Targeting the Pentose Phosphate Pathway in Syndrome X-related Cardiovascular Complications

Abstract

Syndrome X is a combination or co-occurrence of several known cardiovascular risk factors (including central obesity, dyslipidemias, fatty liver disease, hyperinsulinemia, insulin resistance, and hypertension) that affects at least one in five people in developed countries. Syndrome X shortens life and increases morbidity by contributing to the development of both diabetes and cardiovascular disease. Type 1 or 2 diabetes affects approximately 170 million people globally and these numbers are rapidly rising. In patients with diabetes, vascular diseases develop early and progress at an accelerated rate. It has recently become evident that glucose-6-phosphate dehydrogenase (G6PD), the rate limiting enzyme in the pentose-phosphate pathway and its reaction products play key roles in regulating vascular function. Epidemiological studies have also shown that G6PD deficiency markedly reduces retinopathy and mortality due to cardiovascular diseases in males from certain Mediterranean regions. Conversely, G6PD expression and activity are upregulated in rat and mouse models of obesity, hyperglycemia and hyperinsulinemia, and a role for G6PD in the development of insulin resistance in type 2 diabetes has been proposed. Unfortunately, there are no selective drugs available to validate the hypothesis that G6PD and its products are involved in the development of Syndrome X in humans. This review discusses the potential mechanisms by which G6PD could be implicated in vascular diseases in Syndrome X and the need to develop new approaches, including new drugs and molecular tools, to ameliorate diabetes-induced vascular dysfunction and vasculopathies.

Figure 1. Function of glucose-6-phosphate dehydrogenase

Glucose-6-phosphate (G6P) is metabolized by glucose-6-phosphate dehydrogenase (G6PD) to 6-phospho-gluconolactone, which is further metabolized by phospho-6-gluconolactone dehydrogenase (PG6D) to riboses. In this process two molecules of NADPH are generated. NADPH is a coenzyme in many synthetic pathways and cofactor for oxido-reductases.

Figure 2. A putative function for glucose-6-phosphate dehydrogenase in insulin resistance development

In adipocytes, overexpression of glucose-6-phosphate dehydrogenase (G6PD) increases free fatty acid (FFA) and triglyceride (TG) synthesis, decreases adiponectin and leptin synthesis, and upregulates expression of NADPH oxidases, TNFα and pro-inflammatory cytokines. Collectively, these actions induce insulin resistance.

Figure 3. Schematic diagram illustrating of the role of glucose-6-phosphate dehydrogenase overexpression in the development of obesity

Overexpression and activation of glucose-6-phospahte dehydrogenase (G6PD) in adipocytes and liver of obese rats and mice enhances signaling in several pathways that presumably feedback to stimulate food intake (solid arrows) and induce hyperinsulinemia and hyperglycemia. The increased insulin and glucose levels putatively activate G6PD, thereby increasing food intake via the aforementioned feedback loop (broken arrows).

Figure 4. Signaling pathways involved in mediating overexpression and activation of glucose-6-phosphate dehydrogenase in obese, hyperinsulinemic and hyperglycemic models

Current evidence suggests that Src kinases and protein kinase C (PKC) are activated in various tissues and organs in obese, hyperinsulinemic and hyperglycemic rats and mice. Once activated, Src kinases and PKC activate G6PD, which increases oxidative stress and inflammation. When this occurs in the vasculature, it can lead to endothelial dysfunction, coronary artery disease and heart failure.

Figure 5. An overall picture of Syndrome X

The metabolic syndrome, Syndrome X, is a manifestation of the co-occurrence of several risk factors for cardiovascular disease. In Syndrome X, anti-oxidants are significantly downregulated in the liver and cardiovascular system. Under such conditions overexpression and activation of G6PD promotes dyslipidemia and ROS generation, which induces inflammation. All of these factors predispose an individual to T2D and CVD.