{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:38:34Z","timestamp":1787017114158,"version":"build-2736575974"},"reference-count":27,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T00:00:00Z","timestamp":1619049600000},"content-version":"unspecified","delay-in-days":21,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Health Scientific Foundation of Shaanxi Province","award":["2018E11"],"award-info":[{"award-number":["2018E11"]}]},{"name":"Fundamental Scientific Research Foundation of Xi\u2019an Jiaotong University","award":["xzy012019131"],"award-info":[{"award-number":["xzy012019131"]}]},{"name":"Natural Science Basic Research Foundation of Shaanxi Province","award":["2020JQ-941"],"award-info":[{"award-number":["2020JQ-941"]}]},{"name":"Innovative Talents Promotion Project of Shaanxi Province","award":["2019KJXX-019"],"award-info":[{"award-number":["2019KJXX-019"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open Diab Res Care"],"accepted":{"date-parts":[[2021,3,28]]},"published-print":{"date-parts":[[2021,4]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Glucose-induced insulin resistance is a typical character of diabetes. Nicorandil is now widely used in ischemic heart disease. Nicorandil shows protective effects against oxidative and endoplasmic reticulum (ER) stress, which are involved in insulin resistance. Here, we investigated mechanisms of nicorandil\u2019s novel pharmacological activity on insulin resistance in diabetes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Research design and methods<\/jats:title>\n                    <jats:p>Nicorandil was administrated to streptozotocin-induced animals with diabetes and high glucose exposed skeletal muscle cells. Insulin resistance and glucose tolerance were evaluated. Molecular mechanisms concerning oxidative stress, ER stress signaling activation and glucose uptake were assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Nicorandil attenuated high glucose-induced insulin resistance without affecting fasting blood glucose and glucose tolerance in whole body and skeletal muscle in rats with diabetes. Nicorandil treatment suppressed protein kinase C\/nicotinamide adenine dinucleotide phosphate oxidases system activities by reducing cytoplasmic free calcium level in skeletal muscle cells exposed to high glucose. As a result, the oxidative stress-mediated ER stress protein kinase RNA-like endoplasmic reticulum kinase (PERK)\/eukaryotic initiation factor 2\u03b1\/activating transcription factor 4\/CEBP homologous protein\/tribbles homolog (TRB)3 signaling pathway activation was inhibited. Nicorandil downregulated expression of TRB3 and thus facilitated Akt phosphorylation in response to insulin stimulation, leading to glucose transporter4 plasma membrane translocation which promoted glucose uptake capability of skeletal muscle cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>By reducing cytoplasmic calcium, nicorandil alleviated high glucose-induced insulin resistance by inhibiting oxidative stress-mediated ER stress PERK pathway.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjdrc-2020-001884","type":"journal-article","created":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T11:36:45Z","timestamp":1619091405000},"page":"e001884","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":11,"title":["Nicorandil attenuates high glucose-induced insulin resistance by suppressing oxidative stress-mediated ER stress PERK signaling pathway"],"prefix":"10.1136","volume":"9","author":[{"given":"Zhongwei","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Northwest Women\u2019s and Children\u2019s Hospital, Xi'an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhui","family":"He","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Fuwai Hospital State Key Laboratory of Cardiovascular Disease, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"He","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Fuwai Hospital State Key Laboratory of Cardiovascular Disease, Beijing, 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Hospital, Northwestern Polytechnical University, Xi'an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4478-5335","authenticated-orcid":false,"given":"Junkui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, 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