Key To Treating Diabetes Is Making Muscles Burn Fat Better

Dr Clinton Bruce, first working with Professor Ted Kraegen from Sydney's Garvan Institute of Medical Research, and then with Professor Mark Febbraio from Melbourne's Baker IDI Heart and Diabetes Institute, has added to evidence that fat molecules clog up the cytosol, or cell interior, but not the mitochondrion, or energy powerhouse of the cell.

This is an important distinction because the groups have also found a way to reduce the build-up of fat molecules in the cytosol by increasing the ability of mitochondria to take in fat molecules and burn them.

The finding, already online and critical for our understanding of fat metabolism, will be published in a future issue of the journal Diabetes.

Professor Kraegen believes the finding indicates a direction for further pre-clinical research. "There's a lot of work being put into developing new drugs and methodologies for improving insulin action," he said.  "Our work clarifies what are likely to be the important therapeutic directions to improve insulin action in muscle and hence new approaches for the treatment of Type 2 diabetes."

Kraegen and colleagues made one small change to a single muscle in one leg of a rat, allowing that muscle to burn fat molecules better. To do this, they overexpressed a protein (CPT1) that acts like a "gate" or "tap" to control entry of fat molecules into mitochondria.

The changed muscle burned more fat molecules and became significantly more responsive to insulin than the equivalent muscle in the opposite leg, which had not been re-engineered.  While this result is very promising, it also sets up a conundrum, which Professors Kraegen and his colleagues at Garvan are examining in their next phase of research.

The problem they face is that a muscle uses a certain amount of energy depending on the work it is doing. If it gets that energy by burning more fats, it will require less glucose, creating an imbalance of another kind.

"So what we're trying to do is mimic exercise with pharmacological agents," explained Kraegen.

"We're examining agents that make the muscle burn more fuel to get the same amount of energy. In other words, we're trying to make energy conversion less efficient."

"If we succeed in producing this effect, it will make our current finding very potent indeed."

The Garvan Institute of Medical Research