Diabetes Under Investigation

By Jason Socrates Bardi

Julie awakes feeling lightheaded and queasy, and she has a terrific thirst. Her muscles ache and she wants to stay in bed, but she has to go to the bathroom for the fourth time that night. On her way she stumbles, blinks, and rubs her eyes. She is having trouble seeing and begs her mom to do something. Julie's mother, who had at first thought that her daughter had been feigning the flu to skip school that morning, is beginning to realize that her daughter—despite having no temperature—is indeed sick. She takes a good look at her daughter and notices, in alarm, that she has lost 20 pounds in the last few days.

Frightened, Julie's mother takes her to the emergency room of the local hospital. After hearing Julie and her mother describe the symptoms, the doctor suspects that he knows what is going on. The doctor takes a sample of Julie's blood and sends it to be analyzed. When the results return, his suspicion is confirmed—very high glucose levels and the presence of islet cell antibodies. Julie has Type 1 diabetes mellitus.

Although these characters are fictitious, they represents a common enough occurrence—the adolescent onset of a disease with which millions of people are afflicted worldwide.

Type 1, or insulin-dependent, diabetes is a chronic autoimmune disease caused by the destruction of insulin producing b cells in the pancreas, known formally as the islets of Langerhans. The insulin produced by these cells is responsible for regulating blood glucose, which cells normally ingest to provide energy for metabolic processes.

Without insulin, the glucose in the bloodstream increases and is maintained at levels much greater than normal. Over time this can lead to nerve and kidney damage, reduced eyesight, and an increased risk of developing heart disease and vascular degeneration. The therapy of choice for the disease is to inject insulin, and before the discovery and isolation of insulin in the 1920s, having this type of diabetes meant certain death.

Though insulin is a reasonable treatment, Type 1 diabetes is still a chronic infection for which there is no prevention and no cure. Though Type 1 is less common than Type 2 diabetes, the two together are one of the leading causes of blindness and kidney disease in the world and one of the most costly health problems in the United States.

The Scripps Research Institute (TSRI) is home to one of the largest basic Type 1 diabetes research programs in the world.

"Our goal is to understand the etiology of Type 1 diabetes," says Professor of Immunology Nora Sarvetnick. "The idea is that we might be able to go on and design therapies."

Viral Causes

The agent that triggers the onset of Type 1 diabetes is probably a virus that infects cells in the pancreas, and the disease arises out of an adaptive immune response to such a virus. During an infection, antibodies are raised against the virus, and cytotoxic T lymphocytes selectively target and eliminate those cells that are infected.

However, in Type 1 diabetes, the killing proceeds out of control, and the T cells become specific for all the insulin producing b cells in the islets. The T cells attack and kill all the insulin producing cells, causing a depletion of these cells in the pancreas and of insulin in the bloodsteam.

This "autoimmune" reaction may be due to an inflammatory response in the pancreas during the viral infection in which the b cells release their own molecular components, which then get confused as foreign antigen. These components get taken up by B cells, then T cells become specific for pancreatic cells.

However, the exact, detailed mechanisms and molecular interactions that lead to Type 1 diabetes are not clear. While there is a clear link between viral infection of the pancreas and the development of Type 1 diabetes, many more people are infected with viruses that localize to the pancreas than develop the disease. Presumably many people can fight off the viral infection without turning their own immune systems against themselves.

Sarvetnick's laboratory looks at strategies that the immune system uses to get rid of dangerous cells and ways that the body regulates these strategies.

"We're trying to understand how people who are resistant to this disease counter-regulate these processes," says Sarvetnick, "and which molecules they work through."

Diabetes under Glass

Her laboratory uses in vivo pancreatic models and a virus that is useful for studying many aspects of the disease, both basic ones and those that aim more towards pre-clinical development. These models generally involve infecting pancreatic cells under various conditions to induce an immune response that leads to the development of diabetes.

The models allow Sarvetnick and her colleagues to look at such issues as the immune response to viral and pancreatic antigen that is produced following infection with the virus.

More importantly, the models allow the laboratory to sort out the various molecules that are involved in the development of diabetes. For instance, knocking out the CD1d protein—normally displayed on the surfaces of antigen presenting cells—accelerates the onset and increases the incidence of diabetes.

But this is merely one example. There are likely many genes and many molecules involved in the autoimmune attack that leads to Type 1 diabetes. This is a broad area of basic research involving many interacting molecules, but one which could possibly hold keys to the therapy and prevention of insulin-dependent diabetes.

One possible research direction involves the counter-regulation of the primary, inflammatory responses to the viral infection. The body naturally makes substances that counter this process, and Sarvetnick is interested in elucidating both what these factors are and how they work.

Another direction is to study the regulation of the acquired immune cell response. Killer T cells are responsible for the immune reaction that leads to the onset of diabetes, and these are regulated in the body by cytokine molecules. Cytokines are produced by pancreatic and immune cells during infection and can regulate the immune cell response.

"They can affect the half-life of T cells and the antigen presenting cells and change the way that the killer T cells get primed," Sarvetnick explains.

Some of the basic questions are which T cells are involved, how the pancreas tries to defend itself in response to the infection, which antigens are presented by B cells, and what the exact nature of the T cell response is.

Sarvetnick's laboratory has already demonstrated that certain cytokines produced at certain times of infection can lead to the development or inhibition of diabetes in their models. For instance, the molecule Interleukin–4 has a potent inhibitory effect on the development of diabetes in pancreases with cells expressing the molecule.

The current thinking is that the interleukins interfere with the development of specific killer T cells, but the exact mechanism of this inhibition is still unknown. As are the mechanisms of other regulatory effects perpetrated by the other regulatory molecules involved.

"There are really a number of things [the cytokines] do that we are looking at," says Sarvetnick.

Other Therapeutic Implications

Another possibility for treating the disease is to understand and manipulate the growth of the pancreas. One of the great success stories in treating Type 1 diabetes in the last 35 years has been the pancreas transplant, in which a healthy organ from a donor replaces the pancreas of a diabetes patient.

However this is a major, complicated surgery, limited both by its inherent risk and the low availability of donor organs. Perhaps a better approach would be some sort of therapy that would regenerate the insulin producing islet cells in the pancreas of a person with Type 1 diabetes—to use pluripotent stem cells to replace the needed b cells within a patient's own pancreas. This may even eventually be a cure for the disease, though years away at best.

For now, the first step is the identification and isolation of pancreatic progenitor cells. These are the progenitor cells that differentiate to become insulin producing islet cells in the pancreas. They can be identified and isolated through flow cytometry through their unique cell-surface molecules—markers which are yet to be identified.

A closely related issue is the elucidation of the molecular signals that are involved in the differentiation of stem cells into the islet b cells. The ErbB receptors, for instance, seem to be implicated in this process. At the moment Sarvetnick's laboratory is busy characterizing the role of these receptors in the development and regeneration of the pancreas.

Mother of Invention

As our interview is wrapping up, the phone rings. As if by the tone of the buzz, Sarvetnick breaks off in mid-sentence and wheels around to her office door. "Is that ...?" she asks. Yes. Sorry—must take this call. Hello.... OK.... What time?.... Talk to you later then....

"That's the other side of my life," she says when she puts down the phone.

Then she tells me a story. This time it is not a story about cells and viruses but about a working scientist, her daughter, and her two sons—a tale of theatre, ballet classes, and hockey practices. The story seems even more complicated than the science she has been telling me about, involving a daily ritual of coordinating schedules, arranging for school pick-ups and drop-offs, helping with evening homework, and making sure meals are covered. She tells me about the sacrifices she has to make so that neither her children nor her research suffer. Her science and her children are her life.

"You really pare your life down to the bare necessities," she says. "And it's not easy. It's really hard and trying."

"Ok it's murder." She says. But I know that by murder she means happiness.


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Professor of Immunology Nora Sarvetnick investigates the basic biology of diabetes. Photo by Howard Fox.






















Loss of insulin-producing b cells (bottom image, stained in brown) in the pancreas is the hallmark of Type 1 diabetes. Top image shows a healthy pancreas with the islet of Langerhans stained for insulin. Photo by Cecile King.











Professor of Immunology Nora Sarvetnick seen here watching birds with her children Julian (6), Estella (4), and Gabe (9). Photo by Howard Fox.