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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