While diabetes has been recognised as a severe disease since ancient times, it was only during the mid-20th century that National Health and Medical Research Council (NHMRC)-funded researchers at the Baker Heart and Diabetes Institute conclusively demonstrated that there are 2 major types of diabetes – type 2 (T2D) and type 1 (T1D) – based upon whether a person can or cannot produce their own insulin.
This finding enabled future generations of researchers and clinicians to address each type separately, leading to improved treatments and health advice for those living with diabetes.
A PDF poster version of this case study is available – see Download section below.
Diabetes mellitus is a disease associated with high levels of blood sugar, a condition that if untreated can be fatal. It can also lead to serious health problems including cardiovascular disease, nerve damage, kidney damage, eye damage and hearing impairment.
Diabetes was medically described as early as the 5th century BC, in India,1 and by 1866 at least 2 distinct forms of the disease were recognised, requiring distinct courses of treatment.2
In 1889, researchers discovered that the pancreas produced a substance (insulin) that helped to prevent diabetes and in 1921 insulin itself was chemically isolated. Production of insulin commenced soon after, including (in 1922) by Australia's Commonwealth Serum Laboratories.3
In 1930, NHMRC's precursor body, the Federal Health Council, received a report from one of its members – Dr E Robertson, Chair of the Health Commission, Victoria – on 'action taken in Victoria to place the treatment by insulin and the provision of insulin for diabetics on a proper basis'.
This action was to occur within a broader 'Scheme for the reduction of the diabetic mortality in the State of Victoria', which was developed by Dr WJ Penfold of the Baker Medical Research Institute. The scheme comprised a number of steps, including determining which patients with high levels of blood sugar 'were true diabetics'.
Further understanding of this distinction between 'true' and other diabetes was provided in 1936 by the finding that people with diabetes could be divided into insulin-resistant and insulin-sensitive types.4 However, to prove or disprove definitively that these 2 types related to insulin production, it was necessary to estimate the plasma insulin level in those with diabetes5 and in the 1930s no method for doing so existed.
Grants and investment
NHMRC began funding medical research in 1938 and, commencing in 1939, researchers at the Baker Institute – which was established in 1926 as the biochemistry laboratory of The Alfred Hospital in Melbourne – received a succession of grants to support research on carbohydrate metabolism and diabetes. These topics had become highly significant once insulin started to become available.
The grants supported the work of a number of researchers including Charlotte Anderson, Joseph Bornstein, Arnold Ennor, GJ Lincoln, Shirley Richardson, Noel Rome and Phyliss Trewhella.
Insulin is a small protein molecule and a hormone: a chemical messenger within the body. Cells in the pancreas (beta cells) produce insulin in response to raised blood sugar levels.
In turn, insulin causes the cell membranes of muscle cells to draw in glucose, providing them with energy.
If the body has sufficient energy, insulin signals the liver and muscle cells to store glucose as glycogen and it signals the liver and the body's adipose (fat) tissues to convert glucose into triglycerides (a type of fat).
Circulating insulin also promotes protein synthesis inside body cells.
CSL and insulin
A Federal Serum Institute (later known as the Commonwealth Serum Laboratories and now CSL Ltd) was founded in 1916.
CSL established insulin production late in 1922 and treatment with this insulin was initiated in 1923. At this time, CSL was one of only 4 laboratories world-wide to produce insulin and it remains the sole manufacturer of insulin in Australia today.3
Anderson commenced research at the Institute in 1936 by investigating the effect of the pituitary gland upon diabetes. Her work indicated that extracts of the gland reduced the effectiveness of insulin in lowering blood sugar because they also increased the transformation of glycogen (stored in the liver and elsewhere) into glucose.6,7
Ennor recommenced work at the Institute in 1939 following completion of a Masters thesis on the effects of the adrenal gland on carbohydrate metabolism.8 Informed by Anderson's work, he began the search for an 'anti-diabetogenic' hormone whose production was stimulated by exposure to the pituitary gland extracts.9 His work also examined the effect of pituitary gland extracts on levels of the antioxidant glutathione in the liver.10
Informed by the work of Anderson, Ennor, and other researchers at the Institute, Bornstein began working with Trewhella in 1947 on how to measure the concentration of insulin in human blood plasma.11 Their approach was to create a type of rat that was unable to produce its own insulin or the pituitary and adrenal hormones that had previously been found to influence blood glucose (BG) levels and insulin uptake.12 These rats were difficult to work with13 because they tended to experience hypoglycemia (low BG levels)14 but they were also extremely sensitive to insulin and would experience a measurable reduction in BG after receiving only 2 nanograms of insulin.13,15
After being injected with both glucose and insulin, periodic measurement of BG levels in the rats would indicate how much insulin they had received. The more they had received the more their BG levels would fall.14 If such a rat was injected with human blood plasma, and if that plasma contained insulin, then this could be measured by changes in the rat's own BG levels.
Results and translation
In 1949, Bornstein and Trewhella used their technique in a study of 19 diabetic patients and found that 'in the majority no insulin could be detected in their plasma. The minority had, however, normal insulin concentrations in the plasma, suggesting that some mechanism operates which either creates a demand for more insulin than the body can secrete or prevents insulin from operating normally.'13 In 1950, they reported testing 17 patients of the Alfred Hospital diabetic clinic. These patients were found to fall into 2 groups and they concluded '… at least 2 forms of diabetes mellitus exist.'16
Supported by an NHMRC fellowship17, Bornstein travelled to the UK in 1950 to trial the technique with Robert Lawrence, a world leader in diabetes research. They investigated the plasma insulin content of patients who, on clinical grounds, appeared to be diabetic due either to a lack of insulin or to factors other than lack of insulin, and confirmed that the first group had no measurable insulin and the second group did.18 They concluded that they had proved 'that 2 clinical types of diabetes differ also in plasma insulin content.'13
From Bornstein and Lawrence's 1951 paper
From these analyses of plasma insulin related to clinical cases we consider that 2 main types of human diabetes exist and can be distinguished.
The first is severe and is characterized by weight loss and ketosis as well as hyperglycaemia; it occurs at any age, but mainly in the young, and their plasma contains no available insulin … They require insulin treatment to live.
The second type … is distinguished by the absence of ketosis and loss of weight. Their plasma contains available insulin, roughly 70% of normal controls … Their diabetic state is easily controlled by diet alone, especially when obesity is thereby reduced.13
Outcomes and impacts
The ability to distinguish T1D and T2D was globally significant because the 2 types are essentially separate diseases: they have different underlying molecular mechanisms and require different types of treatment.
Since insulin was first isolated, health and medical research has led to continual innovation in the treatment of diabetes and technologies have significantly improved a patient's ability to deliver the right amount of insulin. The most notable innovations include genetically-engineered synthetic 'human' insulin, insulin pumps, advances in glucose monitoring and the capacity for these technologies to interact. These new technologies have provided patients with enhanced flexibility in how and when they receive insulin and the ability to improve glucose levels, leading to better quality of life.
Recognising these benefits, the uptake of advanced technologies in Australians with T1D has increased. In 2018–19, 41% of children and 26% of adults attending hospital diabetes clinics managed their T1D with insulin pumps and 55% of children and 13% of adults newly commenced continuous glucose monitoring (CGM).19
Diabetes remains a significant public health issue in Australia, with an estimated 1.2 million Australians (or almost 5% of the total population) living with diabetes in 2017–18. However, the prevalence of T1D diabetes is much lower than that of T2D (0.3% versus 2.2% of the total burden of disease).
In 2015 in Australia, 4.7% of the total burden of disease was attributed to high blood plasma glucose levels (which includes diabetes and pre-diabetes). In 2015–16, an estimated 2.3% ($2.7 billion) of total disease expenditure in the Australian health system was attributed to diabetes.20
- Grants listed below are NHMRC grants unless indicated otherwise.
|1939||Grants (Anderson, Ennor)|
|1940||Grants (Anderson, Ennor)|
|1947||Grants (Lincoln, Richardson)|
|1949||Grant (Bornstein), Bornstein publishes bioassay method|
|1950||Grant (Bornstein), Bornstein and Trewhella demonstrate method, Fellowship to UK and USA (Bornstein)|
|1951||Bornstein and Lawrence prove to types relate to insulin|
Dr Charlotte Anderson AM
Charlotte Morrison Anderson (1915-2002) worked at the Baker Institute from 1936 to 1941, then as registrar and research fellow at the Royal Children's Hospital, Melbourne, where she made major contributions to the treatment of cystic fibrosis, coeliac disease and sugar intolerance.
In 1968, she became the first female Professor of Paediatrics in the United Kingdom, at the University of Birmingham Medical School, a position she held until she retired in 1980.
In 1997, Anderson was appointed a Member of the Order of Australia for her service to medicine.
Sir Arnold Ennor CBE
Arnold Hughes Ennor (1912-1977) worked from 1938 to 1943 at the Baker Institute and during 1946-1947 in the Department of Biochemistry at Oxford University. He returned to Melbourne in 1948 to be Senior Biochemist at CSL but was then appointed to the Foundation Chair of Biochemistry in the newly formed John Curtin School of Medical Research at The Australian National University, a role in which he remained for nearly 2 decades. He was Permanent Head of the Australian Government Department of Education and Science and then of the Department of Science (1967-1977). He was appointed CBE in 1963 and a Knight Bachelor in 1965.
Professor Joseph Bornstein
Joseph Bornstein was a biochemist who was closely associated with The Alfred Hospital as a student. He joined the Baker Institute in 1947 then worked in The Alfred Hospital Metabolic and Diabetic Unit from its establishment in 1955 until 1961.
Bornstein was then appointed Professor of Medical Biochemistry at Monash University and the Foundation Professor of Monash’s new Department of Biochemistry.
Dr William Penfold
Dr William James Penfold (1875-1941) was recruited from the Lister Institute in London to be CSL's founding director in 1916, where he remained until he left to direct the newly formed Baker Institute in 1926, retiring in 1938.
Phyllis Trewhella B.Sc.
Phyllis Trewhella studied science at The University of Melbourne. She worked at the Baker Institute from 1949 to 1951, then worked as a teaching laboratory demonstrator at the Pharmacy College in Melbourne.
Types of diabetes
T1D often commences during childhood or young adulthood but can actually begin at any stage of life. It results from an autoimmune reaction that destroys the insulin-producing beta cells in the pancreas. Treatment for T1D involves the regular injection of insulin to manage raised blood sugar levels (hyperglycemia).
Such injections are necessary multiple times per day, with dosages adjusted to account for food intake, blood glucose levels and physical activity. Prolonged lack of insulin can result in diabetic ketoacidosis which, if untreated, can rapidly progress to loss of consciousness, coma and death.
T2D diabetes is characterised by a combination of insulin resistance (an impairment of the body's response to insulin) and a reduction in the amount of insulin that is produced. A person may have a strong genetic disposition towards T2D and their risk is greatly increased if they are overweight and inactive.
Those living with T2D can improve their blood glucose levels with regular exercise and by following a healthy diet, as well as by using a range of medications including insulin.
Gestational diabetes occurs during pregnancy and usually disappears after the baby's birth.
This case study was developed in partnership with the Baker Heart and Diabetes Institute.
The information and images from which impact case studies are produced may be obtained from a number of sources including our case study partner, NHMRC's internal records and publicly available materials.
The following sources were consulted for this case study:
- Karamanou M, Protogerou A, Tsoucalas G, Androutsos G, and Poulakou-Rebelakou E. Milestones in the history of diabetes mellitus: The main contributors. World J Diabetes. 2016 Jan 10; 7(1): 1–7
- Harley G. Diabetes: Its Various Forms and Different Treatments. London, Walton and Mabberley. 1866. p5
- Eyre F. Technology in Australia, 1788–1988: A condensed history of Australian technological innovation and adaptation during the first two hundred years. Australian Academy of Technological Sciences and Engineering. 1988. p662. Viewed online at https://www.austehc.unimelb.edu.au/tia/about.html, 25 October 2021
- Alberti KGMM. Chapter 2 The classification and diagnosis of Diabetes Mellitus, In Holt RIG, Cockram CS, Flyvbjerg A, Goldstein BJ (eds), Textbook of diabetes. pp9–12
- Aiman R, Kulkarni RD. Plasma insulin estimation and its significance in diabetes mellitus. Indian Journal of Psychology. 1958 Jul;2(3):430–6. PMID: 13586926
- The Baker Medical Research Institute. Tenth Annual Report. 1935–36
- The Baker Medical Research Institute. Eleventh Annual Report. 1936–37
- The Thomas Baker, Alice Baker, and Eleanor Shaw Medical Research Institute. Thirteenth Annual Report 1938–39
- The Thomas Baker, Alice Baker, and Eleanor Shaw Medical Research Institute. Fifteenth Annual Report 1940–41
- National Health and Medical Research Council. Report upon the work done under the Medical Research Endowment Act during the year 1939. Australian Government. 1940
- The Thomas Baker, Alice Baker, and Eleanor Shaw Medical Research Institute. Twenty-First Annual Report. 1947
- The Thomas Baker, Alice Baker, and Eleanor Shaw Medical Research Institute. Alfred Hospital, Prahran Victoria Australia. Twenty-Third Annual Report 1949 and A Retrospect 1926–1950
- Bornstein J, Lawrence RD. Plasma insulin in human diabetes mellitus. British Medical Journal. 1951 Dec 12;2(4747):1541
- Bornstein J. A technique for the assay of small quantities of insulin using alloxan diabetic, hypophysectomized, adrenalectomized rats. Aust J Exp Biol Med Sci. 1950 Jan;28(1):87–91
- Burns C, Morris T, Jones B, Koch W, Borer M, Riber U and Bristow A. Expert Committee on Biological Standardization, Expert Committee on Specifications for Pharmaceutical Preparations. Proposal to initiate a project to evaluate a candidate International Standard for Human Recombinant Insulin. World Health Organization. Geneva, 18–22 October 2010. WHO/BS/10.2143
- Bornstein J, Trewhella P. Plasma insulin levels in diabetes mellitus in man. Aust J Exp Biol Med Sci. 1950 Sep;28(5):569–72
- The Thomas Baker, Alice Baker, and Eleanor Shaw Medical Research Institute. Alfred Hospital, Prahran Victoria Australia. Twenty-Fourth Annual Report 1950
- Bornstein J, Lawrence RD. Two types of diabetes mellitus, with and without available plasma insulin. British Medical Journal. 1951 Apr 4;1(4709):732.
- Snaith JR, Holmes‐Walker DJ. Technologies in the management of type 1 diabetes. Medical Journal of Australia. 2021 Mar;214(5):202–5.
- Australian Institute of Health and Welfare 2020. Diabetes. Cat. no. CVD 82. Canberra: AIHW. Viewed 09 October 2021, https://www.aihw.gov.au/reports/diabetes/diabetes
Under NHMRC's Funding Agreement, Administering Institutions must comply, and require their Participating Institutions, Research Activities and applications to comply, with relevant legislation. At the time of writing, relevant legislation governing the use of animals for research includes state and territory animal welfare legislation. NHMRC also requires compliance with NHMRC-approved Standards and Guidelines and any applicable NHMRC policies. At the time of writing, and with respect to animals, these include the:
- Australian Code for the Responsible Conduct of Research (2018)
- Australian code for the care and use of animals for scientific purposes 8th edition (2013, updated 2021)
- Best practice methodology in the use of animals for scientific purposes (2017)
- Principles and guidelines on the care and use of non-human primates for scientific purposes (2016)
- A guide to the care and use of Australian native mammals in research and teaching (2014).
Ethical, scientific, veterinary and medical standards and practices related to animal research change over time. NHMRC-funded research activities that occurred before the present time were subject to the legislation and NHMRC's Standards, Guidelines and policies in force at the time that they occurred.