U.S. Department of Health and Human Services

Switching Fuel Sources from Fat to Sugar—Novel Role for Mitochondrial Enzyme and Implications for Type 2 Diabetes

Researchers have discovered an important role for an enzyme called carnitine acetyltransferase (CrAT) in regulating fuel selection under different nutritional conditions. CrAT is located in mitochondria, the structures in cells that extract energy from a variety of fuel sources. Glucose is their primary fuel, but mitochondria can switch to burning fat when glucose levels are low, such as during a fast. Previous research showed that the mitochondria of people with type 2 diabetes are not as adept as those of healthy people when it comes time to switch back to using glucose following a meal—and also suggested that the reason may relate to a problem with CrAT. The major function of CrAT is to catalyze the transfer of the “acetyl” portion of a molecule called acetyl-CoA to an essential nutrient called carnitine. Unlike CoA, carnitine can take acetyl groups out of the mitochondria. This is important, because acetyl-CoA is a major by product of mitochondrial energy production, and, if it accumulates, it can interfere with the work of other mitochondrial enzymes, including those involved in glucose metabolism. The new research explores the role of CrAT in metabolism, and helps explain why fuel switching is reduced in people with type 2 diabetes. 

The researchers genetically engineered mice to lack CrAT in their muscles, finding that such animals became insulin resistant and had high blood glucose levels, two conditions associated with prediabetes and diabetes. These results suggested that CrAT was playing a role in regulating metabolism. Experiments on mitochondria isolated from the animals’ muscles showed that they burn more fat than do normal mitochondria, but were impaired in their ability to switch to burning glucose. The researchers found that experimentally reducing CrAT activity in laboratory cultures of human muscle cells had similar effects to those observed in mice without CrAT, reducing capacity to switch from using fats to using glucose for cellular fuel. Because people with type 2 diabetes have a defect in fuel switching, the researchers hypothesized that people with the disease may have reduced levels of CrAT in their muscles. Indeed, they found that muscles of people with type 2 diabetes seem to make less CrAT than those of people without the disease. Other experiments suggested that loss of CrAT led to the expected build up of acetyl-CoA, apparently inhibiting enzymes that are important in glucose metabolism and thus preventing fuel switching to glucose. These observations suggested that it might be possible to help cells of people with type 2 diabetes get rid of the excess acetyl CoA by providing supplementary carnitine, the nutrient to which CrAT transfers the acetyl group, and thus making it easier for the enzyme to do its job. The researchers tested this approach in a pilot study in older people with modestly elevated blood glucose levels who were given carnitine supplements for 6 months. Insulin sensitivity improved, and the activity of a cellular enzyme involved in glucose metabolism increased, suggesting that carnitine supplementation may help promote fuel switching to glucose. These results confirm that CrAT is an important regulator in transitioning between glucose and fat metabolism. The preliminary results in the human pilot study, if confirmed through placebo-controlled trials, suggest that carnitine supplementation or other strategies to target CrAT may prove to be viable therapeutic approaches to treatment or prevention of type 2 diabetes. 

Muoio DM, Noland RC, Kovalik JP, et al. Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility. Cell Metab 15: 764-777, 2012.