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The Cause of Diabetes....

In order to understand a potential cure for diabetes, it is necessary to look briefly at the cause. In insulin-dependent diabetes, the diabetic's body fails to make insulin, a hormone essential to the metabolism of glucose. Glucose enters the blood stream from the food that we eat and, in the presence of insulin, is taken up and "burned" by cells that require this essential fuel. In the absence of insulin, however, glucose accumulates in the blood causing the condition known as high blood sugar (hyperglycemia), while the cells starve for fuel. Without taking insulin injections, the diabetic will slowly starve to death despite abnormally high blood sugar levels.

Why does a diabetic's body fail to produce insulin? Within the pancreas, the Islets of Langerhans produce insulin in response to blood glucose. These islets are tiny insulin factories that sense the level of glucose in the blood stream, and produce insulin in precise proportion to that level. Therefore, following a meal, blood sugar levels will rise significantly, and the islets will release a large amount of insulin. This insulin will cause body cells to take up the sugar, causing blood sugar to quickly return to its normal range. Once blood sugar is in the normal range, the islets will reduce the output of insulin to an idling state. In this way, the islets adjust their production of insulin on a minute-by-minute basis, always producing just enough insulin to deal with the amount of blood sugar presently in the blood stream.

In insulin-dependent diabetes, the islets are destroyed by the person's own immune system, which mistakenly identifies these essential cells as foreign invaders. This self-destructive mechanism is the basis of many so-called autoimmune diseases. Once the islets are killed, the ability to produce insulin is lost, and the overt symptoms and consequences of diabetes begin.

Why Insulin is Not a Cure....

Some people think that injecting insulin is a cure for diabetes. Unfortunately, it is not. Insulin allows a diabetic to survive, but the effects of crudely controlled blood sugar levels lead to the many devastating consequences of the disease. Unlike the precise matching of blood sugar and insulin levels that occurs normally, a diabetic's insulin injections cannot be precisely and continuously adjusted to maintain safe sugar levels.

When an excess of injected insulin drives blood sugar levels too low, the diabetic risks an immediate dramatic reaction that may include confusion, loss of consciousness, coma, and even death. When injected insulin is below the required amount, blood sugar levels rise, leading to damage to eyes, kidneys, nerves, heart, and blood vessels. Most diabetics are forced to operate at abnormally high blood sugar levels to avoid the more immediate and dramatic consequences of low blood sugar.

Insulin is not a cure for diabetes. A cure must restore the person's ability to adjust insulin production minute-by-minute to precisely match the uncontrollable variations in food intake, exercise, and stress, all of which are a normal part of living.

Toward a Cure...

Over the past twenty years, various approaches have been undertaken with the objective of restoring normal insulin production in humans. One of the most successful approaches, which has proven effective in a handful of cases, has been the allotransplantation of islets or whole pancreases from a suitable human donor into a diabetic recipient. Since the recipient's immune system would immediately attack and destroy the foreign islets, the recipient is required to take immune suppressing drugs for the rest of his or her life. These immunosuppressive drugs are very toxic and have potential adverse side effects, including cancer. For this reason, an islet or pancreas allotransplant is normally only performed in conjunction with a kidney transplant for which immunosuppression is required in any case.

Because of the toxicity of immune suppressing drugs, and the shortage of organ donors, islet and pancreas allotransplantation appears to hold very limited promise as a cure for diabetes.

Today, the best scientific opinion believes that a cure for diabetes must have the following characteristics:

A Plentiful Source of Islets...

To meet the requirement for a plentiful source of islets, medical researchers have looked to the pig, which, for seventy-five years, has provided diabetics with a safe and effective source of injected insulin. Transplanting pig islets into humans is a logical, if somewhat challenging, extension of injecting pig insulin, and has the potential to restore normal and responsive insulin production, without the dangers and deficiencies of injections.

Xenotransplantation refers to the use of organs for transplants that are non-human in origin, and to thereby solve the deficiencies and risks associated with human organ donors. Islet xenotransplantation offers a safe and plentiful source of islets for the treatment of human diabetes.

Transplanted pig islets, however, will be attacked and destroyed by a recipient's immune system. To prevent this attack without the use of toxic drugs, researchers are using technologies that protect the islets from the recipient's defense system.

These technologies encapsulate living pig islets in a semi-permeable capsule. This capsule has openings in its lattice-like structure that are big enough to allow blood sugar, oxygen, and other metabolite molecules to easily reach the islet from the recipient's blood stream, and to allow insulin to be released in precise amounts to maintain accurate blood sugar levels. However, the much larger components of the recipient's immune system, including antibodies and lymphocytes, are unable to pass through the openings in the microcapsules and attack the foreign islets.

In this way, the transplanted islets are able to operate as continuously responsive insulin factories, just as they did in the donor, without being attacked by the recipient's immune system.

How to Prevent an Immune Attack...
Having protected the transplanted islets, the next challenge is to prevent an immune attack against the capsules themselves. There appear to be several combinations of materials that both protect the islet, and invoke little or no immune response from the recipient. For example, capsules made from three layers of alginate, polylysine, and a second layer of alginate offer exceptional biocompatibility, and minimal immune response from the recipient.

To assure that transplanted islets are both protected and nourished, islets are encapsulated either individually (microencapsulation) or in clusters (macroencapsulation). The number of islets protected within a single microcapsule typically ranges between one and eight. In the case of macroencapsulation, a single mass or device may contain tens of thousands of islets, enough to restore normal blood sugar control. Since each islet is a tiny living organ that must not be damaged or killed by the harvesting and encapsulation processes, a significant number of engineering challenges have had to be overcome.

Where do we put these Islets ?

Having produced encapsulated pig islets ready for transplantation, the next question is: Where do we put these islets? Based on animal and human trials, a safe and effective site for injecting microencapsulated islets appears to be the peritoneal cavity, the region containing the major abdominal organs. Transplanting islets into the peritoneal cavity is a very simple procedure, requiring only a local anesthetic and conventional injection. No invasive surgery is required.

Macroencapsulation typically involves a single mass of tissue or a small device containing islets, and  researchers have had early encouraging results from intramuscular transplants. This site offers the advantage of a very simple surgical procedure and ease of retrieval and replacement.

A Success Story...

Perhaps the most dramatic example of the promise of islet xenotransplantation in curing diabetes is the work of Dr. Elliott and Dr. Sun.

Dr. Robert Elliott at the Auckland School of Medicine in New Zealand has succeeded in transplanting microencapsulated pig islets into two people with diabetes in mid-1996. One of the recipients received no immunosuppression, the other required immune-suppressing drugs because of a concurrent kidney transplant. In both cases, there were no adverse effects, and significant improvements in blood sugar control coupled with the avoidance of both hypoglycemic and hyperglycemic episodes. Because the number of islets transplanted in this first trial was below the number needed for complete insulin independence, the recipients still require reduced dosages of injected insulin. However, the existence of even minimal responsive insulin-producing islets results in vastly improved control and quality of life.  The recipient who was not immunosuppressed experienced better efficacy, an outcome that was expected based on the known worsening of diabetes caused by immunosuppression.

Dr. Anthony Sun at the University of Toronto in Canada has reversed diabetes in monkeys through the transplantation of microencapsulated pig islets. In this major demonstration, spontaneously diabetic monkeys received microencapsulated pig islets, transplanted into the peritoneal cavity. Prior to transplantation, these diabetic monkeys were unable to produce insulin internally, and exhibited the same symptoms and damage as human diabetics. Following transplantation, these monkeys achieved normal blood sugar levels for up to 26 months. These pig islets were harvested from ordinary commercial abattoirs under non-optimal conditions, yet yielded extremely encouraging results. Dr. Sun's research paper describing this potential cure for diabetes was, following a peer review process, accepted for publication in the prestigious Journal of Clinical Investigation - September 15 1996, Volume 98, Number 6. Visit The Journal of Clinical Investigation web site for full text of research paper

Neither of these outcomes is proof of a definitive cure for diabetes. However, they are like the early flight of the Wright Brothers at Kitty Hawk. That bumpy 20-second flight was a proof of principle that lead to the development of commercial flight within a few years. If we support the ongoing development needed to build on these early successes, perhaps a cure for diabetes will evolve into commercial reality in the near future.

Other Approaches...

While encapsulated pig islets have delivered more measurable results than any other technology so far, it is essential to explore other promising avenues for curing diabetes. There are many reasons for not taking a single path, including:

There are several competing methods for replacing the islets destroyed by diabetes: While it is essential to support a diversity of promising directions, it is essential that those approaches that have shown the most compelling results to date -- despite many remaining challenges -- receive immediate support. It has proven too tempting over the past decades to abandon an approach that is showing some promise in favor of a new and untested approach that merely sounds good.

The Rest of the Journey...

The Islet Foundation is dedicated to the final push that many researchers feel is needed to reach a cure for insulin-dependent diabetes. Thanks to the work of Dr. Elliott, Dr. Sun, and other researchers throughout the world, we now know of a promising mechanism by which diabetes can be cured.

This stage of research is similar to the point at which Banting and Best knew that animal insulin could control diabetes in humans, and the remaining challenge was one of technology, not fundamental molecular research. Banting and Best could then turn their attention to the technologies of large-scale extraction, purification, packaging, and delivery -- technologies that, for the last 75 years, have allowed millions of diabetics worldwide to lead long and productive lives.

Today, TIF's mission is to support the completion of the technologies needed to allow human trials of transplanted encapsulated pig islets. Based on a successful outcome of these trials, it is reasonable to expect that a widely available cure for insulin-dependent diabetes would quickly evolve. To reach this destination, TIF will support the activity of promising research teams worldwide.

The Puzzle is complete The Islet Foundation 

TIF Foundation Federal Tax Number BN 89439-1994-RR0001

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