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.
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