T2DM is an independent risk factor of CAD. Epidemiological investigation revealed that patients with T2DM had a 2- to 4-fold higher risk than normal individuals of suffering from CAD (24
). In the present study, we demonstrated that the combination of PPARγ and PPARα agonists downregulates the blood glucose and lipid levels more efficiently in T2DM patients with CAD than the PPARγ or PPARα agonist alone. The combination of PPARγ and PPARα agonists also inhibited inflammatory cytokine secretion in the T2DM patients with CAD and attenuated the LPS-induced MCP-1 secretion by PBMCs in the T2DM patients. These results suggest that the combination of RSG and BEZ is more effective than RSG or BEZ alone for T2DM patients with CAD, and acts by inhibiting the secretion of inflammatory cytokines from monocytes.
RSG, a well-recognized oral anti-diabetic drug, belongs to the thiazolidinedione class of drugs. RSG increases the expression of glucose transporter-1 and facilitates the uptake of glucose by muscle and fat tissue through its receptors. Thereby, it reduces the output of liver glucose and blood glucose and improves hyperinsulinemia (25
). RSG also acts as an insulin sensitizer. It inhibits glucagon production and thus increases insulin sensitivity. In the present study, we demonstrated that RSG is capable of alleviating IR and decreasing FBG and HbA1c in T2DM patients. Similar results were observed in the BEZ group. However, when treated with combined RSG and BEZ for 12 weeks, the FBG, HbA1c, insulin and HOMA-IR all reached satisfactory levels. The results indicate that the combination of PPARα/γ agonists improves glucose metabolism more effectively than the PPARγ or PPARα agonist alone.
T2DM patients usually have one or more lipid abnormalities. The main characteristics of dyslipidemia in T2DM patients are an elevated TG level, increased LDL level and decreased HDL level. LDL cholesterol is a major risk factor for CVD in general and in particular in T2DM patients. Statins are extremely effective drugs for reducing the levels of LDL cholesterol. Numerous clinical trials have shown that treatment with statins lowers the rates of heart attack and cardiovascular mortality. Moreover, fibrates reduce TGs and increase the blood levels of HDL cholesterol, which is considered as ‘good’ cholesterol. However, there has been no definitive evidence from previous clinical trials that have used combined fibrate and statin to control blood lipid levels and thereby reduce the risk of heart attack and stroke in T2DM patients. In the present study, we identified that after 12 weeks treatment with combined RSG and BEZ, the TC, TG, LDL-C and HDL-C levels significantly improved. However, no significant changes in the lipid parameters, were observed in the other groups suggesting that the combination of the two drugs produces an improved outcome compared with RSG or BEZ alone.
Chronic inflammation has been shown to be a common precursor of T2DM and CAD, while hyperglycemia and IR may contribute to inflammation. Therefore, inflammation may act as a bridge between T2DM and coronary atherosclerosis (27
). The process of PBMC migration into the vascular intima and transformation to foam cells, constitutes the early event of atherosclerosis and is regulated by plasma inflammatory cytokines, including MCP-1 and CRP. MCP-1 is secreted mainly by endothelial cells, vascular smooth muscle cells, monocytes and macrophages. Elevation of the MCP-1 level in CAD patients often indicates the increase and activation of inflammatory cells in the plaque. The increase of MMPs degrades structural matrices in the fibrous cap, which causes plaque rupture and vessel injury. Therefore, MCP-1 plays an important role in the acute coronary syndrome caused by atherosclerosis and plaque rupture (28
). PPARs negatively regulate NF-κB and stimulate protein-1 activity, thereby inhibiting inflammatory gene transcription (29
). Studies in animal models verified that PPARα and PPARγ are able to exert anti-atherosclerotic effects in vivo
. Clinical studies suggested that PPARα or PPARγ alone are capable of lowering plasma inflammatory cytokine secretion in T2DM patients with CAD (30
). Our study revealed that RSG or BEZ alone was able to lower plasma CRP and MCP-1 levels in T2DM patients with CAD. However, the effect was clearer with combined RSG and BEZ, indicating that a combination of RSG and BEZ alleviates the inflammatory reaction more effectively. The mechanisms underlying the effect of RSG or BEZ on CRP and MCP-1 levels may include the modulation of NF-κB, AP-1 and signal transducer and activator of transcription (STAT) signal pathways. The present study demonstrated that a combination of RSG and BEZ exerts a more efficient anti-inflammatory effect than RSG or BEZ alone, indicating that a combination of PPARα/γ agonists is capable of inhibiting the expression of MCP-1, thus delaying the process of atherosclerosis.
In conclusion, our study demonstrated that a combination of RSG and BEZ is capable of reducing the level of blood glucose, alleviating IR and improving lipid modulation. A combination of RSG and BEZ is also able to lower plasma CRP and MCP-1 levels and decrease low-dose LPS-induced MCP-1 secretion by PBMCs in T2DM patients. The effects of combined RSG and BEZ are greater than those of RSG or BEZ used alone. The results of the present study suggest that the combination of PPARα/γ agonists may be more effective for the treatment of T2DM patients with CAD.