{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:27:09Z","timestamp":1768508829245,"version":"3.49.0"},"reference-count":80,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T00:00:00Z","timestamp":1767916800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background: Uncontrolled diabetes is characterised by a loss of blood glucose control and increased oxidation of fatty acids to produce ATP. Use of metabolic inhibitors to blunt fatty acid oxidation and restore glucose metabolism is a poorly studied intervention for diabetes. Methods: Steptozotocin-induced diabetes was developed in Wistar male rats. A subset was supplemented with mildronate (100 mg\/kg\u201414 days). Exploiting liquid chromatography-mass spectrometry for workflows including ion exchange-, C18-reverse phase- and HILIC-based chromatography methods, metabolite levels were quantified in plasma liver and brain tissue. Using both untargeted and targeted metabolomic analysis changes to the global tissue metabolome and individual metabolic pathways were estimated. Results: We document that an inhibitor of carnitine synthesis, mildronate, decreased plasma (50% p &lt; 0.01) carnitine abundance and decreased plasma glucose concentration by one-third compared to streptozotocin (STZ)-treated rats (p &lt; 0.001). Targeted metabolomic analysis of the liver showed decreased alpha-ketoglutarate abundance (35% p &lt; 0.05) by STZ diabetes that was further decreased following mildronate treatment (50% p &lt; 0.05). For both beta-hydroxybutyrate and succinate levels, STZ diabetes increased hepatic abundance by 50% (p &lt; 0.05 for both), which was restored to control levels by mildronate (p &lt; 0.05 for both). In contrast, brain TCA intermediate abundances were unaffected by either STZ diabetes or mildronate (NS for all). STZ diabetes also decreased abundance of pentose phosphate pathway (PPP) metabolites in the liver (glucose-6-phosphate, 6-phosphogluconolactone, 6-phosphogluconate 50% for all; p &lt; 0.05), which was not restored by mildronate treatment. However, brain PPP metabolite abundance was unchanged by STZ diabetes or mildronate (NS for all). However, mildronate treatment did not affect the increased abundance of brain sorbitol, sorbitol-6-phosphate and glucose-6-phosphate as a result of STZ diabetes. Conclusions: Together, these observations highlight the potential role that metabolic inhibitors, like mildronate, may play in restoring blood glucose for diabetic patients, without a direct effect of tissues that represent obligate consumers of glucose (e.g., brain) whilst manipulating fat oxidation in tissues such as the liver.<\/jats:p>","DOI":"10.3390\/metabo16010061","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T12:52:17Z","timestamp":1767963137000},"page":"61","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Changes in the Metabolome of Different Tissues in Response to Streptozotocin Diabetes and Mildronate Exposure: A Metabolomic Assessment"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3139-7357","authenticated-orcid":false,"given":"David","family":"Hauton","sequence":"first","affiliation":[{"name":"Chemistry Research Laboratory, Metabolomics Research Group, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK"},{"name":"Department of Physiology, Anatomy & Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK"},{"name":"Faculty of Life Sciences, University of Bath, Claverton Down, Bath BA2 7AY, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dragana","family":"Savic","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy & Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK"},{"name":"Oxford Centre for Clinical Magnetic Resonance (OCCMR), Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1287-9580","authenticated-orcid":false,"given":"John","family":"Walsby-Tickle","sequence":"additional","affiliation":[{"name":"Chemistry Research Laboratory, Metabolomics Research Group, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0780-8905","authenticated-orcid":false,"given":"Damian","family":"Tyler","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy & Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK"},{"name":"Oxford Centre for Clinical Magnetic Resonance (OCCMR), Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4733-1205","authenticated-orcid":false,"given":"James S. O.","family":"McCullagh","sequence":"additional","affiliation":[{"name":"Chemistry Research Laboratory, Metabolomics Research Group, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17016","DOI":"10.1038\/nrdp.2017.16","article-title":"Type 1 diabetes mellitus","volume":"3","author":"Katsarou","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"15","DOI":"10.4093\/dmj.2021.0280","article-title":"Insulin resistance: From mechanisms to therapeutic strategies","volume":"46","author":"Lee","year":"2022","journal-title":"Diabetes Metab. 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