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Diabetes is a group of diseases in which the blood glucose is too high. In type 1 diabetes, the patients have an autoimmune disease that causes destruction of their insulin-producing cells (the beta cells of the pancreas). Insulin is the hormone that enables glucose to enter the cells of the tissues and in its absence the glucose remains in the blood and cannot be used. In type 2 diabetes the beta cells are usually somewhat defective and cannot adapt to the increased demand often associated with age and/or obesity. Despite the availability of insulin for treating diabetes since the 1920s, the disease is still a huge problem. If the level of blood glucose is not perfectly controlled it will cause damage to blood vessels and this eventually leads to various unpleasant complications including heart failure, stroke, kidney failure, blindness, and gangrene of limbs. Apart from the considerable suffering of the affected patients, the costs of dealing with diabetes is a huge financial burden for all health services. The prevalence of type 2 diabetes in particular is rising in most parts of the world and the number of patients is now counted in the hundreds of millions.
To get perfect control of blood glucose, insulin injections will never be quite good enough. The beta cells of the pancreas are specialised to secrete exactly the correct amount of insulin depending on the level of glucose they detect in the blood. At present the only sources of beta cells for transplantation are the pancreases taken from deceased organ donors. However this has enabled a clinical procedure to the introduced called “islet transplantation”. Here, the pancreatic islets (which contain the beta cells) are isolated from one or more donor pancreases and are infused into the liver of the diabetic patient. The liver has a similar blood supply to the pancreas and the procedure to infuse the cells is surgically very simple. The experience of islet transplants has shown that the technique can cure diabetes, at least in the short term. But there are three problems. Firstly the grafts tend to lose activity over a few years and eventually the patients are back on injected insulin. Secondly the grafts require permanent immunosuppression with drugs to avoid rejection by the host, and this can lead to problems. Thirdly, and most importantly, the supply of donor pancreases is very limited and only a tiny fraction of what is really needed.
Syringe, by Blausen.com staff. “Blausen gallery 2014″. CC-BY-3.0 via Wikimedia Commons
This background may explain why the production of human beta cells has been a principal objective of stem cell research for many years. If unlimited numbers of beta cells could be produced from somewhere then at least the problem of supply would be solved and transplants could be made available for many more people. Although there are other potential sources, most effort has gone into making beta cells from human pluripotent stem cells (hPSC). These resemble cells of the early embryo: they can be grown without limit in culture, and they can differentiate into most of the cell types found in the body. hPSC comprise embryonic stem cells, made by culturing cells directly from early human embryos; and also “induced pluripotent stem cells” (iPSC), made by introducing selected genes into other cell types to reprogram them to an embryonic state. The procedures for making hPSC into beta cells have been designed based on the knowledge obtained by developmental biologists about how the pancreas and the beta cells arise during normal development of the embryo. This has shown that there are several stages of cell commitment, each controlled by different extracellular signal substances. Mimicking this series of events in culture should, theoretically, yield beta cells in the dish. In reality some art as well as science is required to create useful differentiation protocols. Many labs have been involved in this work but until now the best protocols could only generate immature beta cells, which have a low insulin content and do not secrete insulin when exposed to glucose. The new study has developed a protocol yielding fully functional mature beta cells which have the same insulin content as normal beta cells and which secrete insulin in response to glucose in the same way. These are the critical properties that have so far eluded researchers in this area and are essential for the cells to be useful for transplantation. Also, unlike most previous procedures, the new Harvard method grows the cells as clumps in suspension, which means that it is capable of producing the large number of cells required for human transplants.
These cells can cure diabetes in diabetic mice, but when will they be tried in humans? This will depend on the Food and Drug Administration (FDA) of the USA. The FDA has so far been very cautious about stem cell therapies because they do not want to see cells implanted that will grow without control and become cancerous. One thing they will insist on is extremely good evidence that there are absolutely none of the original pluripotent cells left in the transplant, as they would probably develop into tumours. This highlights the fact that the treatment is not really “stem cell therapy” at all, it is actually “differentiated cell therapy” where the transplanted cells are made from stem cells instead of coming from organ donors. The FDA will also much prefer a delivery method which will enable the cells to be removed, something which is not the case with current islet transplants. One much discussed possibility is “encapsulation” whereby the cells are enclosed in a semipermeable membrane that can let nutrients in and insulin out but will not allow cells to escape. This might also enable the use of immunosuppressive drugs to be avoided, as encapsulation is also intended to provide a barrier against the immune cells of the host.
Stem cell therapy has been hyped for years but with the exception of the long established bone marrow transplant it has not yet delivered. An effective implant which is easy to insert and easy to replace would certainly revolutionize the treatment of diabetes, and given the importance of diabetes worldwide, this in itself can be expected to revolutionize healthcare.
Featured image credit: A colony of embryonic stem cell. Public Domain via Wikimedia Commons
The first time I increased a patient’s insulin dose I lay awake all night worrying that his blood sugar might fall too low. I was a house officer, and insulin was scary! The patient slept well and safely.
Diabetes is common, chronic and complicated. A recent nationwide audit of 12,191 people with diabetes in 206 English acute hospitals found that 15% of beds were occupied by people with diabetes. Worryingly, 37% of these patients experienced at least one error with their diabetes medications (the full results can be read here).
The National Patient Safety Agency (NPSA) has had over 16,000 reports of insulin incidents. In 2010 the NPSA issued an alert requiring action for all health care professionals to improve prescribing and administration of insulin, which was linked to a “Safe use of insulin” e-learning course.
I trained over 30 years ago. Are junior doctors more confident now? Apparently not. A study of 2149 junior doctors by George et al provides worrying evidence that UK trainees lack confidence in managing diabetes. Just 27% were fully confident in diagnosing diabetes, 55% in diagnosing and managing dangerous low glucose and 27% in managing intravenous insulin. Regarding management of diabetes, 24% of respondents would “not often, rarely or never” take the initiative to improve diabetes control. 43% would not adjust insulin in patients with poor glucose control.
Confidence is a combination of knowing what to do and believing you can do it. Experience helps. Also, we all need to know what we don’t know and when to ask for help. An unconfident doctor may make the patient anxious. Galen believed that in the 2nd Century: “Confidence and hope do more good than physic”.
Trainee doctors receive varying amounts of diabetes training and variable supervised experience of looking after people with diabetes. With too little training, trainees may rightly be worried about managing diabetes. Inadequate care of people with diabetes in hospital could worsen virtually every clinical outcome regardless of the main reason for admission. It also worsens patient experience. Diabetes is a common, potentially dangerous but eminently treatable condition. All units in all hospitals should have access to a specialist diabetes team. And trainee doctors should have training and support in diabetes management until they each feel confident in looking after people with diabetes under their care.
Robert Tattersall is an internationally recognized authority on diabetes. He received specialist training at King’s College Hospital, London and the University of Michigan in Ann Arbor. He moved to Nottingham in 1975 where he became Professor of Clinical Diabetes. His most recent book, Diabetes: The Biography, is part of the series Biographies of Disease which we will be looking at in the upcoming weeks. Each volume in the series tells the story of a disease in its historical and cultural context – the varying attitudes of society to its sufferers, the growing understanding of its causes, and the changing approaches to its treatment. In the excerpt below we learn about the discovery of insulin- a moment that changed the lives of diabetics forever.
After war service in Europe, Frederick Grant Banting (1891-1941) failed to get a surgical job at the prestigious Toronto Hospital for Sick Children and so set up as a doctor in London, Ontario. This was not a success, and to make ends meet he got a part-time job at the University of Toronto. In October 1920 he had to lecture the students on carbohydrate metabolism, about which he knew little. While preparing, he read an article about a man in whom a stone had blocked the pancreatic duct leading to atrophy of the digestive-enzyme-producing part of the gland but leaving the islets intact. This was hardly new, since it had been known for thirty years that this was what happened when the duct was tied in animals, but in his notebook Banting wrote:
Diabetus [sic]
Ligate pancreatic ducts of dog. Keeping dogs alive until ancini degenerate leaving Isletes.
Try to isolate the internal secretion of these to relieve glycosurea [sic]
Against the background of the fruitless attempts described in the previous chapter, it is not surprising that Macleod did not take Banting seriously. Macleod wrote: ‘I found that Dr Banting had only a superficial textbook knowledge of the work that had been done and no familiarity with the methods by which such a problem could be investigated in the laboratory.’ Quite apart from Banting’s ignorance, Macleod had lost interest in diabetes and was researching acid-base balance. Banting later said that during the first interview Macleod was so disinterested that he started reading letters on his desk. Nevertheless, he offered Banting a disused lab and two students, Charles Best (1899-1978) and Clark Noble (1900-78), who were to do alternate months. They tossed a coin to decide who should to the first month. Best ‘won’, but was so involved at the end of the first month that Noble agreed that he should continue.
Banting need an assistant, because he did not know how to measure blood sugar, and Macleod had wisely insisted on this as the end point of their experiments. During his research on the blood sugar of the turtle, Best had learned the new Lewis-Benedict method, which needed as little as 0.2 ml blood, whereas other methods needed 25 ml. Another stumbling block was that Banting had never done a pancreatectomy, an operation that at the time was used only in animal research. Macleod assisted at the first operation, but Banting and Best then worked alone, writing from time to time to Macleod, who replied with advice. In August 1921they depancreatized two dogs and treated one with pancreatic extract leaving the other as a control. The untreated dog died in four days which the treated one remained well. Macleod was encouraged by their results but felt that the falls in blood sugar might be due to dilution or even normal fluctuations. He suggested further experiments, to which Banting objected violently and accused Macleod of trying to steal their thunder. Nevertheless, the experiments were done. When Macleod returned in October, he had a stormy interview with Banting, who threatened to go elsewhere if better facilities were not provided. At a departmental meeting on 14 November 1921 Banting and Best gave a preliminary presentation of their work. One important suggestion at this meeting was that the best of showing that the extract worked would be if regular injections could prolong the life of diabetic dogs.
This was a logistic problem, because the duct-ligation method needed many dogs and a wait of seven weeks while the exocrine tissue degenerated. Banting’s solution was to use foetal calf pancreas, which Best got from the local abattoir. The rationale, as Sobolev had suggested twenty years before, was that it contained a high proportion of islets in relation to exocrine tissue. An important breakthrough came in December, when Banting decided to use alcohol in making extract (an idea Macleod had suggested some months before). It worked well and led them to wonder whether they could get a similar result with the more easily available adult beef pancreas. That they did must have been a surprise, because the original rationale for duct ligation was that the internal secretion would be destroyed by pancreatic enzymes. In fact, although Macleod and others believed this, it had been known since 1875 that fresh pancreas did not break down proteins. The intact gland contains an inactive precursor trypsinogen, which is converted into the protein-dissolving enzyme trypsin only by contact with duodenal juice. Around this time Banting and Best were joined by a biochemist, Bert Collip (1892-1965)-more accurately, he was foisted on them by Macleod, who regarded him as a proper scientist. Collip had come on a Rockefeller fellowship and was studying the effect of pH on blood sugar. Later he was asked to help with the purification of insulin and made rapid progress, although afterwards he downplayed his role, suggesting that any biochemist could have done the same.
Some time in December 1921 Collip began making extracts from whole pancreas and, at Macleods suggestion, tested them on rabbits. The extracts reduced the rabbit’s blood sugar, and how far it fell was a useful and cheap way of telling how potent the extract was.
The first use of insulin (an extract made by Charles Best) on a human being was on 11 January 1922. The pancreatic extracts were relatively impure, and the house physician at Toronto General Hospital described what he injected into the buttocks of 14-year-old Leonard Thompson as ‘15 cc of thick brown muck’. Thompson has been on the Allen diet since 1919 and weighed only 65 lb (29.5 kg). After the injection, his blood sugar fell from 440 to 320 mg/dl (24.4 to 18.3 mmol/l), but no clinical benefit was seen. The experiment was resumed on 23 January, when he was given Collip’s extract, and now his blood sugar fell during one day from 520 mg/dl (29 mmol/l) to 120 mg/dl (6.7 mmol/l). He continued treatment for ten days with marked clinical improvement and complete elimination of glucose and ketones from his urine. Subsequently he lived a relatively normal life, although reliant on insulin injections, before dying of pneumonia in 1935.
The first clinical results were published in the March 1922 Canadian Medical Association Journal, where the authors reported that they had treated seven cases…
0 Comments on The Discovery of Insulin as of 11/2/2009 10:09:00 AM
Toronto Hospital for Sick Children and so set up as a doctor in London, Ontario. This was not a success, and to make ends meet he got a part-time job at the University of Toronto. In October 1920 he had to lecture the students on carbohydrate metabolism, about which he knew little. While preparing, he read an article about a man in whom a stone had blocked the pancreatic duct leading to atrophy of the digestive-enzyme-producing part of the gland but leaving the islets intact. This was hardly new, since it had been known for thirty years that this was what happened when the duct was tied in animals, but in his notebook Banting wrote: