09 July 2014
UNSW Australia has awarded a Doctor of Science (DSc) to Garvan's Professor Ted Kraegen. The degree is accorded in recognition of a body of work that has made a significant contribution to a field of knowledge.
In a career that has spanned over 45 years at Garvan alone, Professor Kraegen has furthered our understanding of the physiology and biochemistry of the action of the hormone insulin, and the metabolic disturbance underlying type 2 diabetes.
His submitted body of work contains over 140 publications that profile the mechanisms modulating insulin action – representing many highly-cited peer-reviewed research breakthroughs.
Among his many achievements, he was one of the first in the world to develop – for experimental purposes – an artificial pancreas that worked in people with type 1 diabetes. He also played a significant role in a team that initiated low dose intravenous insulin infusion for treatment of human ketoacidosis, a life-threatening complication in people with diabetes; this approach helped bring down the mortality rate in that condition from 12% to 3%.
Kraegen is honoured to receive the DSc, and at the same time quick to share his laurels. “I regard it as a privilege to have worked for so long in a place like Garvan, because I’ve collaborated with some incredibly clever people, all of whom have been very creative, and research is always a team effort,” he said.
The Doctor of Science degree requires contenders to provide a dissertation on their work, including the papers they are forwarding for consideration. “This is an opportunity for reflection and synthesis, allowing you to tell the story your own way,” explained Kraegen. “You need to outline significant milestones in your career, including what has led you to undertake particular experiments, what has triggered ideas, and how you’ve developed those ideas.”
“A particularly important collaborative project spanned the mid-to-late 80s, when our group was researching factors that lead to insulin resistance, or defective insulin action. We found that it was related strongly to fat metabolism and the build up of lipids in non-fat tissues – so-called ‘ectopic’ fat accumulation – particularly in muscle and liver.”
“That research highlighted a major mechanism that leads to insulin resistance and, down the line, to type 2 diabetes. It has provided a target for pharmaceutical development of different agents.”
Professor Kraegen and colleagues undertook collaborative work with several major pharmaceutical companies during the 1990s to develop agents that would reduce tissue accumulation of fat – and direct it back into fat storage depots where it could do less harm to metabolism. The thiazolidinediones or ‘glitazones’ were a major class of compound that were designed to achieve this effect.
“Our first collaboration was with Beecham UK, and the development of rosiglitazone, which became the second biggest selling anti-diabetic drug. Its mode of action, in part, was sequestering fat into adipose tissue and out of the other tissues.”
“Unfortunately, the thiazolidinedione class of compounds has some side effects, so there is still some work to be done. In principle, however, it has provided a useful target for ameliorating insulin resistance.”
“Earlier in my career, in the early-to-mid 70s, I studied the effect of insulin infusions in patients – finding that if insulin was infused optimally in someone, it is more potent than was generally given credit for at that time.”
“This method of low-dose insulin infusion led to collaborations with clinical colleagues, and ultimately changed the treatment of hospitalised patients with severe diabetic ketoacidosis.”
As an offshoot of the ketoacidosis project, Kraegen and colleagues developed an ‘artificial pancreas’ – “a closed loop system, where we sensed the blood glucose level of a patient and used that to control the insulin infusion rate, in the same way as a normal pancreas works”.
“We managed to define more closely the importance of delivering insulin very promptly with meals to simulate the normal anticipatory release mechanisms in people. When you start to eat, you release insulin before your blood glucose levels start to go up. That process is related to gut hormones, as well as the central nervous system.”
Kraegen has retired from his formal duties at Garvan, although he will “still continue to be involved, more on a consultative basis”.
“I think the future is exciting, particularly as we move more into molecular medicine, and the prospect of being able to manipulate and influence various biochemical pathways,” he said.
“There is still plenty of scope to develop agents without side effects; to better understand the difference between insulin and exercise; to try and mimic in people with diabetes the pathways that are activated during exercise.”
Professor Don Chisholm AO, a colleague of Kraegen for over 45 years, has shared much of his journey and witnessed his successes. “Among many scientific triumphs, Ted has made substantial contributions to understanding the physiological mechanisms underlying insulin resistance – which is of course the major feature in type 2 diabetes.”
“Repeatedly over the years, Ted has done things that are innovative and original and that have really attracted worldwide attention.”
“Other colleagues who have been important collaborators with him include Lesley Campbell, Greg Cooney, Les Lazarus, David James, Len Storlien, Warren Kidson, and John Casey. I am sure they will all join with me to congratulate him on his achievement.”