Discovery of type 1 diabetes

The subdivision into type 1 and type 2 diabetes is fundamental to the way we think about the disease. Clinicians recognised that there were two forms of the condition more than 100 years ago. Children with diabetes died rapidly, for example, whereas older overweight individuals could survive for years by following a diet. Himsworth deduced that there were two forms of diabetes, an insulin-deficient form and an insulin resistant form, in the 1930s, and the terms type 1 and type 2 diabetes were first proposed in 1951. The concept of autoimmunity became established (against great resistance) in the 1950s, but recognition of the existence of an immune-mediated form of diabetes was delayed until the 1970s. Many of the key observations leading up to the new discovery were made possible by developments in areas unrelated to diabetes. The model of disease proposed in 1976 is still widely accepted, and its essential features have been modified only in detail since then. Dogmatic thinking prevented the realisation that there were at least two forms of diabetes for decades. The current dogma will no doubt be challenged and revised in the course of time.

Two types of diabetes?

Lancereaux
Lancereaux
Harley, a British physician, commented in 1866 that 'there are at least two distinct forms of the disease [diabetes] requiring diametrically opposing forms of treatment', but the French physician Lancereaux is generally credited with making the distinction between fat and thin diabetes: diabete gras and diabete maigre.

The distinction between the two forms of diabetes was indeed stark in the preinsulin era. Most children and some adults died of diabetes within months, whereas overweight older patients often survived for years. When insulin became available, those in the first category no longer wasted away, whereas those in the second continued to get by on diet alone.[1] [a]

Insulin-deficient and insulin-insensitive diabetes

The first test used to distinguish between the two main forms of diabetes was response to insulin. Wilhelm Falta and other investigators in Vienna drew attention to the existence of insulin-sensitive and -resistant forms of diabetes. Insulin-sensitive patients readily suppressed urinary excretion of glucose and became hypoglycaemic in response to a few units of insulin, whereas withdrawal of insulin rapidly resulted in glycosuria and ketosis. Harold Himsworth, a British physician, developed a challenge test in which glucose was given by mouth while insulin was injected intravenously. Himsworth's insulin sensitivity test
Himsworth's insulin sensitivity test
He found that lean young patients had similar insulin sensitivity to that of non-diabetic individuals, whereas older overweight patients were markedly insensitive. From these simple clinical observations, he concluded that 'in insulin-sensitive diabetics the disease is due to deficiency of insulin, whilst in insulin-insensitive patients diabetes mellitus results, not from lack of insulin, but from lack of an unknown factor which renders the body sensitive to insulin'.

Pancreatic and non-pancreatic diabetes

Despite the success of pancreatic extract in treating diabetes, pancreases from patients with diabetes often appeared normal under the microscope, which led investigators to look outside the pancreas for the causes of diabetes. In 1927 it was shown that blood glucose in the dog rose in response to injections of extract of anterior pituitary. Houssay
Houssay
Soon after this, Houssay, aware that acromegaly had recently been reported to cause diabetes, made his classic observation that hypophysectomy improved features of diabetes in experimental animals. Investigators in the 1930s accepted that there was more than one form of diabetes, but looked for its origins in the pituitary or in other factors causing insulin insensitivity.

Type 1 diabetes makes its first appearance

The term type 1 diabetes came indirectly from the science of anthropometry. W.H. Sheldon introduced somatotyping in 1940 in the belief that certain types of disease were associated with certain physical characteristics. The technique was performed by a trained observer, who scored the physique of subjects using a standard photograph measured against a grid. A physical anthropologist called Dupertuis examined 225 patients with diabetes in a New York clinic, on behalf of a physician called Draper, in the belief that diabetes was a single disease. He was puzzled to find that there were two distinct morphological types. He referred to these as group I and group II; group I was further subdivided into IA and IB according to the degree of body fat. These observations were taken further by John Lister and colleagues, who combined the insulin sensitivity test of Himsworth with the somatotyping technique of Sheldon. They reported in 1951 that there are 'two broad groups of diabetics—the young, thin, non-arteriosclerotic group with normal blood pressure and usually an acute onset to the disease, and the older, obese, arteriosclerotic group with hypertension and usually an insidious onset. ... These types we have provisionally designated type I and type II, respectively.' The new terminology did not catch on, and was forgotten until resurrected by Andrew Cudworth (who learned of it from John Lister) in 1976.

More evidence that juvenile diabetes is insulin-deficient

Further evidence that insulin is lacking in early-onset diabetes came from attempts to measure the insulin content of pancreases removed at autopsy from those with diabetes. A landmark study from Toronto demonstrated that insulin was almost undetectable in the pancreas of those who died before the age of 20 years, whereas pancreases from individuals over that age contained on average 40–50% as much insulin as did those from non-diabetic individuals.

The geneticist's nightmare

In the absence of reliable gene markers, such as those that are now available, geneticists studied inheritance, and developed highly sophisticated statistical models for analysis of complex data. Harris, writing of diabetes in 1950, was typical of others in wondering if 'we were dealing not with a single disorder but several genetically distinct diseases'. He noted the high sib–sib correlation in early-onset diabetes, suggesting a genetic basis for the disease. At the same time, he noticed that 'cases of late onset and mild diabetes occur not infrequently among the parents and other relatives of the severe juvenile and young adult forms of the disease [and] this evidence is hardly in line with the view that we are dealing with two genetically distinct and separate diseases'. He concluded that early-onset patients are homozygous for a gene present in heterozygous form in later onset disease. By 1970, almost every mode of transmission had been proposed for diabetes, and Rimoin had concluded that definitive genetic studies of diabetes would not be possible until the basic defects underlying the disease were elucidated and reliable disease markers became available.

The autoimmune paradigm

Ehrlich commented in 1900 that the organism 'possesses certain contrivances, by means of which the immunity reaction, so easily produced by all kinds of cells, is prevented from acting against the organism’s own elements and so giving rise to autotoxins ... so that one might be justified in speaking of a horror autotoxicus'. It soon became dogma that the immune system was unable to attack tissues from the same individual. Noel Rose
Noel Rose
In 1957 Witebsky and Rose demonstrated that antibodies could be generated against crude extracts of thyroid from animals of their own species and even against their own thyroid tissue when reinjected.

Roitt and Doniach soon described human thyroid autoantibodies and suggested that 'destruction of the thyroid in Hashimoto’s disease results from progressive interaction of thyroglobulin in the gland with the autoantibody present in the patient’s circulation'.

Insulin antibodies

Another step in the story was the demonstration by Berson and Yalow that insulin-binding globulin was present in the serum of insulin-treated diabetic patients. This suggested that these antibodies might even cause diabetes. The immunology of diabetes, and the first steps towards cleaner insulins, began with this key observation.

The rediscovery of insulitis

Lymphocytic infiltration of the pancreatic islets was described as an incidental finding by pathologists at the start of the twentieth century, and the term 'insulitis' was first used by von Meyenberg in 1940. The lesion escaped greater notice because it is transient and is not always obvious, and is found only in the islets of patients with early-onset autoimmune diabetes who die soon after diagnosis. In 1965, Willy Gepts, published a careful analysis of pancreases from patients with juvenile diabetes, 22 of whom had died within 6 months of diagnosis. He found insulitis in 15 and speculated that the islet lesions might have 'an immunological origin'.

Cellular immune changes

The first clue to autoimmunity in many diseases has been the identification of circulating antibodies directed agains the target tissue, but in diabetes these proved elusive (see below), and the first direct evidence came from a test of cellular immune function. Nerup exposed mononuclear cells from the young insulin-dependent patients to porcine islet material, spun them into capillary tubes, and incubated on the surface of an agar plate. Under normal circumstances, macrophages will migrate out of the tube, but this process is inhibited if T-cells in the mixture respond to the antigen by production of inhibitory factors. The assay therefore detects the presence of T-cells primed against the antigen tested. These mechanisms were unknown at the time, but the test, although crude, was recognised as a measure of 'cellular hypersensitivity'.

Associations with the HLA system

Meanwhile, the mouse major histocompatibility complex (MHC) and the human HLA system had been identified as 'transplantation antigens' by immunologists working toward human transplantation. Further, immune response genes were identified and shown to be linked to the MHC in several animal species. The genes were soon shown to control patterns of response to viral infection, and it seemed likely that some of these responses could cross-react with antigens on host tissue, thus providing a link between virus infection and the development of autoimmunity.

By 1974, HLA associations had been reported for a range of autoimmune conditions Nerup, meanwhile, had struggled in vain to demonstrate that diabetic patients had cellular hypersensitivity directed against viral antigens. Turning to HLA, he published associations with HLA-B8 and -B15; Cudworth and Woodrow published the same observations in a letter very soon after. The concept that genes transmit the tendency to develop diabetes, but not the disease itself, was now established.

The discovery of ICAs

Early attempt to identify ICA by indirect immunofluorescence were unsuccessful for several reasons. The fluorescent signal is relatively weak, and required a new generation of microscopes to be seen with ease; furthermore, ICA are most easily detected in the newly diagnosed, and are lost with increasing duration of diabetes. Good quality group O human pancreas is needed. ICA staining persists in those with GAD antibodies, however, since these last longer in the circulation and contribute to the staining pattern. These conditions finally came together to enable Bottazzo and Doniach to make the first report in 1974, shortly followed by a confirmatory study from a group in Scotland.

Acceptance of type 1 diabetes

The 1985 WHO classification of diabetes was the first international classification to recognise the existence of two forms of diabetes, then called insulin-dependent and non-insulin-dependent diabetes (IDDM and NIDDM). Type 1 and 2 diabetes were recognised as alternative designations. It was only by the end of the century, 50 years after the terms were first proposed by Lister, that they became the accepted currency of classification. The dogma that there are two distinct types of diabetes has now become as solidly entrenched as the dogma of one single type was prior to 1974.

References

  1. ^ Gale EAM. The discovery of type 1 diabetes. Diabetes 2001;50:217–26

Footnotes

  1. ^ This article is condensed from the single review cited above, and detailed references are cited in this source.

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