{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T11:03:20Z","timestamp":1784286200264,"version":"3.55.0"},"reference-count":63,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PRIMA Program","award":["CUP D33C22002150007"],"award-info":[{"award-number":["CUP D33C22002150007"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Insulin resistance (IR) is the underlying pathogenic mechanism for Type 2 Diabetes Mellitus, which is interconnected with Fatty Liver Disease. To investigate the molecular mechanisms by which different metabolic triggers contribute to hepatic IR onset, we exposed human HepG2 hepatocytes to varying glucose concentrations (25\u201350 mM), and\/or insulin (1 nM), and a free fatty acid mixture (0.3 mM), mimicking moderate or severe hyperglycemia, hyperinsulinemia, and steatosis. Glucose consumption, glycogen and lipid droplet (LD) accumulation, gene expression, oxidative stress, and insulin signaling were assessed. Under severe hyperglycemia, both insulin and fatty acids decreased glucose consumption, whereas under moderate hyperglycemia, only insulin had this effect. Glycogen accumulation was increased across all treated conditions. Both insulin and fatty acids triggered steatosis and downregulated PPAR\u03b3 and SIRT1 mRNA, with insulin increasing LD number, while FFAs increased both LD number and size. All conditions enhanced ROS production, resulting in oxidative stress, but with differences in antioxidant enzyme response. Insulin receptor expression was reduced by insulin and FFAs under moderate hyperglycemia but increased by these stimuli under severe hyperglycemia. Both stimuli enhanced AKT phosphorylation under both hyperglycemic conditions. We conclude that different triggers cooperate in promoting hepatic IR through distinct molecular and signaling mechanisms, suggesting that effective treatments may need to target multiple pathways simultaneously.<\/jats:p>","DOI":"10.3390\/cimb48070729","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T09:00:52Z","timestamp":1784278852000},"page":"729","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic and Signaling Dysregulation in a Cellular Model of Hepatic Insulin Resistance"],"prefix":"10.3390","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1451-6441","authenticated-orcid":false,"given":"Hawraa","family":"Zbeeb","sequence":"first","affiliation":[{"name":"Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Corso Europa 26, 16132 Genova, Italy"},{"name":"Nanoscopy and NIC@IIT, Istituto Italiano di Tecnologia (IIT), via Enrico melen 83, 16153 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chourouk","family":"Joumaa","sequence":"additional","affiliation":[{"name":"Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Corso Europa 26, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"De Negri Atanasio","sequence":"additional","affiliation":[{"name":"Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Corso Europa 26, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4916-5928","authenticated-orcid":false,"given":"Alberto","family":"Diaspro","sequence":"additional","affiliation":[{"name":"Nanoscopy and NIC@IIT, Istituto Italiano di Tecnologia (IIT), via Enrico melen 83, 16153 Genova, Italy"},{"name":"Department of Physics (DIFI), University of Genova, via Dodecaneso 33, 16146 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1268-4724","authenticated-orcid":false,"given":"Laura","family":"Vergani","sequence":"additional","affiliation":[{"name":"Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Corso Europa 26, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref_1","unstructured":"Courtney, C.H., and Olefsky, J.M. 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