{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T19:17:27Z","timestamp":1781119047266,"version":"3.54.1"},"reference-count":65,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Centre, Poland","award":["grant no. 2018\/29\/N\/NZ4\/00616"],"award-info":[{"award-number":["grant no. 2018\/29\/N\/NZ4\/00616"]}]},{"name":"Mossakowski Medical Research Institute","award":["MMRI statutory budget theme no.7."],"award-info":[{"award-number":["MMRI statutory budget theme no.7."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Type 2 diabetes mellitus (T2DM) is a chronic disease that has become a serious health problem worldwide. Moreover, increased systemic and cerebrovascular inflammation is one of the major pathophysiological features of T2DM, and a growing body of evidence emphasizes T2DM with memory and executive function decline. Bioactive sphingolipids regulate a cell\u2019s survival, inflammatory response, as well as glucose and insulin signaling\/metabolism. Moreover, current research on the role of sphingosine kinases (SPHKs) and sphingosine-1-phosphate receptors (S1PRs) in T2DM is not fully understood, and the results obtained often differ. The aim of the present study was to evaluate the effect of metformin (anti-diabetic agent, MET) on the brain\u2019s sphingosine-1-phosphate-related signaling and ultrastructure in diabetic mice. Our results revealed elevated mRNA levels of genes encoding sphingosine kinase 2 (SPHK2) and sphingosine-1-phosphate receptor 3 (S1PR3), which was accompanied by downregulation of sphingosine-1-phosphate receptor 1 (S1PR1) in the hippocampus of diabetic mice. Simultaneously, upregulation of genes encoding pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor \u03b1 (TNF-\u03b1) was observed. Administration of MET significantly reversed changes in mRNA levels in the hippocampus and reduced Sphk2, Il6, and Tnf, with concomitant upregulation of S1pr1 gene expression. Ultrastructural analysis of diabetic mice hippocampus revealed morphological alterations in neurons, neuropil, and capillaries that were manifested as mitochondria swelling, blurred synaptic structure, and thickened basal membrane of capillaries. The use of MET partially reversed those changes. Our research emphasizes the important role of insulin sensitivity modulation by metformin in the regulation of SPHKs and S1PRs and inflammatory gene expression in a murine model of T2DM.<\/jats:p>","DOI":"10.3390\/ijms26199832","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:50:16Z","timestamp":1760107816000},"page":"9832","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Metformin Induces Changes in Sphingosine-1-Phosphate-Related Signaling in Diabetic Mice Brain"],"prefix":"10.3390","volume":"26","author":[{"given":"Przemys\u0142aw Leonard","family":"Wencel","sequence":"first","affiliation":[{"name":"Laboratory of Preclinical Research and Environmental Agents, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kinga","family":"Czubowicz","sequence":"additional","affiliation":[{"name":"Laboratory of Preclinical Research and Environmental Agents, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7409-1799","authenticated-orcid":false,"given":"Magdalena","family":"Gewartowska","sequence":"additional","affiliation":[{"name":"Electron Microscopy Research Unit, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u0142gorzata","family":"Frontczak-Baniewicz","sequence":"additional","affiliation":[{"name":"Electron Microscopy Research Unit, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert Piotr","family":"Strosznajder","sequence":"additional","affiliation":[{"name":"Laboratory of Preclinical Research and Environmental Agents, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"ref_1","unstructured":"Emerging Risk Factors Collaboration (2023). 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