{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T23:25:15Z","timestamp":1791329115794,"version":"4.3.1"},"reference-count":36,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deanship of Scientific Research at Imam Mohammad Ibn Saud Islamic University","award":["IMSIU-DDRSP2601"],"award-info":[{"award-number":["IMSIU-DDRSP2601"]}]},{"award":["IMSIU-DDRSP2601"],"award-info":[{"award-number":["IMSIU-DDRSP2601"]}],"id":[{"id":"https:\/\/ror.org\/05gxjyb39","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Diabetic neuropathy (DN) is a multifactorial complication of diabetes mellitus driven by chronic hyperglycemia, insulin resistance, and disturbed metabolic homeostasis, leading to progressive injury of both the peripheral and central nervous systems. This study investigated whether L-serine supplementation could attenuate DN through dose-dependent metabolic and neuroprotective mechanisms in a high-fat diet (HFD) plus streptozotocin (STZ)-induced diabetic rat model. Male Wistar rats (n = 8 per group) were allocated to five groups: normal control (NC), diabetic control (DC), pioglitazone (PIO; 1.5 mg\/kg\/day), low-dose L-serine (S1; 200 mg\/kg\/day), and high-dose L-serine (S2; 400 mg\/kg\/day). After 60 days of oral gavage, behavioural testing, glucose and insulin profiling, HOMA-IR calculation, brain histopathology, nerve growth factor (NGF) immunohistochemistry, and LC\u2013MS\/MS-based proteomic analysis of cerebral tissue were performed. Diabetic rats exhibited marked hyperglycaemia (355.33 \u00b1 4.72 mg\/dL), hyperinsulinaemia, severe insulin resistance (HOMA-IR 16.8 \u00b1 3.2; a 14-fold increase), impaired thermal nociception, motor dysfunction, and pronounced neuronal degeneration. L-serine supplementation significantly improved metabolic status: S1 reduced HOMA-IR by 77.4% and S2 by 87.5% relative to diabetic controls (p &lt; 0.001). High-dose L-serine produced greater improvements in thermal sensitivity, motor coordination (rotarod latency 26.67 \u00b1 1.52 s vs. 16.1 \u00b1 0.85 s in DC; p &lt; 0.05), and NGF expression (8.6-fold increase vs. DC). Histopathology confirmed attenuation of neuronal injury and gliosis in both treatment groups. Exploratory, group-level proteomic profiling identified dose-specific molecular signatures: S1 was predominantly associated with carbohydrate, lipid, and biosynthetic pathways, whereas S2 was associated with synaptic, neurotransmission-related, and proteostasis pathways. Within the constraints of an exploratory design\u2014group-level pooled proteomics, analysis of cerebral rather than peripheral-nerve tissue, and only two doses\u2014these findings indicate that L-serine attenuates the metabolic and behavioural features of experimental diabetic neuropathy and generates the testable hypothesis of dose-dependent neuro-metabolic remodelling. The proteomic signatures are hypothesis-generating and require orthogonal validation before any mechanistic or translational inference can be drawn.<\/jats:p>","DOI":"10.3390\/biom16060881","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:49:42Z","timestamp":1781743782000},"page":"881","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["L-Serine Attenuates Metabolic and Behavioural Features of Diabetic Neuropathy with Dose-Dependent Central Proteomic Correlates in a Rat Model"],"prefix":"10.3390","volume":"16","author":[{"given":"Menna","family":"Hamdy","sequence":"first","affiliation":[{"name":"Department of Pharmacology & Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3412-4138","authenticated-orcid":false,"given":"Dina M.","family":"Khodeer","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13317, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayada E.","family":"Elsakka","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Faculty of Physical Therapy, Horus University\u2014Egypt, New Damietta 34517, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2015-9161","authenticated-orcid":false,"given":"Ali M.","family":"Alaseem","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13317, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasser M.","family":"Mostafa","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt"},{"name":"Department of Pharmacology & Toxicology, Faculty of Pharmacy, Badr University in Cairo, Cairo 11829, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4171-9850","authenticated-orcid":false,"given":"Afaf","family":"Alharthi","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2494-6004","authenticated-orcid":false,"given":"Mohammad","family":"El-Nablaway","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh 13713, Saudi Arabia"},{"name":"Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3582-0562","authenticated-orcid":false,"given":"Mohamed M.","family":"Tawfik","sequence":"additional","affiliation":[{"name":"Zoology Department, Faculty of Science, Port Said University, Port Said 42526, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"505","DOI":"10.7861\/clinmedicine.10-5-505","article-title":"Microvascular complications: Pathophysiology and management","volume":"10","author":"Vithian","year":"2010","journal-title":"Clin. 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