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Vildagliptin (Vilda) is dipeptidyl peptidase-4 inhibitor approved as oral antidiabetic agent. Docosahexaenoic (DHA) could attenuate hyperglycemia and insulin resistance. The current study was conducted to evaluate the effect of DHA\n                    <jats:italic>versus<\/jats:italic>\n                    Vilda on insulin resistance and hyperglycemia in type 2 diabetes (T2D) rat model\n                    <jats:italic>via<\/jats:italic>\n                    SIRT1\/Akt\/PI3K. Eighty male Wistar rats were divided into five groups: normal control, diabetes control (the diabetic rats fed high carbohydrate\u2013high fat diet for four weeks, followed by a single intraperitoneal injection of 35\u00a0mg\/kg streptozotocin, Vilda\u2009+\u2009diabetic (diabetic rats received 6\u00a0mg\/kg vildagliptin), DHA\u2009+\u2009diabetic (diabetic rats received 300\u00a0mg\/kg DHA), and DHA only group (normal non-diabetic rats received 300\u00a0mg\/kg DHA). All treatments were given orally for 4\u00a0weeks. Each of Vilda and DHA significantly (p\u2009&lt;\u20090.001) decreased blood glucose (131.40.\u2009\u00b1\u20096.10\u00a0mg\/L and 137.10\u2009\u00b1\u20097.37, respectively\n                    <jats:italic>vs<\/jats:italic>\n                    . 449.9\u2009\u00b146.28\u20091.84\u00a0mg\/L), increased insulin levels (7.77\u2009\u00b10.26\u2009 \u00b5IU\/mL and 7.56\u2009\u00b1\u20090.42, respectively\n                    <jats:italic>vs.<\/jats:italic>\n                    3.86\u2009\u00b1\u00a00.37\u2009),  decreased HOMA-IR (2.52\u2009\u00b1\u20090.09 and 2.55\u2009\u00b1\u20090.091, respectively\n                    <jats:italic>vs.<\/jats:italic>\n                    4.26\u2009\u00b1\u20090.34),\u00a0 \u00a0decreased pancreatic malondialdehyde (MDA) (3.84\u2009\u00b1\u20090.29 nmol\/mg protein and 3.18\u2009\u00b1\u20090.21, respectively\n                    <jats:italic>vs.<\/jats:italic>\n                    6.65\u2009\u00b1\u20090.71), increased gluthathione\u00a0(2.18\u00b10.11\u03bcmol\/mg protein and 2.51\u00b10.09, respectively\n                    <jats:italic>vs<\/jats:italic>\n                    . 1.00\u00b10.29), catalase (104.50\u00b16.74 nmol\/mg protein and 122.30\u00b16.20, respectively\n                    <jats:italic>vs.<\/jats:italic>\n                    70.30\u00b113.98),\u00a0increased glutathione peroxidase activity (GPx) (0.76\u00b10.19\u00a0U\/mg protein and 0.99\u00b10.16, respectively\n                    <jats:italic>vs.<\/jats:italic>\n                    0.47\u00b1 0.14) and increased superoxide dismutase activity\u00a0(SOD) (6.43\u00b11.15\u00a0U\/mg protein and 8.13\u00b11.16, respectively\n                    <jats:italic>vs.<\/jats:italic>\n                    3.98\u00b11.4) compared with diabetic group. DHA &amp; Vilda significantly (p\u2009&lt;\u20090.001) improved lipid profile (total cholesterol, triglycerides, LDL-C &amp; HDL-C). DHA was superior to Vilda in increasing levels of glutathione (2.51\u2009\u00b1\u20090.09 \u00b5mol\/mg protein\n                    <jats:italic>vs.<\/jats:italic>\n                    2.18\u2009\u00b1\u20090.11),  catalase activity (122.30\u2009\u00b1\u20096.20 nmol\/mg protein\n                    <jats:italic>vs.<\/jats:italic>\n                    104.50\u2009\u00b1\u20096.74 ), SOD activity (8.13\u00b11.16 U\/mg\n                    <jats:italic>vs.<\/jats:italic>\n                    6.43\u00b11.15)\u00a0and GPx activity (0.99\u00b10.16 U\/mg protein\n                    <jats:italic>vs<\/jats:italic>\n                    . 0.76\u00b10.19). Moreover, both Vilda and DHA significantly increase gene expression of SIRT1, Akt, and PI3K and markedly restored normal pancreatic tissue architecture compared with diabetic control group. DHA was comparable to Vilda as insulinotropic and anti-hyperglycemic agent in T2D rats via activation of SIRT1\/Akt\/PI3K pathway &amp; reducing oxidative stress.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-44514-4","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T10:38:29Z","timestamp":1776422309000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Docosahexaenoic acid is comparable to vildagliptin in improving hyperglycemia and pancreatic insulin signaling of diabetic rats via SIRT1\/Akt\/PI3K pathway"],"prefix":"10.1038","volume":"16","author":[{"given":"Mariam A.","family":"Abo-Saif","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5983-3993","authenticated-orcid":false,"given":"Rehab H.","family":"Werida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salma Ashraf","family":"Mohamed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4539-8940","authenticated-orcid":false,"given":"Naglaa F.","family":"Khedr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"44514_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2021.109119","volume":"183","author":"H Sun","year":"2022","unstructured":"Sun, H. et al. 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