1. Geranylgeranyl pyrophosphate depletion by statins compromises skeletal muscle insulin sensitivity
- Author
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Lai Wang, Zuguo Zheng, Lijun Zhu, Lingchang Meng, Hanling Liu, Keke Wang, Jun Chen, Ping Li, and Hua Yang
- Subjects
Statin ,GGPP ,Skeletal muscle ,Insulin resistance ,RhoA ,RAB8A ,Diseases of the musculoskeletal system ,RC925-935 ,Human anatomy ,QM1-695 - Abstract
Abstract Background Statins are widely prescribed cholesterol‐lowering 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. Methods The effects of geranylgeranyl transferase I and II (GGTase I and II) inhibition on insulin‐stimulated 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‐induced insulin resistance were evaluated in vitro and in vivo. The effect of GGTase II inhibition in skeletal muscle on insulin sensitivity in vivo was confirmed by adeno‐associated virus serotype 9 (AAV9)‐mediated knockdown of the specific subunit of GGTase II, RABGGTA. The regulatory mechanisms of GGTase I on insulin signalling and GGTase II on insulin‐stimulated GLUT4 translocation were investigated by knockdown of RhoA, TAZ, IRS1, geranylgeranylation site mutation of RhoA, RAB8A, and RAB13. Results Both inhibition of GGTase I and II mimicked simvastatin‐induced insulin resistance in skeletal muscle cells. GGPP and GGOH were able to prevent simvastatin‐induced skeletal muscle insulin resistance in vitro and in vivo. GGTase I inhibition suppressed the phosphorylation of AKT (Ser473) (−51.3%, P
- Published
- 2022
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