Lipid Metabolism

When glucose supplies are low, the body is able to draw upon lipids as an alternative energy source. Lipids are generally stored as triglycerides and the first step in lipid metabolism is the conversion to glycerol and fatty acids. Glycerol (dihydroxyacetone phosphate) can enter the glycolysis pathway, and proceed to the Krebs cycle and oxidative phosphorylation. Fatty acids are converted to acetyl CoA, which can directly enter the Krebs cycle and subsequently oxidative phosphorylation. Each fatty acid molecule produces many acetyl CoA molecules (whereas glucose yields two), so much more ATP can be generated from a single fatty acid molecule than one glucose molecule. Ketones are produced as a by-product of lipid metabolism and can be used by the nervous system as a partial alternative to glucose. This is a protective mechanism, allowing the body to conserve glucose when energy intake becomes limited.

Lipid metabolism and glucose metabolism are closely linked. Type II diabetes is associated with dyslipidemia, which is characterized by increased triglyceride and reduced high density lipoprotein cholesterol (HDL-C) levels. Impaired glucose control results in elevated glucose levels, which promotes hepatic and intestinal lipoprotein overproduction and hypertriglyceridemia. However, lipid changes could also be a cause of impaired glucose metabolism, as well as a consequence, since elevated triglyceride levels lead to increased free fatty acid (FFA) levels, which appear to induce insulin resistance and β cell dysfunction, although the mechanisms by which this occurs are at present unclear. It has been proposed that this effect on insulin resistance may be the result of FFAs inducing inflammation, possibly via activation of Toll-like receptor 4 or the inflammasome.

Disorders of lipid metabolism may also be caused by a mutation in one of the enzymes involved in this complex pathway, resulting in the accumulation of a specific intermediate in tissues. Examples include Gaucher's disease, which leads to accumulation of glucocerebrosides, causing an enlarged liver and spleen with nervous system and skeletal abnormalities, and Tay-Sachs disease, which causes progressive mental retardation due to ganglioside accumulation.