{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T23:56:56Z","timestamp":1779926216161,"version":"3.53.1"},"reference-count":42,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,2,23]],"date-time":"2025-02-23T00:00:00Z","timestamp":1740268800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003712","name":"Korea Food Research Institute","doi-asserted-by":"publisher","award":["E0210203"],"award-info":[{"award-number":["E0210203"]}],"id":[{"id":"10.13039\/501100003712","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003712","name":"Korea Food Research Institute","doi-asserted-by":"publisher","award":["E0210601"],"award-info":[{"award-number":["E0210601"]}],"id":[{"id":"10.13039\/501100003712","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Insulin resistance (IR) disrupts hepatic glucose metabolism and mitochondrial function, which contributes to metabolic disorders. The present study examined the effects of tomatine on glucose metabolism in high-glucose-induced IR hepatocytes and explored its underlying mechanisms using AML12 and HepG2 cell models. The results showed that tomatine did not exhibit cytotoxic effects. Under IR conditions, tomatine dose-dependently improved glucose metabolism by enhancing glucose consumption and restoring the mRNA expression of the glucose transporter Glut2 and gluconeogenesis-related genes (Pepck and G6pase). Mechanistically, tomatine activated the phosphorylation of AMP-activated protein kinase (AMPK) and upregulated the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1\u03b1), reversing the IR-induced suppression of the AMPK\/PGC1\u03b1 pathway. In addition, tomatine enhanced mitochondrial oxidative function by restoring the oxygen consumption rate, increasing ATP production, and upregulating mitochondrial oxidative phosphorylation complex proteins. Both genetic and pharmacological inhibition of AMPK abolished these beneficial effects, confirming its central role in mediating tomatine\u2019s actions. Overall, our findings suggest that tomatine is a promising therapeutic candidate for enhancing hepatic glucose metabolism and mitochondrial function in IR-associated metabolic disorders through AMPK activation.<\/jats:p>","DOI":"10.3390\/cells14050329","type":"journal-article","created":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T07:46:57Z","timestamp":1740383217000},"page":"329","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Tomatine Improves Glucose Metabolism and Mitochondrial Respiration in Insulin-Resistant Hepatocyte Cell Lines AML12 and HepG2 via an AMP-Activated Protein Kinase-Dependent Pathway"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0501-8930","authenticated-orcid":false,"given":"Yu Geon","family":"Lee","sequence":"first","affiliation":[{"name":"Food Functionality Research Division, Korea Food Research Institute (KFRI), Wanju-gun 55365, Jeonbuk-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0139-2494","authenticated-orcid":false,"given":"Donghwan","family":"Kim","sequence":"additional","affiliation":[{"name":"Food Functionality Research Division, Korea Food Research Institute (KFRI), Wanju-gun 55365, Jeonbuk-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3611","DOI":"10.2147\/DMSO.S275898","article-title":"Obesity, insulin resistance, and type 2 diabetes: Associations and therapeutic implications","volume":"13","author":"Wondmkun","year":"2020","journal-title":"Diabetes Metab. 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