INTRODUCING DR. AARON I. VINIK & INGAP RESEARCH

by Deb Butterfield

Dr. Vinik, Director of Research at the Strelitz Diabetes Institutes, is often described as the man who could cure diabetes, and with good cause. Dr. Vinik is approaching the problem of how to put an end to diabetes by working to regenerate, rather than to transplant, islets.

The main difference between islet regeneration and islet transplantation is that regeneration will allow the re-growth of islets from your own cells so there may be no need to take the anti-rejection drugs that are required when foreign cells are transplanted. Most importantly, islet regeneration is not limited by the scarcity of pancreas organs.

The assault on the pancreas that causes diabetes is directed at the beta cells, the cells within the islets in the pancreas that make insulin. The other hormonal cells in the islets, such as those that make glucagon, escape the attention of the antibodies and other destructive forces that cause autoimmune diabetes. Similarly, the precursor cells (stem cells from which, for example, islet cells grow) seem to survive the autoimmune attack that leads to diabetes, and they appear to survive diabetes indefinitely.

In 1983, when Dr. Vinik was an endocrinologist at the University of Michigan, a colleague, Dr. Lawrence Rosenberg, wrapped a hamster pancreas in cellophane (Saran Wrap) to better understand the inflammatory processes of pancreatic disease. But in a moment that Dr. Vinik describes as "Saran-dipity," they noticed that instead of inducing inflammation, the pancreases bound in Saran Wrap were growing new islets cells. Thus began Dr. Vinik's search to find out why and how these islets grew, and ultimately how to replicate the process to cure diabetes.

At first he identified the protein mixture called Ilotropin in the Saran Wrap that could be credited for stimulating cell growth and used it to cure chemically induced diabetes in animal models. The question then became, is there a gene that precipitates the rebirth of islet cells? And so he embarked on a very long, often disheartening and frustrating, search for the gene that causes islet neogenesis.

Dr. Vinik has an engaging combination of curiosity, confidence, vision and wit. "If you come to a fork in the road, take it," he says, and that is what he did after almost 15 years of hunting through millions of possibilities to find the gene that is responsible for the growth of islets. With advances in the human genome project and some informed and intelligent observations, Dr. Vinik realized that he could limit the scope of the search for the gene by searching for the gene's messenger and tracking it back to the gene itself. And so he discovered the gene that stimulates the growth of beta cells from immature precursor cells and named it "INGAP," which is an acronym for Islet Neogenesis (new growth, birth) Associated Protein.

Since the discovery of INGAP, Dr. Vinik and his team have identified that INGAP is the major constituent within Ilotropin, a protein extract that reverses diabetes in hamsters. They have also inserted the INGAP gene in a variety of different cell lines and produced recombinant INGAP, which reverses diabetes in almost as many animals as did the original Ilotropin protein.

Now they have found a small fragment of the sequence of INGAP that is fully capable of achieving all the effects of the whole protein, improving the percentage of animals cured, and making it likely that this fragment could be synthesized in a laboratory, much as insulin is mass-engineered today. This is a vitally important issue because for a cure to have a meaningful impact on the toll of diabetes, it must transcend the lab setting to become widely available to all diabetics, of all ages, all economic backgrounds, and in all countries.

Researchers at the Strelitz Diabetes Institutes have found INGAP in cells associated with new cell growth in samples of pancreatic tissue from people who have had diabetes for as long as 75 years. Even in cases of long-standing diabetes in adults, INGAP could stimulate these cells to transform into insulin producing cells.Dr. Vinik believes that most people with diabetes in which there is a deficiency of insulin, whether they have type 1 or type 2 diabetes, will benefit when the use of INGAP to regenerate islets becomes a clinical reality.

Dr. Vinik cannot yet confirm that all forms of diabetes are due to a deficiency of INGAP hindering the precursor cells from maturing. But from all the tissues he has studied, he does know that whenever he observes normal neogenesis, or growth of new islets, INGAP is there. When islets cease to grow INGAP disappears.

So what protects regenerated islets from a recurrent or continued autoimmune attack similar to that which caused diabetes in the first place? Antibodies may attack the newly formed islets, but as long as the rate of growth of new cells exceeds the rate of destruction, regenerated islets should be capable of overcoming diabetes. With the relatively less toxic immunotherapy protocols being used in the latest round of islet transplant trials, researchers at the Strelitz Diabetes Institutes are optimistic that they can enhance the re-growth of islets using INGAP in combination with immunotherapy.

And what stops the cells from growing out of control, like a malignant tumor?It seems that nature has provided a natural restraining mechanism. There is a clear balance between islet neogenesis and islet apoptosis, or programmed cell death, so that when islets reach a critical mass a natural feedback mechanism restricts further growth.

Before therapies using INGAP can be tried in humans, they must be tried in large animals. "I am the eternal optimist and hope to see a cure in my lifetime," he says, adding with well-deserved confidence, "we have a very ambitious schedule and intend to begin curing humans of diabetes using INGAP in 2004."