History 1900 to 1950

The first half of the twentieth century saw increasing use of tissue extracts to treat hormone deficiency disorders. Extracts of sheep thyroid were first used in the 1890s, and both thyroxine and adrenaline were synthesised in the early part of the century. Peptide hormones such as insulin presented a much greater challenge, and the triumphant "discovery" of insulin in 1921, followed by its purification, standardization and clinical use represent the great success story of this period. Diabetes was converted from an acute to a chronic medical condition almost overnight, and the euphoria persisted until the horrific morbidity and mortality of small and large blood vessel complications became apparent from the 1930s onwards. In scientific terms, this period also saw the rise of clinical chemistry with increased understanding of the fundamental metabolic pathways and the role of enzymes in regulating the flow of nutrients from one tissue to another. The revolution in molecular biology had yet to come.

Organotherapy

The road to insulin began with what was referred to as "organotherapy"; the attempt to treat a range of conditions with tissue extracts. The most effective of these were sheep thyroid, taken by mouth to treat hypothyroidism (thyroxine is not broken down in the stomach), and extracts of adrenal medulla from which adrenaline was soon derived.

Peptide hormones, as we now appreciate, were an order of magnitude more difficult to extract. Testicular extracts had an understandable appeal to Victorian gentlemen passing their prime, and Brown-Séquard astounded medical audiences with accounts of the effects of injections of calf seminal fluid upon his own prowess. The Sherlock Holmes adventure known for the "dog that did not bark in the night" revolved around a Cambridge professor who took monkey gland extracts in the attempt to find favour with a much younger lady, and developed some unfortunate simian traits (such as climbing out of windows) in consequence.

The word "hormone" was coined by Bayliss and Starling in 1902 following their preparation of a duodenal extract which contained secretin (gastrin was identified in 1906), but the nature of the "pancreatic factor" was unknown and it was generally assumed that it would act like an enzyme.

The Road to Insulin

Some of the milestones along this road are listed in Timeline 1900-1950. By the beginning of the century it was known that excision of a pancreas produced diabetes, which could be reversed by transplanting the gland elsewhere in the body. Further evidence of a circulating factor came from cross-circulation experiments in which blood from a healthy dog was perfused through another dog without a pancreas, causing a prompt fall in blood glucose. It was also known that blocking the pancreatic duct with paraffin caused atrophy of the exocrine pancreas but not diabetes, suggesting that the pancreatic factor came from the islets (which were not affected by the procedure).

Several came very close to producing an effective pancreatic extract, and possibly even succeeded; these include Zuelzer, Scott and Paulesco. Banting's insight (shared by others before him) was a belief that the hypothetical pancreatic factor produced by the islets was broken down by digestive enzymes released from the exocrine pancreas in the course of the extraction process. He proposed to get around this by blocking the pancreatic duct and allowing the exocrine pancreas to atrophy before attempting the extraction. This was in fact entirely unnecessary - but was not the only time in the history of diabetes when the wrong idea would set someone on the right road.

The discovery of insulin involved more than a bit of serendipity. In retrospect, it is obvious that many of those who tried came very close; conversely, so many had failed that only someone very inexperienced would be optimistic enough even to try. That someone was Frederick Banting, an unsuccessful orthopaedic surgeon still traumatized by his wartime experience, aided by Charles Best, a medical student brought in to measure blood glucose. Professor John Macleod showed exceptional insight (or tolerance) in letting such rank amateurs loose in his laboratory.

The story of the discovery of insulin is memorably told by Michael Bliss[1]. The inexperienced pair lurched from one failed experiment to another through a long hot Toronto summer, and were at times reduced to buying dogs for their experiments in the street. Eventually they succeeded in producing a "brown muck" which lowered blood glucose in dogs, but failed in its first human trial in a patient called Leonard Thompson. Macleod brought James Collip in to help, and in January 1922, working late into the night, Collip hit upon an extraction procedure that cause insulin to be precipitated, and thus became the first person to "see insulin".

At this point the pharmaceutical industry stepped in, as it would later do with the manufacture of penicillin, and scaled the extraction into an industrial procedure. This began with the Connaught laboratories in Canada and the licence was soon extended to Eli Lilly in the USA and to three manufacturers in the UK. Danish insulin manufacture got going in 1923, and pioneers around the world set out to make insulin, often in their kitchens. Robert Tattersall has described the stumbling and sometimes pig-headed way in which this magical new therapy was introduced in the UK[2]

Despite the important step of crystallisation, which was thought to guarantee its purity, commercial insulin still contained many contaminants including glucagon, isolated and named well in advance of its subsequent characterization by Murlin in 1923. Others observed that administration of intestinal or gastric extracts lowered blood glucose in experimental animals - as we now appreciate, because they contained GLP-1 and/or GIP - and the term "incretin" was coined by La Barre in Belgium.

Other impurities resulted in painful and sometimes disfiguring allergic reactions, and Erik Jorpes in Sweden made the important observation that thrice-crystallised insulin did not cause allergic reactions, an observation that pointed the way to the later development of the highly purified insulins by the Danish manufacturers.

Early insulin preparations were unstandardised and international efforts involving the League of Nations resulted in the introduction of standard units, based upon the quantity of insulin required to produce hypoglycaemic convulsions in rabbits and (later) in mice[3].

The major complication of insulin therapy was hypoglycaemia, a condition rarely encountered under other circumstances. The pattern of hypoglycaemic reactions changed with the introduction of the longer-acting insulins (NPH and PZI) in the 1930s and 1940s. People taking the long-acting insulins were more likely to slip into hypoglycaemia without knowing it, sometimes producing bizarre behavioural changes as well as coma or convulsions. Sadly, this led to the public perception that people with diabetes were odd; more sadly still, it led academics to study a mythical "diabetic personality".

Explorers of Unknown Seas

The future of children whose lives had been transformed by insulin was unknown, as exemplified by the medal that Joslin gave to 10-years survivors in the 1930s. The medal showed a small boy (one of Joslin's patients) adrift in a small boat at sea, accompanied only by his dog. The sun was rising, expressing the dawn of a new future; the sea expressed an uncertain future.

Joslin himself over-estimated the survival of his patients, for the unknown seas led to the microvascular complications of diabetes. Paul Kimmelstiel, a refugee from Nazi Germany crossed the Atlantic in the 1930s with a suitcase containing the histological slides and clinical details of patients who died from a clinico-pathological syndrome characterized by hypertension, renal failure with albuminuria, widespread oedema and retinitis in longstanding and often mild diabetics whose kidneys demonstrated histologically what they termed intercapillary glomerulosclerosis[4].

In the same year Root and Sharkey published an analysis showing the massive contribution of arteriosclerosis to the early deaths of people with diabetes[5]. In 1943, according to Joslin[6], diabetes was 8th in the list of causes of death in the USA, accounting for 1 death in 40.

Most clinicians, including Edward Tolstoi considered the vascular complications of diabetes to be inevitable, and in any event unconnected with the level of glucose in the blood. They therefore advocated purely symptomatic management of diabetes with an emphasis on avoiding hypoglycaemia. Joslin and his followers, in marked contrast, argued for the best possible glucose control. War was waged with almost theological intensity over such issues as the right diet for diabetes[7].

The question as to control and microvascular complications would not be settled decisively until the publication of the Diabetes Control and Complications Trial (DCCT) some 50 years later.

Two types of diabetes

Clinicians were for the most part aware that there were two major presentations of diabetes: the young, who died without insulin, and older people with milder symptoms who could survive without insulin but had a reduced life expectancy. Geneticists hypothesised that the young had two copies of the hypothetical diabetes gene whereas older people had only one. Sir Harold Himsworth MD, FRS (1905-1993) expressed the difference most clearly, and decades ahead of his time, in concluding that there were insulin-sensitive and insensitive variants of diabetes, thus introducing the concept of insulin resistance into what came to be called type 2 diabetes. He felt that diabetes was often caused by over-activity of the anterior pituitary, like almost all clinicians at the time, and pituitary irradiation was sometimes attempted in the attempt to delay its course.

Meanwhile, in the Laboratory...

Although not as yet of limited relevance to the understanding and management of diabetes, this period also saw the rise of biochemistry, together with early understanding of the roles of subcellular fractions (most importantly the mitochondria) in energy metabolism. The Krebs (citric acid) cycle led to an understanding of the unending flux of nutrients though the tissues, the delineation of metabolic pathways and discovery of the enzymes that control them. The Coris uncovered the secrets of glycogen formation and breakdown.

Meanwhile, endocrinology was making parallel leaps forward. The role of the anterior pituitary in diabetes was identified by Alberto Houssay, Frank Young and others, but was also (unfortunately) over-estimated, paving the way to the misuse of hypophysectomy as a treatment for diabetic retinopathy in the 1950s. Philip Hench pioneered the use of steroids in the treatment of arthritis, and glucagon was isolated soon after the mid-century.

Other areas were largely unexplored. The word epidemiology had yet to be applied to diabetes, and genetic studies were in their infancy. In the words of a later writer, diabetes remained the "geneticist's nightmare". The term "molecular biology" was coined by Warren Weaver in 1936, but the reality was still to come.

References

  1. ^ Bliss M. The Discovery of Insulin.

  2. ^ Tattersall RB. A force of magical activity: the introduction of insulin treatment in Britain 1922-1926. Diabetic Medicine 1995;12(9):739-55

  3. ^ Jensen HF. Insulin. Its chemistry and physiology. Commonwealth Fund, New York, 1938

  4. ^ Kimmelstiel P, Wilson C. Intercapillary Lesions in the Glomeruli of the Kidney: Amer J Path 1936;83-98.7

  5. ^ Root HF, Sharkey TP. Arteriosclerosis and Hypertension in Diabetes: Ann Int Med 1936;873-882

  6. ^ Joslin EP. The Treatment of Diabetes Mellitus. 8th Edition, Henry Kimpton, London, 1946

  7. ^ Sawyer L, Gale EAM. Diet, delusion and diabetes. Diabetologia 2009;52(1):1-7

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