Glucose-6-phosphate: A key compound in glycogenosis I and favism leading to hyper- or hypolipidaemia

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Abstract
The glycogen storage disorders (GSD)-I,-III,-VI and VIII are associated with hypertriglyceridaemia or mixed hyperlipidaemia which poses the question whether these patients have an increased risk for atherosclerosis. The atherogenicity of triglycerides has remained controversial, while increased plasma cholesterol levels are generally accepted as a significant risk factor for coronary heart disease. However, clinical data show that one has to differentiate between metabolic conditions where triglycerides are atherogenic and those which are not significantly related to early onset of atherosclerosis but may cause other disorders such as pancreatitis. Among the disorders of carbohydrate metabolism patients with diabetes mellitus frequently have enhanced plasma triglycerides associated with a higher risk for coronary heart disease, while patients with certain types of glycogen storage disease have high triglyceride levels but do not seem to have an enhanced risk for atherosclerosis. Here we have compared the biochemical abnormalities and the atherogenic risk of three different disorders of glucose metabolism including GSD-I (glucose-6-phosphatase deficiency), favism (glucose-6-phosphate dehydrogenase deficiency), and diabetes mellitus which are related to either hyper- or hypolipidaemia. The available data indicate that glucose-6-phosphate (Glc-6-P) is a central molecule in cellular glucose metabolism which critically influences pentose phosphate cycle activity and, via NADPH2-generation, regulates glutathione peroxidase activity for radical detoxification and also cholesterol and triglyceride synthesis. Radical detoxification is a major protective factor for cell membrane integrity and together with an appropriate renewal of membrane lipids may protect against the development of atherosclerosis. In GSD-I, the accumulation of Glc-6-P leads to enhanced radical detoxification and thereby increases the generation of “reducing”-equivalents. In contrast in both glucose-6-phosphate dehydrogenase deficiency and diabetes mellitus there is an impaired activity of the glutathione-peroxidase system and the NADPH2-generation pentose phosphate cycle which might predispose these patients for membrane damage thus leading to haemolysis, platelet activation and atherosclerosis.