Diabetes is a growing health concern in the United States. Although it is estimated that 20.8 million Americans suffer from diabetes, only two-thirds are actually diagnosed with the disease (1). Diabetes occurs when the body cannot properly metabolize sugar, which results in high glucose levels in the blood. Normally, the hormone insulin is normally released into the blood by specialized β islet cells in the pancreas in response to high blood glucose levels. Insulin binds to receptors embedded in the cell membrane of muscle and fat cells, which allows insertion of glucose transporters in the membranes of these cells and the uptake of glucose.

blood_testing.jpgDiabetes occurs when glucose is not taken up into cells due to insulin deficiency or insulin resistance. Therefore, diabetes leads to excess glucose in the bloodstream. This can have serious consequences such as blindness, kidney failure, heart disease, and stroke.

There are two primary forms of diabetes: Type I and Type II. Type I diabetes, or juvenile diabetes, occurs when the body’s immune system attacks its own β-islet cells. In Type I diabetes, the immune system attacks β islet cells, which results in extreme insulin deficiency in the body. In order to compensate for the lack of insulin producing cells in the body, Type I diabetics inject themselves with insulin multiple times per day. Although recent technological breakthroughs have facilitated the regulation of blood sugar levels for Type I diabetics like the insulin pump and the insulin inhaler, Type I diabetics still remain completely insulin dependent.

Type II diabetes, or adult onset diabetes, occurs when β cells fail to secrete enough insulin and/or the insulin-sensitive cells builds up a resistance to insulin molecules. Type II diabetes is the most common form of diabetes. The onset of Type II diabetes has been linked statistically with age, racial background, genetics and lifestyle. In particular, there has been shown to be a direct correlation between obesity or inactivity and the likelihood of develping Type II diabetes. Generally, Type II diabetics rely on supplement pills that either help the pancreas make more insulin, keep the liver from overproducing glucose, help cells to use insulin better, or slow down carbohydrate digestion.

With careful insulin regulation and medication, diabetics can lead relatively normal lives. However, there is a huge motivation to cure diabetes. In recent years, improvements in medical transplantations have made it possible for a small number of Type I diabetics to receive pancreatic islet transplantations (2). In one study, insulin production was seen early on in 43% of patients and 50-80% of patients at a later time point (3). However, there are many complications with this procedure. While it is a minimally invasive surgery, patients are required to take immunosuppressive drugs, which increases the risk of diseases. Additionally, many surgeons refuse to perform the surgery without also transplanting kidneys because the kidneys become so compromised during insulin deprivation. There is a higher demand for pancreatic transplants than willing or capable donors. Lastly, there is also the possibility of immune rejection of the pancreas. Because of the limited supply of pancreatic organs for transplants and the concern over immune rejection, scientists are investigating ways to improve pancreatic islet transplantation.

A potential source of these cells is stem cells, which have the potential to self-renew and differentiate. It was originally thought that transplantation of a single embryonic stem cell into a patient could differentiate and give rise to a β cell. However, it has been shown that β islet cells arise only from pre-existing β cells (4). Thus, the current hope is to culture embryonic stem cells in vitro, providing the proper conditions for them to differentiate into insulin-secreting cells that can respond to the presence of glucose (5). Creating patient-specific β cells from embryonic stem cells that can be transplanted into patients is a long-term goal because it will overcome the hurdle of rejection by the immune system. At the same time, it is only a temporary treatment because it does not address the autoimmune destruction of β cells that is the primary cause of Type I diabetes. After two or three years, the autoimmune response will attack the β islet cells and prevent the normal production of insulin once again. One potential solution to this problem could be the implantation of insulin-secreting cells in other organs of the body. This may prevent the immune system from locating and destroying the cells, which could lead to a long-term cure for diabetes.

insulin.pngThe first step toward being able to culture these cells in vitro is understanding the basic developmental biology that controls the process of differentiation. A complex array of transcription factors act in the expression of certain genes at certain time points in this process. If we can understand which genes are being turned on or off at each point, we can work toward directed differentiation of embryonic stem cells into β islet cells (6). Recent data shows that we are now able to culture human embryonic stem cells in vitro, but with minimal efficiency (7). More work must be done to verify these results and improve percent yield in order for transplantation to become a reality.

Potential research that would be geared specifically toward treatment of Type I diabetes is using small molecule inhibitors that block the autoimmune destruction of β islet cells. In studying this link, we might be able to develop drugs that could act at the molecular level to prevent cell death and, in turn, reverse the symptoms of diabetes. (8)

Another way of trying to prevent the autoimmune destruction of β cells to treat Type I diabetes is to perform autologous bone marrow transplants alongside β islet transplants. Bone marrow transplantation has been done in diabetic mice and been shown to repress the autoimmune destruction of β cells. Combining this therapy with a transplant of a pancreatic cells from the same donor should prevent rejection of the cells. While this technique has much promise, there are many long-term problems that have to be addressed before this technique is used in humans. First, the chances of obtaining both a pancreas and bone marrow from the same donor are slim. At the same time, however, stem cells could potentially be differentiated into both types of tissues so that their genetic identity matches each other and the patient. Second, this technique only seems to work in mice when they were extremely young. In humans, it may take years before diabetes actually sets in, and at this point it may be too late to perform this therapy. (9)

More research is needed to be able to use stem cell technology to treat diabetes in a safe, reliable and inexpensive way. Nevertheless, the current research is promising, and many are working toward making this prospect into a reality.

References
1. Diabetes Overview, National Institute of Health, July 5, 2007 <http://diabetes.niddk. nih.gov/dm/pubs/overview/index.htm>.
2. Langenbecks Arch Surg, Islet Cell Transplantation Today, May 2007, p. 239-53, Epub March 28, 2007.
3. Langenbecks Arch Surg, May 2007, p. 239-53.
4. Nature, Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation, p. 41-46, May 6, 2004.
5. Trends Mol Med, Towards stem-cell therapy in the endocrine pancreas, Apr 2007, p. 164-73. Epub Feb 20, 2007.
6. Devel Cell, A multipotent progenitor domain guides pancreatic organogenesis, July 2007, p.103-14.
7. Cell Research, In vitro derivation of functional insulin-producing cells from human embryonic stem cells, Apr 2007, p. 333-44.
8. Sia C and Hänninen A, Apoptosis in Autoimmune Diabetes: The Fate of beta-Cells
in the Cleft between Life and Death. Rev Diabet Stud, 2006, p. 39-46.
9. Ikehara S. et al. Prevention of type I diabetes in nonobese diabetic mice by
allogeneic bone marrow transplantation, PNAS, 1985, p. 7743-7