ArticleJournal of cachexia, sarcopenia and muscle2022
Geranylgeranyl pyrophosphate depletion by statins compromises skeletal muscle insulin sensitivity.
Article in Journal of cachexia, sarcopenia and muscle, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 7 citations in OpenAlex.
- Loss of Intestinal MSTN Promotes GLP-1 Secretion Through SGLT1 Palmitoylation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Geranylgeranylation is required for B-cell proliferation and plasma cell survival implications for autoimmune therapy.Cellular & molecular immunology · 2026Article
- Statins and Myasthenia Gravis: Clinical Implications and Pathogenesis.International journal of molecular sciences · 2026Review
- Protease-Activated Receptor-2 as a Proteolytic Rheostat in Colorectal and Pancreatic Cancer: From Mechanism to Biomarker-Guided Therapy.International journal of molecular sciences · 2026Review
- Ethnic and Gender Disparities in Risk Factors for Prediabetes-A Retrospective Exploratory Analysis in Southern Israel.Journal of clinical medicine · 2026Article
- Dietary Geranylgeraniol Mitigates Pain-Associated Behaviors via Improving Mitochondrial Function and Colon Integrity and Suppressing Neuroinflammation in Male Diabetic Neuropathy Rats.International journal of molecular sciences · 2025Article
- A rationally designed CD19 monoclonal antibody-triptolide conjugate for the treatment of systemic lupus erythematosus.Acta pharmaceutica Sinica. B · 2024Article
- Potential role of geranylgeraniol in managing statin-associated muscle symptoms: a COVID-19 related perspective.Frontiers in physiology · 2023Article
- The Biomedical Importance of the Missing Pathway for Farnesol and Geranylgeraniol Salvage.Molecules (Basel, Switzerland) · 2022Review
- Geranylgeranyl pyrophosphate depletion by statins compromises skeletal muscle insulin sensitivity.Journal of cachexia, sarcopenia and muscle · 2022Article
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundStatins 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.
methodsThe 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.
resultsBoth 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 < 0.01), while GGTase II inhibition had no effect on it. AAV9-mediated knockdown of RABGGTA in skeletal muscle impaired glucose disposal without disrupting insulin signalling in vivo (-46.2% for gastrocnemius glucose uptake, P < 0.001; -52.5% for tibialis anterior glucose uptake, P < 0.001; -17.8% for soleus glucose uptake, P < 0.05; -31.4% for extensor digitorum longus glucose uptake, P < 0.01). 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-stimulated GLUT4 translocation and concomitant glucose uptake in skeletal muscle cells (-42.8% for GLUT4 translocation, P < 0.01; -50.6% for glucose uptake, P < 0.001).
conclusionsGeranylgeranyl pyrophosphate regulates glucose uptake via GGTase I-mediated insulin signalling-dependent way and GGTase II-mediated insulin signalling-independent way in skeletal muscle. Supplementation of GGPP/GGOH could be a potential therapeutic strategy for statin-induced insulin resistance.
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