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This month, it was reported that scientists at Harvard University have successfully made insulin-secreting beta cells from human pluripotent stem cells. This is an important milestone towards a “stem cell therapy” for diabetes, which will have huge effects on human medicine.

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.

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

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Every month OUP editor and author Jonathan Crowe answers your science questions in the monthly SciWhys column. Got a burning question about science that you’d like answered? Just email it to us, and Jonathan will answer what he can. Today: Why do we eat food?

By Jonathan Crowe

You may well be thinking that the question posed in the title of this blog has an all-too-obvious answer. We all know that we eat food to keep ourselves alive. But why do we find ourselves slaves to our appetites and rumbling stomachs? What is actually happening inside each of us that couldn’t happen without another slice of toast, or piece of fruit, or that most vaunted of mid-afternoon pick-me-ups, the sneakily-consumed bar of chocolate?

We’re all familiar with the concept of something needing fuel to keep it going. Just as a power station requires gas or coal to power its turbines and generate energy, so we need fuel – in the form of food – to power our continued existence.

The foods we eat provide us with a range of nutrients: vitamins, minerals, water, fat, carbohydrates, fibre, and protein. These nutrients are put to different uses — as building materials to construct the tissues and organs from which our bodies are made; as the components of the molecular machinery that keeps our cells running as they should. All of these uses are unified by a common theme: a requirement for energy to make them happen. And this is where one particular type of nutrient comes into its own. Step forward the carbohydrates.

Carbohydrates are better known to us as sugars, but in fact the sweet crystals we know as sugar are only part of this group. Carbohydrates come in very different shapes and sizes. One of the smallest is glucose, which acts as a chemical building block — multiple copies of glucose can join together to form a range of much larger molecules. For example, starch – found in potatoes and flour – is a carbohydrate formed from many individual molecules of glucose joined together in long chains. (Based on taste alone, you wouldn’t think that starch was made of glucose. Even though individual molecules of glucose taste sweet to us, once they are linked together to form starch the sweetness is lost.)

To understand how the sugar in our food can power the processes occurring in our cells every minute of every day, let’s follow some starch on its journey through the body. Many of the foods we consume aren’t in a form with which our bodies can do anything useful. Instead, they need to be digested. And so it is with carbohydrates such as starch. This process of digestion starts as soon as the food enters our mouth; our saliva contains special substances (called enzymes) that start attacking the long chains of starch, breaking it into smaller fragments.

Digestion continues as our food is swallowed and slides down into our stomach, where an arsenal of other chemical weapons set to work on the mouthful we’ve just consumed. Before long, what were initially mouth-watering morsels are reduced to something rather less appetising and leave the stomach to enter the long, snaking tunnel of our intestines. By now, the long chains of starch have been broken down into glucose, which is small enough to pass through the lining of our intestine and into our bloodstream. Our bloodstream acts as a short- and long-distance transport network, carrying the newly-arrived sugar molecules to cells all over the body.

When glucose arrives at its destination and first enters the cell, it u

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By Rowan Hillson

 
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 2^nd 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.

Table from the paper ‘Lack of confidence among trainee doctors in the management of diabetes: the Trainees Own Perception of Delivery of Care (TOPDOC) Diabetes Study’, QJM: An International Medical Journal, Advanced Access, 21 April 2011 

Read on for an excerpt from Dr Hillson’s commentary ’Diabetes – big problem, little confidence’, which is published in QJM: An International Journal of Medicine, Advanced Access, 21 April 2011. You can read the 0 Comments on Diabetes: big problem, little confidence as of 1/1/1900