{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T16:54:41Z","timestamp":1792083281086,"version":"4.4.0"},"reference-count":41,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,8,12]],"date-time":"2022-08-12T00:00:00Z","timestamp":1660262400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2019YFC1711000"],"award-info":[{"award-number":["2019YFC1711000"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Statins are widely prescribed cholesterol\u2010lowering drugs but have been shown to increase the risk of type 2 diabetes mellitus. However, the molecular mechanisms underlying the diabetogenic effect of statins are still not fully understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The effects of geranylgeranyl transferase I and II (GGTase I and II) inhibition on insulin\u2010stimulated glucose uptake and GLUT4 translocation, and the dependence of these effects on insulin signalling were investigated in skeletal muscle cells. The protective effects of geranylgeranyl pyrophosphate (GGPP) and its precursor geranylgeraniol (GGOH) on simvastatin\u2010induced insulin resistance were evaluated <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. The effect of GGTase II inhibition in skeletal muscle on insulin sensitivity <jats:italic>in vivo<\/jats:italic> was confirmed by adeno\u2010associated virus serotype 9 (AAV9)\u2010mediated knockdown of the specific subunit of GGTase II, RABGGTA. The regulatory mechanisms of GGTase I on insulin signalling and GGTase II on insulin\u2010stimulated GLUT4 translocation were investigated by knockdown of RhoA, TAZ, IRS1, geranylgeranylation site mutation of RhoA, RAB8A, and RAB13.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Both inhibition of GGTase I and II mimicked simvastatin\u2010induced insulin resistance in skeletal muscle cells. GGPP and GGOH were able to prevent simvastatin\u2010induced skeletal muscle insulin resistance <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. GGTase I inhibition suppressed the phosphorylation of AKT (Ser473) (\u221251.3%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01), while GGTase II inhibition had no effect on it. AAV9\u2010mediated knockdown of RABGGTA in skeletal muscle impaired glucose disposal without disrupting insulin signalling <jats:italic>in vivo<\/jats:italic> (\u221246.2% for gastrocnemius glucose uptake, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001; \u221252.5% for tibialis anterior glucose uptake, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001; \u221217.8% for soleus glucose uptake, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05; \u221231.4% for extensor digitorum longus glucose uptake, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). Inhibition of RhoA, TAZ, IRS1, or geranylgeranylation deficiency of RhoA attenuated the beneficial effect of GGPP on insulin signalling in skeletal muscle cells. Geranylgeranylation deficiency of RAB8A inhibited insulin\u2010stimulated GLUT4 translocation and concomitant glucose uptake in skeletal muscle cells (\u221242.8% for GLUT4 translocation, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01; \u221250.6% for glucose uptake, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Geranylgeranyl pyrophosphate regulates glucose uptake via GGTase I\u2010mediated insulin signalling\u2010dependent way and GGTase II\u2010mediated insulin signalling\u2010independent way in skeletal muscle. Supplementation of GGPP\/GGOH could be a potential therapeutic strategy for statin\u2010induced insulin resistance.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13061","type":"journal-article","created":{"date-parts":[[2022,8,12]],"date-time":"2022-08-12T22:22:12Z","timestamp":1660342932000},"page":"2697-2711","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Geranylgeranyl pyrophosphate depletion by statins compromises skeletal muscle insulin sensitivity"],"prefix":"10.1002","volume":"13","author":[{"given":"Lai","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuguo","family":"Zheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Zhu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingchang","family":"Meng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanling","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keke","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key 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