Insulin resistance and disease

The second research focus of the diabetes and obesity program is the connection between insulin resistance and disease. This phenomenon called insulin resistance is clearly one of the earliest abnormalities to precede disease with respect to type 2 diabetes.

Insulin resistance is defined as the inability of insulin in the body to work correctly in peripheral tissues. There is an enormous amount of interest in insulin resistance because the feeling, pharmacologically, is that drugs that prevent it from happening might substantially delay the onset of disease.

"At the moment, there are many efforts and drugs out there that target the complications of the disease once it has taken hold, but that is not where we want to be," James says. "It is like putting bandaids on a wound that is never going to go away."

Recent work in the program has provided novel insights into the mechanisms of insulin resistance, which, according to James, is again not exactly what people think it is. "Our evidence implicates oxidative stress, and particularly that occurring in the mitochondria, as a very early step in the development of insulin resistance. In fact, we already have very revealing and quite neat results from experiments in animals to support this proposal."

As part of the second focus, the basic scientists in James's program have also just embarked on a large collaboration with hospital-based clinical researchers. The clinicians are recruiting individuals at risk of developing diabetes, but without any clinical signs of onset.

"Now armed with all the data and information and insights from our work in cells and animals models, we can now go into the human and ask if any of this stuff is relevant to the human condition. At the end of the day, the best model for what is going on with insulin resistance and diabetes is the human being, and we are very cognisant of that."

Cucumbers with warts

The third and newest area of the program is drug development. This is an expanding focus, and according to James, one of the flagship programs currently is the use of traditional Chinese medicines.

It started about four years ago with a visit from scientists of the Shanghai Institutes for Biological Sciences in China. They were looking for potential collaborative projects in the area of type 2 diabetes, a rapidly growing problem in China that correlates with its status as an emerging economy and the average body weight of the population.

It is estimated that by 2020, there will be as many Chinese suffering from type 2 diabetes as the total number in the world today. Sadly, the other economic powerhouse, India, is rapidly following suit.

"Our program seemed to fit quite well with what they wanted and it just went from strength to strength," James says. "In fact, we just had a paper accepted in one of the leading chemistry journals."

The work centres on a vegetable of the cucurbit family, which has been used to treat diabetes in China for several hundreds of years. It is called bitter melon (Momordica charantia) and is described by James as "looking a bit like a cucumber with warts".

"Our collaborators in China literally got hold of a tonne of the stuff, ground it up and started purifying all the small molecular components by high-throughput HPLC and other methods." The Chinese scientists solved many of the component structures to the atomic level, and many have turned out to be completely novel compounds - never before described.

The ones of most interest to James and colleagues fall into a chemical group called triterpenoids. The Garvan researchers tested a host of purified candidates using their established cellular assays and animal models of diabetes, and James was genuinely surprised at the results.

"Lo and behold, some of these compounds seemed to have insulin-like effects in our cells. Furthermore, when we administered them to animals, they had an insulin-sensitising effect. In other words, they improved the animal's glucose tolerance.

"This stuff really does blow me away. You start with a vegetable that has been used for eons to treat the disease in China, plus more than a little scepticism, and end up with new compounds that might one day be used to treat diabetes. It has turned out to be more exciting and promising than I ever would have imagined."

The importance of preventing or even delaying the onset of type 2 diabetes is clear simply from cost-benefits alone. Last year, Australia spent several billion dollars treating diabetes, which is fifth highest on the list in this regard. Delaying the onset of disease by 10 years, or even five years, could save the health system an enormous amount of money, not to mention dramatically improving the health of Australians.

The other interesting thing about the disease, according to James, is whether it is just a lifestyle disease - clearly a longer discussion than these pages allow, but it is one of the reasons that diabetes gets a bad rap. He and his colleagues at the Garvan have come to realise through their research that it is just not that simple. If it were, more would have it as our population ages and gets heavier by the mouthful.

As James says, "it is in a way a disease of progress and we could stop it if we could turn the clock back, but we can't. The desire to eat is very powerful. What coming back to the Garvan has emphasised for me is that at the end of the day we can't just sit in our labs and pretend it is just about curiosity. You have to constantly re-evaluate where you are going in terms of the human health perspective. It may be just a reflection of getting older, but I honestly believe that."