{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T14:33:35Z","timestamp":1786113215065,"version":"build-2736575974"},"reference-count":61,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"32","funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32071166"],"award-info":[{"award-number":["32071166"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008804","name":"Ministry of Science and Technology, Government of the People\u2019s Republic of Bangladesh","doi-asserted-by":"publisher","award":["2025YFF1107603"],"award-info":[{"award-number":["2025YFF1107603"]}],"id":[{"id":"10.13039\/501100008804","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Research Program of State Key Laboratory of Food Science and Resources Jiangnan University","award":["SKLF-ZZB-202514"],"award-info":[{"award-number":["SKLF-ZZB-202514"]}]},{"name":"the Young Elite Scientists Sponsorship","award":["2020QNRC001"],"award-info":[{"award-number":["2020QNRC001"]}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,8,7]]},"abstract":"<jats:p>\n                    The mechanisms underlying the dynamic interplay between skeletal muscle and systemic glucose homeostasis in type 2 diabetes remain elusive. Increased lactate level has long been noticed in diabetes, however, whether the elevated lactate is a cause or consequence of impaired glucose metabolism is unclear. Here, we found that elevated circulating lactate levels originated from skeletal muscle with high expression of lactate dehydrogenase A (\n                    <jats:italic toggle=\"yes\">Ldha<\/jats:italic>\n                    ), and both metrics correlated strongly with hyperglycemia in both hyperglycemic mouse models and human subjects. Paradoxically, ablation of\n                    <jats:italic toggle=\"yes\">Ldha<\/jats:italic>\n                    in skeletal muscle (LDHA mKO) disrupted whole-body glucose homeostasis, primarily via augmented hepatic gluconeogenesis. Mechanistically, lactate deficiency in muscle epigenetically activated NF-\u03baB signaling through H3K18 lactylation (H3K18la)-mediated transcriptional control of I\u03baB\u03b1, which then promoted the transcription of IL-6, thereby reshaping hepatic gluconeogenesis. Lastly, we showed that loss of\n                    <jats:italic toggle=\"yes\">Ldha<\/jats:italic>\n                    in skeletal muscle enhanced hepatic gluconeogenesis and aggravated hyperglycemia in high-fat high-sucrose diet-fed mice. Collectively, our study provides evidence that in glucose intoxication contexts, skeletal muscle-derived lactate acts as the signal to provide negative feedback for hepatic gluconeogenesis, which induces skeletal muscle H3K18la acting as a negative regulator of IL-6 to sustain suppression of hepatic gluconeogenesis, while dysregulation of this network contributes to unrestrained gluconeogenesis in diabetes.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aed5600","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T18:01:42Z","timestamp":1785952902000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Skeletal muscle H3K18 lactylation inhibits hepatic gluconeogenesis through IL-6 mediated interorgan communication"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-4105-4492","authenticated-orcid":true,"given":"Yu","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Food Science and Resources, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China."},{"name":"College of Life Sciences and Food Engineering, Hebei University of Engineering, Handan, 056038, Hebei, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feijie","family":"Wang","sequence":"additional","affiliation":[{"name":"Healthy Aging Research Center, Nutrilite Health Institute, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Sun","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Food Science and Resources, School of Food Science and Technology, Jiangnan University, Wuxi 214122, 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