Philadelphia - Researchers at the University of Pennsylvania School of Medicine have discovered a potential new target for treating type 2 diabetes, according to a new study that appeared online this week in Nature. The target is a protein, along with its molecular partner, that regulates fat metabolism.
"Over the last 10 years, we have begun to understand the importance of fat metabolism in diabetes," notes lead author Morris J. Birnbaum, MD, PhD, the Willard and Rhoda Ware Professor of Diabetes and Metabolic Diseases at Penn and an Investigator of the Howard Hughes Medical Institute. "Type 2 diabetics are at a higher risk for cardiovascular disease because they also have disorders in fat metabolism as a result of obesity and abnormal insulin action." Birnbaum is also the Associate Director of the Type 2 Diabetes Unit for Penn's Institute for Diabetes, Obesity, and Metabolism.
When a person eats a meal, the pancreas usually responds by secreting insulin that signals the liver to stop making glucose and burning fat. When a type 2 diabetic eats a meal, insulin cannot stop the manufacture of glucose in the liver, but it can stop the burning of fat stores. This gives the diabetic person a "double whammy": fatty acids accumulate from food and from the liver. Consequently, more fat is deposited in tissues and obesity worsens.
Until now there was no clear connection between insulin and the control of fat metabolism. This study shows that when insulin is present, as it is after a meal, the protein Akt2/PKB adds a phosphate group to its molecular partner PGC-1Ą. When this happens, PGC-1Ą cannot activate the genes needed for fat metabolism.
The findings suggest that if a drug could induce Akt2/PKB to add the phosphate group (phosphorylation) to PGC-1Ą, then the liver of a diabetic might be "fooled" into stopping the oxidation of fat stores. "Muscle and fat tissue also burn fat stores, and we are currently investigating whether PGC-1Ą and Akt2/PKB have the same role in those tissues," says Birnbaum.
The researchers also found that insulin-stimulated phosphorylation of PGC-1Ą was blunted in mice that had non-functional Akt2/PKB. Finally, they showed that livers with too much PGC-1Ą or with PGC-1Ą that could not be phosphorylated put out many copies of the genes for fat metabolism. Each approach pointed to the same conclusion: PGC-1Ą had phosphate groups added to it by Akt2/PKB in the presence of insulin and this prevented the turning on of genes that make fat.
There are currently no drugs that target PGC-1Ą and Akt2/PKB. "We hope that drug companies will look for new ways to modify fat metabolism in type 2 diabetics using these possible targets," says Birnbaum.
Co-authors are first author Xinghai Li and Bobby Monks, both of Penn and Qingyuan Ge of Cell Signaling Technology, Inc. Dr. Birnbaum is an Investigator of the Howard Hughes Medical Institute and receives additional support for this work from the National Institute of Diabetes and Digestive and Kidney Diseases. This release can be viewed at http://www.pennhealth.com/news.
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Journal
Nature