**6. Statins and new onset of diabetes**

Recent studies suggest that chronic use of statins is associated with risk of developing type 2 diabetes [200–202]. Meta-analyses of large-scale statin trials support the concept of the diabetogenic effect of statins, but the precise mechanisms have not yet been identified [203, 204]. We have recently revealed diabetes-related mechanisms induced by statin treatment in a familial hypercholesterolemia animal model, the *LDLr−/−*. We demonstrated that pravastatintreated *LDLr−/−* mice exhibit marked reductions of insulinemia and of glucose-stimulated insulin secretion by isolated pancreatic islets. These effects were associated with increased oxidative stress and apoptosis [205] and were counteracted by co-treatment with CoQ10 (Lorza-Gil et al., unpublished data). Therefore, we have proposed that pancreatic toxic effects of pravastatin could be caused by statin inhibition of CoQ10 biosynthesis. On the other hand, we and others have hypothesized that insulin signaling in their target tissues (such as muscle) could also be impaired by chronic statin treatment. However, studies relating statins therapy and insulin sensitivity are controversial [206–208]. A meta-analysis by Baker and colleagues shows that while pravastatin improved insulin sensitivity, atorvastatin, simvastatin, and rosuvastatin worsened it [209]. Experimental studies suggest that atorvastatin leads to reduced expression of GLUT4 in adipocytes *in vivo* and *in vitro* [210] and that simvastatin decreases IGF-1 signaling (pAKT, pERK) in muscle cells [211]. Kain et al. [212] showed that myotubes treated with simvastatin and atorvastatin presented impaired insulin signaling pathway and glucose uptake. We have evidence that long-term pravastatin treatment of hypercholesterolemic mice also induces marked insulin resistance and increased muscle protein degradation (Lorza-Gil et al., unpublished data). Therefore, toxic effects on insulin secreting cells in conjunction with impaired muscle insulin signaling may explain the new onset of diabetes reported in statin-treated subjects.

doses of atorvastatin and/or a cholesterol-rich diet [237]. Despite all data correlating CoQ10 depletion with statin toxicity, the efficacy of ubiquinone supplementation in patients with side

Mitochondrial Oxidative Stress and Calcium-Dependent Permeability Transition are Key Players…

http://dx.doi.org/10.5772/intechopen.71610

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Creatine is a guanidine compound synthesized endogenously [241] and widely and safely used as supplement by athletes to increase their performance [242]. The role of creatine on the maintenance of ATP/ADP ratio by activating CK is very well known, but it also exerts other actions. Creatine participates on a protein complex involved in MPT regulation [55, 243, 244] and was firstly mentioned as antioxidant in 1998 [245]. A few years later, Lawler and coworkers showed that this compound was capable of scavenging radicals such as superoxide and peroxynitrite [246]. In our recent work, we showed that diet supplementation with creatine protected *LDLr−/−*

L-carnitine stimulates β-oxidation by increasing carnitine palmitoyltransferase 1A mRNA expression. This action prevents mitochondrial oxidative stress induced by free fatty acids, increasing mitochondrial function [22, 247]. Another property of L-carnitine is to bind Fe2+ [248] that participates in the mitochondrial oxidative stress involved in MPT [249]. Thus, it is feasible to propose that L-carnitine protects complexes I and II of the respiratory chain against superoxide attack by interacting with 4Fe-4S clusters in these sites. In a previous work performed in PC3 prostate cancer, we showed that L-carnitine and piracetam (a membrane stabilizer) prevented MPT and

Taken together, these experimental results suggest that ROS generation and mitochondrial

Cardiovascular benefits of statins therapy are undoubted and appear to be present across diverse demographic and clinical groups. However, the side effects may affect a minority of patients. In this review, we addressed the cellular and molecular mechanisms related to statin side effects. Mitochondrial oxidative stress seems to be the main cause of toxicity in statin sensitive tissues (**Figure 1**). The levels and consequences of mitochondrial oxidative stress seem to be more deleterious in skeletal muscle. This effect is secondary to: (a) inhibition of electrons flow at the levels of respiratory complexes I, II, and III, and (b) decrease in the levels of CoQ10 due to inhibition of the mevalonate pathway. In association with mitochondrial Ca2+ overload due to increased cytosolic free Ca2+ concentrations, the PTP may open and trigger cell death. *In vitro* experiments provide evidence that this can be blocked in a concerted manner by L-carnitine plus the membrane stabilizer piracetam. Experiments performed with muscle biopsies taken from hypercholesterolemic mice, chronically treated with pravastatin, show that either CoQ10 or creatine can protect against statin-induced mitochondrial muscle toxicity both *in vitro* and *in vivo*. Statin treatment may also result in pro- or antioxidant actions depending on statin class (lipophilicity), dose, and patient's background. We suggest that mitochondrial oxidative stress caused by statin treatment may be a signal for cellular antioxidant system response (such as

effects is still under debate [231, 238–240].

necrosis induced by simvastatin (60 μM) [22].

**8. Conclusions**

oxidative stress play an important role on statins toxicity.

mice against pravastatin sensitization to Ca2+-induced MPT [166].
