The etiological heterogeneity of idiopathic diabetes has been recognized for 25 years, and subdivision into type 1 and type 2 diabetes is fundamental to the way we think about the disease. Review of the literature suggests that the concept of type 1 diabetes as an immunemediated disease emerged rapidly over the period from 1974 to 1976 and showed many of the features of a classic paradigm shift. A few key observations triggered recognition and acceptance of the new paradigm, but the necessary context was provided by scientific developments in areas mainly unrelated to diabetes. The disease paradigm established by 1976 is still widely accepted, and its essential features have been modified only in detail by the revolution in molecular biology that has occurred over the intervening period. Notwithstanding, some of the underlying assumptions remain imprecise, unchallenged, or unconfirmed. Appreciation of the historical origin and subsequent evolution of these fundamental concepts could stimulate critical analysis and help prepare the way for a new paradigm.
The word “paradigm” has the root meaning “to show side by side” and is used when an ideal or theoretical model is held up against reality. The historian Thomas Kuhn has pointed out that groups of scientists working within an area form loosely interwoven communities with a common working map, or paradigm.
As he put it, “A paradigm is what the members of a scientific community share, and, conversely, a scientific community consists of men who share a paradigm.” Scientific communities can be surprisingly resistant to new ideas or data that do not fit the accepted model, and change, when it comes, comes suddenly. Kuhn refers to this as a “paradigm shift.” Paradigm shifts typically occur among small networks of scientists who interact informally and at meetings. At such junctures, thinking unfreezes and new ideas fly around within the group until the best fit is found and competing views resolve themselves into the new paradigm. Recognition and acceptance of the new paradigm by the wider scientific community comes much more slowly.
Our current view of type 1 diabetes as an autoimmune disorder arose from two dramatic reversals of previous opinion, both of which fit well into Kuhn’s classic description of a paradigm shift. The first was the discovery of autoimmunity in the 1950s, and the second was the recognition in the 1970s that juvenile diabetes has an autoimmune basis. Both shifts in perception gained the acceptance of a key section of the scientific community within the space of a few months. In the second paradigm shift, the prevailing view—which pictured early- and late-onset diabetes as gradations or variants of the same genetically determined disease process—was rejected. Instead, juvenile diabetes was seen to fit the paradigm of an organ-specific autoimmune disorder. New knowledge and understanding accumulated so explosively that one authority claimed in 1976 that “new cases of juvenile diabetes may be prevented if our present rate of knowledge about the disease continues to grow over the next two or three years at the rate that it has for the past five years”. This promise was not fulfilled, however, and the paradigm established 25 years ago has persisted with minor modification right up to the present. This review will trace the developments leading up to the discovery of type 1 diabetes in 1976 and will ask why the paradigm has proved so stable since then.
THE HETEROGENEITY OF DIABETES
Although 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”, 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. Clinicians sorted their patients according to the triad of age of onset, perceived requirement for insulin, and body mass, just as they do to this day. Many acute clinical observations were based on this difference in phenotype. For example, Joslin noted that the incidence of diabetes in lean individuals was relatively constant in each decade of life, but that diabetes in the obese was related to age. He attributed the increasing prevalence of diabetes in the 1930s to increasing obesity, this observation being made when there was much less diabetes in the population. Clinical observations suggesting that diabetes was a heterogeneous condition were, however, of limited value in the absence of biological markers. As Sydney Brenner has remarked, “Progress in science depends on new techniques, new discoveries and new ideas, probably in that order.” This comment accurately characterizes the discovery of type 1 diabetes.
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 developed hypoglycemia in response to a few units of insulin, whereas withdrawal of insulin rapidly resulted in glycosuria and ketosis. These features were lacking in insulin-insensitive patients. In the U.K., Himsworth developed a challenge test in which glucose was given by mouth while insulin was injected intravenously. He found that lean young patients had insulin sensitivity equivalent to that of nondiabetic individuals, whereas older overweight patients were markedly insensitive to insulin. Analysis of arteriovenous glucose levels during these tests led him to conclude that insulin insensitivity resided at the level of skeletal muscle. 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 nonpancreatic diabetes. What might this “unknown factor” be? Despite the success of pancreatic extract in treating diabetes, pancreata from patients with diabetes often appeared normal under the microscope, and this lent weight to the search for extrapancreatic causes of diabetes. In 1927, it was shown that hyperglycemia could be induced in the dog by injections of extract of anterior pituitary; and shortly 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. The etiological heterogeneity of diabetes was widely assumed in the 1930s, but was based on the search for circulating pituitary or other factors causing insulin insensitivity. This quest, which proved fruitless—at least insofar as understanding of diabetes was concerned—occupied the attention of investigators for many years. In a sense it occupies us still, because the relative importance of factors intrinsic and extrinsic to the pancreas remains controversial in both immune-mediated and non-immune-mediated diabetes.
Type 1 diabetes makes its first appearance. Rather curiously, 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 from a New York clinic. Having undertaken the study 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. Group IA tended “to possess skeletal linearity and delicacy,” whereas in group IB, “the muscle sculpturing is obscured by the smooth and often slight overlying panniculus of fat”. In other words, the patients in group IA were skinnier. These observations were taken further by Lister et al., who noted 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.” These terms, used then as we use them today, were not to be mentioned again until they were reintroduced by Cudworth—who was collaborating with Lister at the time—in 1976.
More evidence that juvenile diabetes is insulin-deficient. The first direct evidence that early-onset diabetes is insulin-deficient was based on a crude bioassay for circulating insulin. In this study from 1951, 1 ml of plasma from each of six patients was injected into alloxan-induced diabetic, hypophysectomized, and adrenalectomized rats, and the fall in blood glucose was measured after one hour; standard curves were constructed by injection of commercial insulin into the same animals. The study appeared to demonstrate the existence of insulin-deficient and non-insulin-deficient forms of diabetes. Meanwhile, attempts had been made to measure the insulin content of pancreata removed at autopsy. These culminated in a massive report from Toronto that described the extractable insulin content of pancreata from 64 diabetic and 139 nondiabetic individuals. Insulin content was assessed by the mouse convulsion test used at that time to calibrate batches of commercial insulin. This study demonstrated that insulin was almost undetectable in the pancreata of diabetic patients who died before the age of 20 years, whereas pancreata from individuals over that age contained on average 40-50% as much insulin per gram wet weight as did pancreata from nondiabetic individuals.
THE GENETICIST’S NIGHTMARE
It takes an act of imagination for the modern reader to conceive of studying genetics in the absence of any gene markers. What geneticists studied was inheritance, and classic geneticists 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: autosomal-recessive, autosomal-dominant, juvenile-homozygous/adult-heterozygous, sex-linked, and multifactorial . Simpson had proposed polygenic inheritance, and this was supported by other studies. In 1966, Rimoin 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.
Edwin A.M. Gale
From Diabetes and Metabolism, Division of Medicine, University of Bristol, Bristol, U.K.