hesperidin, quercetin, kaempferol), phenolic acids, carotenoids, dietary fibre (pectin, β-glucan, arabinoxylan), fat, protein, and minerals. The maximum tolerated dose is 0.5 g/kg/day. Prior animal and limited human studies suggest date seed improves hyperglycaemia, inflammation, oxidative stress, and hyperlipidaemia, but no trial has examined its effects specifically in T2DM patients.
**Methods:** This is a randomised, triple-blind, placebo-controlled trial conducted at Afzalipour Hospital and other clinics in Kerman, Iran. Forty-eight patients with T2DM (FPG ≥126 mg/dL, age 30–50 years, BMI 25–35, no insulin therapy, ≥6 months diabetes duration) will be recruited. Exclusion criteria include insulin use, antidepressants/amphetamines/oral steroids, antioxidant supplements within 3 months, weight change >5–7% in 3 months, special/low-calorie diet in 6 months, thyroid/heart/kidney/liver/lung disorders, infections, digestive problems, cancers, alcohol/smoking, pregnancy, lactation, athletic status, or strenuous physical activity. After a 2-week run-in period for diet stabilisation, participants are randomised 1:1 (n=24 per group) via stratified randomisation (age, gender, BMI) with random block sizes 2 and 4. The intervention group receives 5 g/day DSP (2.5 g at breakfast and 2.5 g at dinner) for 8 weeks; the placebo group receives identical maltodextrin powder. Both powders are odourless, flavourless, and provided in identical opaque packages. Compliance is monitored via twice-weekly contact, checklists, and package counting (>10% non-compliance leads to exclusion). Sample size was calculated based on HDL change from Jubayer et al. (mean difference 6.2 mg/dL), requiring 22 per group for 80% power at 95% confidence; increased to 24 per group to account for 10% dropout. At baseline and 8 weeks, fasting blood samples (10 mL) are collected. Biochemical assays include enzymatic colorimetric methods (FPG, TG, TC, HDL, uric acid, hs-CRP), Friedewald LDL calculation, ELISA (LPS, fructosamine, TOS, TNF-α, IL-4, IL-6, IL-10, IL-18, pentosidine, CML, sRAGE, 8-iso-PGF2α, BDNF, cortisol, TRP, KYN, ACTH, leptin, adiponectin), flow cytometry (CD4, CD8), HPLC (HbA1c), chemiluminescent immunoassay (insulin), colorimetric methods (GSH-Px, SOD, TAC), thiobarbituric acid spectrofluorometry (MDA), and the Aebi method (CAT). Derived indices include OSI = 100×(TOS/TAC), HOMA-IR, and QUICKI. Anthropometrics (weight, height, waist/hip/neck circumference, BMI), blood pressure (mean of 3 readings after 30 min rest), dietary intake (3-day food diary analysed by Nutritionist 4), physical activity (IPAQ Short-Form), and mental health (DASS with 14 items across depression/anxiety/stress subscales; 28-item GHQ covering somatic symptoms, anxiety, insomnia, social dysfunction, severe depression) are assessed at baseline and post-intervention. Data are analysed using SPSS V.16.0 with intention-to-treat. Normality is tested via Kolmogorov-Smirnov. Baseline comparisons use χ² and unpaired t-tests. Post-intervention between-group comparisons use ANCOVA; within-group use paired t-tests. Log transformation is applied for non-normal data. Significance threshold is p<0.05.
**Key Results:** This is a protocol paper; no results are yet available. The study is currently recruiting participants (protocol version dated 25 May 2022). The primary outcomes span glycaemic indices (FBG, HbA1c, fructosamine, insulin), lipid profile (TC, HDL, LDL, TG), inflammatory markers (hs-CRP, TNF-α, IL-6, IL-4, IL-18, IL-10), metabolic endotoxaemia (LPS), oxidative stress (TAC, MDA, OSI, TOS, SOD, GSH-Px, CAT, sRAGE, CML, pentosidine, 8-iso-PGF2α, uric acid, protein carbonyl, NO), and 8-OH-G. Secondary outcomes include anthropometrics, blood pressure, dietary intake, HPA axis biomarkers (cortisol, ACTH), neurotrophins (BDNF), tryptophan/kynurenine pathway, immune markers (CD4, CD8), adipokines (leptin, adiponectin), and mental health.
**Clinical Implications:** If DSP supplementation demonstrates improvements in glycaemic control, lipid profile, oxidative stress, inflammation, metabolic endotoxaemia, and mental health, it could provide an inexpensive, accessible, adjunctive dietary strategy for managing T2DM complications. The prebiotic fibre and polyphenol content of date seeds may act through multiple mechanisms: scavenging free radicals, inhibiting lipid peroxidation, suppressing nuclear factor-κB, reducing NO production, modulating mitogen-activated protein kinases and nuclear factor erythroid-related factor 2, and shifting gut microbiota toward beneficial bacteria (Lactobacillus, Bifidobacterium) while reducing pathogenic Clostridium. As the first trial of date seed in T2DM, results will inform evidence-based recommendations for clinicians, nutritionists, and patients. The study is approved by the Ethical Committee of Tabriz University of Medical Sciences (IR.TBZMED.REC.1400.752) and registered at Iranian Registry of Clinical Trials (IRCT20150205020965N10).