50 years ago, at a College meeting in Melbourne in late 1973, Warren Kidson gave the world's first presentation on the effectiveness, safety and simplicity of low-dose insulin infusion in the treatment of diabetic ketoacidosis (DKA) (Australian and New Zealand Journal of Medicine 4:106 (1974)).

The treatment was revolutionary, not only simplifying therapy but disproving long-held theories about resistance to insulin action in DKA.

Prior to the discovery of insulin, a patient diagnosed with Type 1 diabetes (T1DM or IDDM), would usually die from diabetic ketoacidosis (DKA) within two months. After the development of insulin therapy by Banting, Best, Macleod and Collip in Toronto 100 years ago, mortality from DKA dropped to around 10-13% over the ensuing 50 years. Recovery from DKA would be slow, over 1- 4 days after many hundreds of units of subcutaneous insulin, suggesting that DKA must cause resistance to insulin action.

In 1970, Edward (Ted) Kraegen, George Smythe and Les Lazarus of the Garvan Institute began investigating low level (physiologic) insulin infusions, initially demonstrating their potency in lowering blood glucose in nondiabetic subjects. At the time there was some controversy as to the importance of small insulin elevations in glucoregulation. Quantitation of circulating insulin levels commenced following the development of radio-immunoassays by Yalow and Berson in the 1960s.

In 1972, Warren Kidson, John Casey, Edward Kraegen and Les Lazarus decided to test the efficacy of low-dose insulin infusion as a therapy for DKA, presenting the results at the RACP meeting in Melbourne in October 1973 and publishing in the following year.

Insulin was infused at a rate of 1.2 U/hr, with hourly steps to 2.4 and 4.8 U/hr. Glucose levels fell promptly, with no improvement at infusion rates above 2.4 U/hr, achieving insulin levels of 60-80 mU/L, equivalent to levels seen post-prandially in non-diabetic individuals. The rate of response to physiological levels of insulin disproved the theory that DKA is associated with and/or causes insulin resistance.

Our findings that glucose levels could be normalised by 15 units of insulin over only 6 hours triggered controversy and even disbelief. However, simultaneous with our paper, two other papers were published in the same issue of the British Medical Journal, one from London and Edinburgh, with similar results, creating acceptance of low-dose insulin infusion as the treatment of choice for DKA throughout the Western world. Most major medical journals throughout the UK, Europe, America and Australia published editorials or leading articles on this revolutionary but simple and effective therapy.

'Low-dose insulin infusion has remained the treatment of choice for DKA world-wide over the past 50 years. The knowledge that this method is being used hundreds of times each day all around the world is certainly of great satisfaction.'

However, the benefits of our work were not just in the treatment of DKA. Professors Ted Kraegen, Lesley Campbell and Don Chisholm used the data to develop rational protocols for insulin-infusion rates in the development of the artificial pancreas.

After publicity of our results, two mothers of children with Type 1 diabetes approached Warren for advice on the prevention of the frequent hospitalisation of their children from DKA, hypoglycaemic coma and vomiting illnesses. In discussion with them and with a young man with T1D, Warren developed a three-pronged protocol for the home management of these emergencies:

1. For hyperglycaemia and early DKA, hourly intramuscular injections of low doses of insulin, 8 u for a man, 6 u for a woman and 4 u for a child until the glucose level was normalised.

2. For hypoglycaemic coma or confusion, the immediate injection of 1mg of glucagon followed by sweetened oral fluids when swallowing has been re-established and then solid food.

3. For vomiting illnesses, frequent small mouthfuls of sugary soft drinks until vomiting had settled.

This protocol became known as Sick-day management and spread world-wide.

Not only does low-dose insulin infusion remain the treatment choice for diabetic ketoacidosis after 50 years, it has driven the development of computer-controlled insulin infusion devices that have become widely used in routine treatment of T1D. It has improved our understanding of the physiology of T1D and insulin therapy, enabling people with T1D to take control of intercurrent events in their lives, preventing hospitalisation and reducing school- and work-absenteeism.

Les Lazarus passed away in December, 2022. John Casey has retired to Brisbane to be close to his family. Ted Kraegen and Warren Kidson are alive, retired and kicking in Sydney.