Mechanism by which statins influence insulin signaling pathway

Recent studies have shown that statins can influence insulin resistance (IR) in animal models and in humans.1,2 However, the mechanism by which statins influence the insulin signaling pathway (ISP) remains obscure. It has been proposed that the pleiotropic effects of statins might be involved in regulation of IR. The phosphatidylinositol 3-kinase (PI3K)-Akt/protein kinase B (PKB) pathway is the main ISP. Insulin binding to insulin receptor initiates PI3K-Akt pathway by phosphorylates tyrosine residue of IR substrate proteins (IRSs) including IRS-1 and IRS-2. Activation of the PI3K leads to the accumulation of phosphatidylinositol 3,4,5-triphosphate (PIP3). PIP3 activates serine/threonine kinase (Akt). Glucose transporter-4 (GLUT-4) translocates to plasma membrane from cytosol by serine phosphorylation of Akt and directly regulates glucose metabolism in liver, muscle and adipose tissue (Figure 1). However, an overall mechanism by which statins influence ISP remained obscure.Figure 1.: Insulin signaling pathway.Effect of statins on ISP via regulation of adipocytokines adiponectin Adiponectin, a prototypic adipocytokine, has an anti-inflammatory and anti-insulin resistance function.3 An increment of serum adiponectin level and amelioration of IR has been reported after the administration of pravastatin and pitavastatin.4,5 The adiponectin-deficient mice developed more severe IR within 2 weeks of a high-fat, high-sucrose diet than control group.6 Replenishment of adiponectin significantly ameliorated high-fat diet-induced IR. Adiponectin signaling pathway activates ISP. Leucine zipper containing 1 (APPL1) is an endosomal protein binds to the N-terminal domains of AdipoR1 and AdipoR2. APPL1 activates insulin signaling of PI3K and interferes with Tribble-3 (TRB3) binding which in turn resulted in insulin-stimulated Akt/PKB activation (Figure 2).Figure 2.: Adiponectin signaling pathway activates ISP.Leptin Leptin is a 16-kDa protein produced mainly by adipocytes and encoded by Ob gene. Leptin and insulin may coordinately act to control energy homeostasis. Leptin receptor b (ObRb) activation induces phosphorylation of IRS2 via SH2B1, an interaction partner of JAK2 (Figure 3).7 ObR-deficient rats improved insulin sensitivity in a PI3K-dependent way after expression of the ObRb.8Figure 3.: Leptin signaling pathway activates ISP.It is indicated that there is an interaction between leptin and statins. Atorvastatin was reported to decrease leptin levels in patients with coronary artery disease (CAD).9 Moreover, statins inhibit the leptin expression in vascular smooth muscle cells, adipocytes and human coronary artery endothelial cells.10 Resistin Hyperglycemia, which occurs in type 2 diabetes mellitus, could produce an increased resistin expression. Plasma resistin concentrations were higher in type 2 diabetic patients than in normal subjects.11 Administration of recombinant resistin will lead to glucose intolerance in mice and impaired insulin action in rat's liver.12 Resistin level was significantly decreased after 12 weeks of pitavastatin.13 Simvastatin was also demonstrated to inhibit resistin over-expression. The c-jun N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase family which phosphorylates serine 307 of IRS proteins (Figure 4). JNK pathway mediates the inhibitory effect of resistin on IRS- 1 activity.14 Moreover, resistin disturbs single nucleotide polymorphisms (SNP)-420 which is a gene found to be associated with IR.15Figure 4.: The JNK pathway.RBP4 RBP4, a molecule secreted by adipocytes and liver, contributes to systemic IR. Elevated RBP4 levels have been reported in people with IR and type 2 diabetes mellitus.16 Increased serum RBP4 levels impair postreceptor insulin signaling at the level of PI3K in muscle and liver. Rosuvastatin significantly decreases the level of serum RBP4.17 Thus, statin therapy provides a rationale for improving the IR by lowering RBP4. Visfatin Circulating visfatin, an adipokine interfering with the central regulation of insulin sensitivity, was positively associated with IR. A meta-analysis demonstrated that plasma visfatin concentrations were increased in participants diagnosed with type 2 diabetes mellitus and metabolic syndrome.18 Visfatin show a dose-dependent significant up-regulation in PI3K activity.19 However, atorvastatin and rosuvastatin administration decreased visfatin serum levels significantly.20 Effect of statins on ISP via regulation of inflammatory factors Interleukin-1β The cytokine interleukin 1β has been implicated as a pathogenetic factor in the initial events leading to insulin-dependent diabetes mellitus. However, a study showed JNK can be activated by interleukin-1β indicating that interleukin-1β plays a role in IR and type 2 diabetes mellitus as well.21 Statins are lipid-lowering drugs that exhibit anti-inflammatory and immune-modulatory properties. It is demonstrated that interleukin-1β was significantly decreased in the atorvastatin treated group.22 Therefore, statin treatment inhibits interleukin-1β and prevents activation of JNK. Tumor necrosis factor (TNF)-α TNF-α is also linked to the presentation of IR in humans supported by substantial evidences. Direct exposure to TNF-α impairs ISP and induces IR in myocytes and adipocytes.23 Protein-tyrosine phosphatase (PTP) 1B acts as a negative regulator of insulin signaling by dephosphorylating the phosphotyrosine residues of insulin receptor and IRS-1 (Figure 5). Up-regulation of PTP 1B expression was recently found in cells and animals treated with TNF-α. Consistently, PTP-1B expression is up-regulated in the insulin-resistant hamsters. Moreover, JNK pathway can be activated by TNF-α leading to phosphorylation of serine residue of IRS.Figure 5.: The PTP 1B pathway.Rosuvastatin, simvastatin and pitavastatin lowered plasma levels of TNF-α in patients with type 2 diabetes mellitus.24,25 TNF-α production was also reduced in lipopolysaccharide-activated monocytes from patients treated with atorvastatin.26 Rosuvastatin normalizes elevated PTP-1B protein levels associated with fructose-induced insulin resistance.27 Effect of statins on ISP via reduction of oxidative stress Oxidative stress is enhanced in adipose tissue before diabetes development suggesting that adipose tissue may be a major source of reactive oxygen species (ROS). A study by Wei et al28 claimed that the ISP is impaired in cultured skeletal muscle cells due to ROS. ROS leads to a decrease of Akt phosphorylation by JNK pathway resulted in deterioration of IR.29 Treatment with anti-oxidative agents improves IR and restores adiponectin production.30 In subjects with metabolic syndrome, statins are associated with a reduction in markers of oxidative stress.31 Effect of statins on ISP via inhibition of isoprenoid synthesis Statins by inhibiting the synthesis of isoprenoids, block the activation of small GTPases which are involved in the GLUT4 expression to the plasma membrane of adipocytes.32,33 Lovastatin downregulates GLUT4 expression and decreases the insulin-mediated glucose uptake in adipocytes.33 Atorvastatin was shown to dosedependently inhibit insulin-mediated glucose uptake by inhibiting GLUT4 translocation and phosphorylation of IRS-1 and Akt.34 Effect of statins on ISP via regulation of lipid metabolism Treatment with low-density lipoprotein (LDL) resulted in increased JNK phosphorylation and release of cytokines from macrophages. High-density lipoprotein (HDL) cotreatment reversed phosphorylation of JNK and release of pro-inflammatory cytokines.35 LDL impairs ISP while HDL restores defective glucose uptake. Levels of free fatty acids (FFAs) are increased under obese diabetic conditions with IR. The JNK pathway which leads to IR can be activated by FFAs.36 It is widely accepted that statins can increase HDL, decrease LDL and FFAs level. Statins have multi-targets on ISP and exhibit different effect on IR under different conditions. Statins with different dose, potency and hydrophilicity perform different effect on IR. It is reported that statins increase the risk of new onset of diabetes mellitus.37 The incidence of diabetes mellitus seems to be type and dose dependent on statins.38 Another study drew a conclusion that risk of new onset diabetes is associated with the potency of statins. Compared with low potency statins such as pravastatin, treatment with higher potency statins, especially atorvastatin and simvastatin, is correlated with an increased risk of new onset diabetes.39 Comparison trials also suggest a preferable IR improving effect of the hydrophilic statins pravastatin, rosuvastatin and pitavastatin as compared to lipophilic statins including atorvastatin and simvastatin.40 Hydrophilic statins increased the serum adiponectin level and decreased ox-LDL level after switching from lipophilic statins, indicating that insulin sensitizing effect of hydrophilic statins is more significant than lipophilic statins.41 However, there are opposite voices claiming that statins have no beneficial effect or even adverse effect on IR. A study by Kostapanos et al42 claimed that rosuvastatin therapy was associated with a dosedependent increase in IR. Another study claimed that atorvastatin treatment increased homeostasis model assessment index (HOMA-IR) by 36.1% and pitavastatin increased HOMA-IR by 27.0%.43 Moreover, a few studies indicated no change in the degree of IR was observed with statin therapy. 40 In conclusion, statins play an important role in regulating ISP due to the pleiotropic effect. This effect of statins is mediated by regulation of serum adipocytokines, pro-inflammatory factors, oxidative stress, isoprenoid and lipid metabolism. The views of this article is that statins have opposite effect on ISP. Statins inhibit ISP at the level of IRS2, PI3K and GLUT4 by leptin, visfatin and isoprenoid respectively (Figure 6).Figure 6.: The mechanisms by which statins inhibit ISP.However, Statins also activates ISP by regulating a variety of mediators. Adiponectin is up-regulated by statins and stimulates both PI3K and Akt. HDL level is increased by statins and thus activates IRS1. Resistin, interleukin-1β, TNF-α, ROS, LDL, FFAs interferes with ISP at the level of IRS1 by JNK pathway. TNF-α alone impairs ISP by PTP 1B pathway. In contrast with adiponectin, RBP4 disturbs the activation of PI3K. All of these interferences are suppressed by statin therapy (Figure 7).Figure 7.: The mechanisms by which statins activate ISP.Therefore, our conclusion is that the activation and inhibition of ISP by statins coexist due to the pleiotropic effect. Statins have bidirectional effect on ISP.