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However, numerous studies indicate that consumption of artificial sweeteners exerts adverse effects on glycemic homeostasis. Although sucralose is among the most extensively utilized sweeteners in food products, the effects and detailed mechanisms of sucralose on insulin sensitivity remain ambiguous. In this study, we found that bolus administration of sucralose by oral gavage enhanced insulin secretion to decrease plasma glucose levels in mice. In addition, mice were randomly allocated into three groups, chow diet, high-fat diet (HFD), and HFD supplemented with sucralose (HFSUC), to investigate the effects of long-term consumption of sucralose on glucose homeostasis. In contrast to the effects of sucralose with bolus administration, the supplement of sucralose augmented HFD-induced insulin resistance and glucose intolerance, determined by glucose and insulin tolerance tests. In addition, we found that administration of extracellular signal-regulated kinase (ERK)-1\/2 inhibitor reversed the effects of sucralose on glucose intolerance and insulin resistance in mice. Moreover, blockade of taste receptor type 1 member 3 (T1R3) by lactisole or pretreatment of endoplasmic reticulum stress inhibitors diminished sucralose-induced insulin resistance in HepG2 cells. Taken together, sucralose augmented HFD-induced insulin resistance in mice, and interrupted insulin signals through a T1R3-ERK1\/2-dependent pathway in the liver.<\/jats:p>","DOI":"10.3390\/nu15122814","type":"journal-article","created":{"date-parts":[[2023,6,21]],"date-time":"2023-06-21T02:01:33Z","timestamp":1687312893000},"page":"2814","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Long-Term Consumption of Sucralose Induces Hepatic Insulin Resistance through an Extracellular Signal-Regulated Kinase 1\/2-Dependent Pathway"],"prefix":"10.3390","volume":"15","author":[{"given":"Meng-Jie","family":"Tsai","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5062-8128","authenticated-orcid":false,"given":"Chung-Hao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Family Medicine, An Nan Hospital, China Medical University, Tainan 70965, Taiwan"},{"name":"School of Medicine, College of Medicine, China Medical University, Taichung 40402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0611-8427","authenticated-orcid":false,"given":"Hung-Tsung","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, School of Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6413-7669","authenticated-orcid":false,"given":"Hsin-Yu","family":"Kuo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Teng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, School of Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsiu-Ling","family":"Pai","sequence":"additional","affiliation":[{"name":"Graduated Institute of Metabolism and Obesity Science, College of Nutrition, Taipei Medical University, Taipei City 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Jen","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Family Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City 60002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Horng-Yih","family":"Ou","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan"},{"name":"Department of Internal Medicine, School of Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1161\/CIRCRESAHA.119.315896","article-title":"Metabolic Inflammation and Insulin Resistance in Obesity","volume":"126","author":"Wu","year":"2020","journal-title":"Circ. 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