geranylgeranyl-pyrophosphate and Insulin-Resistance

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.. 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.. 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 < 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).. Geranylgeranyl 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.

Topics: Diabetes Mellitus, Type 2; Glucose; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Insulin; Insulin Resistance; Muscle, Skeletal; rab GTP-Binding Proteins; Simvastatin

Resistin is a novel cysteine-rich protein that plays a role in the development of insulin resistance and atherosclerosis in rodents, while its role in humans is unclear. C-reactive protein (CRP) is an important risk predictor for coronary heart disease, and it can also modify the expression of genes involved in atherogenesis. Statins have been demonstrated to possess lipid lowering effects as well as pleiotropic properties. We hypothesize that CRP may result in overexpression of resistin, and statin may decrease CRP-induced resistin expression in cultured human peripheral blood monocytes (PBMC).. The aim of the present study, therefore, was to assess the effects of both CRP on resistin expression and simvastatin on CRP-induced of resistin expression in cultured human PBMC.. Human PBMC were isolated from the whole blood of healthy volunteers by density gradient centrifugation. First, cells were incubated with varying concentrations of CRP (0, 5, 10, 25 and 50 microg/ml) for 24h for assessing the dose-dependent effects on resistin expression. Second, 25 microg/ml of CRP was used to time-dependent evaluation on resistin expression (0, 3, 6, 12 and 24h). Moreover, cells were pretreated with simvastatin at concentrations from 0.1 to 1 microM for 2h, and then co-incubated with 25 microg/ml CRP for 24h for evaluating effect of statin on resistin production subjected to CRP. Finally, in additional experiments, monocytes were incubated with 1 microM simvastatin in the absence or presence of 100 microM mevalonate or 10 microM geranylgeranyl-pyrophosphate (GGPP) or 10 microM farnesylpyrophosphate (FPP) for 2h, then co-incubated with CRP for 24h for examining whether effects of statin on CRP-induced resistin expression was independent of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors.. The results showed that CRP induced both mRNA expression and protein secretion of resistin in a dose- and time-dependent manner. Co-incubation with simvastatin significantly inhibited CRP-induced up-regulation of mRNA and protein expression of resistin. Treatment with mevalonate, GGPP, but not FPP, reversed the inhibition of resistin expression caused by simvastatin, suggesting that simvastatin regulated resistin expression in culture human PBMC through the mevalonate-GGPP signal pathway.. In the present study, the data showed that CRP could significantly increase resistin expression in cultured human PBMC, and this effect was inhibited by simvastatin, suggesting that CRP and resistin might be involved in the pathogenesis of atherosclerosis, and statin therapy might be beneficial for atherosclerotic disease by modifying CRP-induced resistin overexpression in PBMC.

Topics: Animals; Atherosclerosis; C-Reactive Protein; Cells, Cultured; Coronary Disease; Diterpenes; Dose-Response Relationship, Drug; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Insulin Resistance; Mevalonic Acid; Monocytes; Polyisoprenyl Phosphates; Resistin; Risk Factors; Rodentia; Signal Transduction; Simvastatin; Time Factors; Up-Regulation