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Diabetes mellitus types 1 and 2 are chronic metabolic diseases caused by an increase in blood glucose levels, also known as hyperglycaemia.
Currently there are around two million cases of diabetes mellitus in the UK, costing the NHS approximately £1 million per hour (Nursing in practice, 2008). In the US there are an estimated fifteen million people diagnosed with diabetes and it is the seventh biggest cause of death (NIH Stem Cell, 2001).
Is an auto immune disease where by the individuals own immune system fails to distinguish between self from non-self. This leads to the destruction of the Islets of Langerhans insulin producing ß-cells, which are located in the pancreas (Nursing times, 2009).
Most common form of diabetes mellitus, affecting around 90% of all diabetes sufferers.
Type 2 diabetes is associated with either a low production of insulin or insulin resistance, which is characterised by an inadequate response to glucose levels in the blood. Although the causes of Type 2 diabetes are unclear, there are a number of risk factors associated with it such as obesity, age and genetic traits (Nursing times, 2009).
Currently there is no cure for diabetes mellitus. The widely accepted treatment for Type 1 diabetes is daily or multiple daily injections of insulin into the body. The individual's blood glucose levels must be monitored several times a day by carrying out a prick blood test (Nursing times, 2009).
The treatment however fails to adequately adjust blood glucose levels, which could lead to a risk of hypoglycaemia (Nursing times, 2009).
Pancreas and Islets of Langerhans
The pancreas consist of three different types of cells; endocrine, ductal and acinar cells. The islets of Langerhans are comprised of endocrine clusters situated throughout the pancreas. Endocrine cells secrete four main hormones including insulin ß-cells, glucagon a-cells, somatostatin delta cells and pancreatic polypeptide PP cells.
Islets are comprised of around 80% ß-cells, 15% a-cells, around 4% delta cells and 1% PP cells (Docherty et al., 2007).
Potential cures for diabetes mellitus
Whole pancreas and Islet of Langerhans transplantations have been seen as a potential cure for Type 1 diabetes. Around 1500 diabetes patients are given pancreas transplants per year. Transplant rates have been successful with around 80% of patients exhibiting no further symptoms of diabetes and are able to regulate blood glucose concentrations. However due to the lack of available donors, and the increase risk of infection from immunosuppressant drugs, also the possibility of complications during surgery, means that pancreas transplants are not a suitable cure for everyone with diabetes.
Due to the increased susceptibility of contracting other diseases while on immunosuppressant's, many transplants are only carried out on patients that also require a kidney transplant.
Islet of Langerhans transplants
In recent years islet transplantation protocols have been established as an effective alternative to whole pancreas transplants. Islet cells are transplanted into the patient by injecting the cells into the hepatic portal vein (Sameer et al., 2006).
In 1999 James Shapiro et al in Edmonton, Canada devised the 'Edmonton Protocol'. The protocol was developed to reduce the need for steroid immunosuppressant's, which reduced the success of previous islet transplant trials. Islet cells were injected in two infusions to deliver a large dose of cells to the liver without the requirement for steroid base immunosuppressants (Sameer et al., 2006; NIH Stem Cell, 2001).
In 2006 islet transfusions were given to around 500 patients around the world. Although the Edmonton protocol has delivered positive results, there are however limitations. Around 80% of patients were insulin dependent after only five years due to low graft survival rates. The transplants still require immunosuppressants, although reduced to prevent islet rejection. Current immunosuppressants are unable to prevent graft rejections and have potential side effects, such as nephrotoxicity and an increase in infections due to a suppressed immune system. Islet cells are obtained from two donor tissues and must be fresh, which is major disadvantage due to the lack of sufficient donors and the costs involved. Transplants may also result in portal vein conditions and thrombosis. The metabolic conditions of the liver have also been identified as a possible cause of reduced graft survival (NIH Stem Cell, 2001).
The Edmonton protocol has highlighted the potential of using islet cell transfusions to treat diabetes. However due to the lack of sufficient donor's alternative sources of insulin secreting cells are required.
Cell based therapies
Alternative methods are required to replace existing donor pancreas cells with a renewable supply of insulin secreting endocrine cells.
Stem cells have received considerable attention as a possible supply of islet cells due to their pluripotency capabilities.
Embryonic stem cells (ESC)
Human ESC's were first isolated and maintained in 1998 by James Thompson et al.
ESC's are undifferentiated, exhibit pluripotency and are obtained from the inner cell mass of blastocysts (NIH Stem Cell, 2001).
Five day old embryos consist of a hollow ball of 30-150 cells known as blastocyst. The blastocyst comprises three main structures: the blastocoel; a fluid filled cavity, the trophectoderm; layer of surrounding cells and the inner cell mass; which is a collection of around 30 cells situated at one end of the blastocyst (NIH Stem Cell, 2001).
The embryo is developed from the in vitro fertilisation of human donor eggs. The oocyte (egg) is fertilised in vitro forming a zygote. By 24 hours the zygote divides into two cells (embryo). At 72 hours the embryo comprises eight cells known as a morula. By day four the cells adhere to one another forming a blastocoel. Day five embryos consisting of around 250 cells are used as the source of ESC's. The trophectoderm is removed through immunosurgery or microsurgery to enable the cells to be extracted from the inner cell mass (NIH Stem Cell, 2001).
The Inner Cell Mass (ICM)
Human embryonic stem cells are isolated by growing ICM cells in a culture of mouse fibroblasts known as "feeder cells", bovine serum, cytokines and LIF. The feeder layer provides a surface to which the ICM cells can attach. Current human ESC's culturing techniques are inefficient. New methods of culturing are required to promote the growth of ESC's. The addition of growth factors such as bFGF could replace the current use of serum, and the use of a protein matrix will allow for a feeder free culture, due to the risks of pathogens and viruses from mouse cells (NIH Stem Cell, 2001).
ESC's have the ability to differentiate into many different cell types and in multiple numbers, when grown on a culture containing specialist media.
These factors make ESC's ideal candidates for insulin secreting endocrine cell regenerators.
Research has identified that ESC's develop through a range of different steps before becoming differentiated islet cells (Docherty et al., 2007). Undifferentiated stem cells are cultured on a single layer of media containing activin A and wnt3a; this stimulates stem cell differentiation to a definitive endoderm (DE) (Docherty et al., 2007). Addition of FGF10, RA and CYC induce development of DE to a posterior foregut. Notch y secretase and inhibitor DAPI induce the formation pancreatic endoderm and finally islet precursors (Docherty et al., 2007).
A variety of hormones are required to induce islet precursor cell differentiation to islets of langerhans (Docherty et al., 2007).
Adult stem cells (ASC)
Discovered in the 1950's, ASC's are undifferentiated cells located in specific regions of tissues and organs known as the "stem cell niche." ASC's occur in small numbers, amongst other specialist cells (NIH Stem Cell, 2001).
The cells are pluripotent and are able to differentiate into a variety of specialised cells, with the main role of maintenance, repair and renewal. ASC's have been indentified in a number of different human tissues and organs, such as bone marrow, which contains two types of stem cells hematopoietic and mesenchymal. Stem cells are also found in the brain, blood, heart, liver, skin, skeletal muscle and testis. ASC's can remain in a non dividing form for long periods of time. Once activated the cells divide and differentiate into cells with the same characteristics and specialist capabilities of other mature cells in the tissue or organ (NIH Stem Cell, 2001).
It was originally thought that ASC's had a narrow capacity to differentiate into cell types other than the expected tissue or organ lineage with which they are located. Research has identified that bone marrow stem cells have an incredible capacity to differentiate into many cell types known as transdifferentiation. Further research in mice has shown that a single stem cell graft can regenerate cell blood lineages and differentiate into multiple cell types. Brain stem cells have found to be able to differentiate into a wide variety of cell types and can regenerate the hematopoietic system (NIH Stem Cell, 2001).
Islet cells can also be generated from ASC's located in the pancreatic duct, pancreas, liver and bone marrow (Sameer et al., 2006).
Undifferentiated stem cells are located with other mature differentiated cells in the pancreatic duct. Susan Bonner-Weir et al generated clusters containing insulin secreting cells from pancreatic duct stem cells. The clusters also exhibited the ability to release insulin when provided with high concentrations of glucose (Sameer et al., 2006). Currently there are no established duct stem cell lines due the inability to proliferate indefinitely.
There is also the possibility of using pancreas and liver stem cells. Much of the research carried out on pancreas stem cells has been to grow ß-cells and not the islets themselves. Research carried out on diabetic rodents discovered that the rodents were completely free of diabetes when transplanted with pancreatic stem cells (Sameer et al., 2006).
Stem cells from bone marrow have great potential due to their ability to differentiate into a wide variety of specialised cells. Research by banerjee et al found that bone marrow grafts were able to regenerate damaged cells and differentiate into pancreatic endocrine cells (Sameer et al., 2006).
A significant amount of research has been carried out in relation to diabetes mellitus and a possible cure. Stem cells will become an important part of treating diabetes and other diseases in the future.
There are however certain areas that need further research such the use of immunosuppressant's and the problems with autoimmunity in type 1 diabetes.