{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T02:35:26Z","timestamp":1783823726511,"version":"3.55.0"},"reference-count":37,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,4,3]],"date-time":"2020-04-03T00:00:00Z","timestamp":1585872000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Basic Clin Pharma Tox"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Naringenin possesses many pharmacological effects and may modulate metformin disposition. The purpose of this study was to evaluate the role of naringenin on hepatic expression of organic cation transporter 1 (OCT1) protein and its associated effects on metformin\u2010associated hyperlactataemia in diabetes. Forty\u2010nine male Sprague Dawley rats randomly assigned to seven groups (n\u00a0=\u00a07) were orally treated daily with 3.0\u00a0mL\/kg body\u2010weight (BW) of distilled water (group 1) or 60\u00a0mg\/kg BW of naringenin (groups 2 and 5) or 250\u00a0mg\/kg BW of metformin (groups 3 and 6), respectively, dissolved in distilled water. Similarly, group 7 was given metformin and naringenin. Groups 4, 5, 6 and 7 were administered intraperitoneally with streptozotocin at a single dose of 60\u00a0mg\/kg BW to induce diabetes. Glucose tolerance tests were performed. The animals were killed after 8\u00a0weeks of treatment, blood was collected, and livers excised for further biochemical analysis. Lowered body\u2010weight, increased polydipsia and reduced hepatic glycogen concentrations were observed in diabetic rats compared to controls. Naringenin only significantly decreased plasma lactate levels, while metformin only or with naringenin significantly increased plasma lactate levels in diabetic compared to non\u2010treated diabetic animals. Metformin only but not naringenin significantly increased plasma lactate levels in non\u2010diabetic compared to control rats. Furthermore, naringenin with or without metformin but not metformin only significantly increased hepatic organic cation transporter 1 (OCT1) expression in diabetic compared to non\u2010treated diabetic rats. Contrastingly, metformin only but not naringenin significantly increased hepatic OCT1 expression in non\u2010diabetic rats compared to controls. Diabetic rats treated with metformin exhibited significantly increased plasma metformin concentrations compared to non\u2010diabetic but naringenin significantly dropped this parameter. Conversely, hepatic metformin concentrations were significantly lower in diabetic rats treated with metformin compared to non\u2010diabetic rats but significantly increased when naringenin was added. These results suggest that naringenin ameliorated hyperglycaemia\u2010induced reduction in hepatic OCT1 expression leading to metformin accumulation and increased lactic acid production.<\/jats:p>","DOI":"10.1111\/bcpt.13407","type":"journal-article","created":{"date-parts":[[2020,3,17]],"date-time":"2020-03-17T06:59:41Z","timestamp":1584428381000},"page":"211-220","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Citrus fruit\u2010derived flavonoid naringenin and the expression of hepatic organic cation transporter 1 protein in diabetic rats treated with metformin"],"prefix":"10.1111","volume":"127","author":[{"given":"Edith P.","family":"Mato Mofo","sequence":"first","affiliation":[{"name":"Molecular and Clinical Pharmacology Research Laboratory Department of Pharmacology Discipline of Pharmaceutical Sciences School of Health Sciences University of KwaZulu\u2010Natal Durban South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Faadiel","family":"Essop","sequence":"additional","affiliation":[{"name":"Cardio\u2010Metabolic Research Group (CMRG) Department of Physiological Sciences Stellenbosch University Stellenbosch South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter M. O.","family":"Owira","sequence":"additional","affiliation":[{"name":"Molecular and Clinical Pharmacology Research Laboratory Department of Pharmacology Discipline of Pharmaceutical Sciences School of Health Sciences University of KwaZulu\u2010Natal Durban South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,4,3]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2014.15298"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199602293340906"},{"key":"e_1_2_9_4_1","first-page":"CD002967","article-title":"Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus","volume":"1","author":"Salpeter SR","year":"2010","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.7326\/M16-1901"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jemermed.2007.11.055"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.1992.00400230129023"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI30558"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.49.32776"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.2217\/14622416.9.4.415"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.63.4.844"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.701"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/134.12.3479S"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4615-1833-4_25"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/jsfa.3959"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2016.08.014"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2016.02.019"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/83.5.1097"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270009342251"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1067\/mcp.2002.121152"},{"issue":"9","key":"e_1_2_9_21_1","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1358\/mf.2009.31.9.1435463","article-title":"Grapefruit juice improves glycemic control but exacerbates metformin\u2010induced lactic acidosis in non\u2010diabetic rats","volume":"31","author":"Owira PM","year":"2009","journal-title":"Methods Find Exp Clin Pharmacol"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.13059"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2005.04.006"},{"issue":"1","key":"e_1_2_9_24_1","first-page":"191","article-title":"The estimation of glycogen with the anthrone reagent","volume":"25","author":"Seifter S","year":"1950","journal-title":"Arch Biochem"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1134\/S1061934816080037"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(76)90527-3"},{"issue":"4","key":"e_1_2_9_27_1","first-page":"398","article-title":"Metformin\u2010associated lactic acidosis: case reports and literature review","volume":"15","author":"Chang CT","year":"2002","journal-title":"J Nephrol"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1159\/000323739"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-007-0886-7"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2017.03.042"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1097\/FJC.0b013e31823827a4"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.2174\/1568026615666141209163013"},{"key":"e_1_2_9_33_1","first-page":"69","article-title":"How does insulin stimulate glycogen synthesis?","volume":"43","author":"Cohen P","year":"1978","journal-title":"Biochem Soc Symp"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(88)90617-X"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/bjaceaccp\/mkl018"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.1.223"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3480607"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2008.08.013"}],"container-title":["Basic &amp; 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