Gene Linked to Thymus, Type 1 Diabetes in Rats
July 25, 2002, Acurian
Source: Acurian Inc.
by: Carrie Wingate, Ph.D.
A gene that appears to play an important role in diabetes among rats,
and is also present in humans in nearly identical form, has been
discovered by researchers at the University of Washington. Further
study of the gene may shed light on little-understood processes of
the thymus, a vital part of the body’s immune system that sometimes
attacks insulin-producing cells in the pancreas, thus causing type 1
diabetes.
“This gene appears to be absolutely necessary for the development of
diabetes in the BB rat, the best model for human type 1 diabetes,”
says Dr. Ake Lernmark of the University of Washington in
Seattle. “The identification of this gene will help us figure out how
a gene can fully control if the rat will get diabetes or not. We
think this gene may also contribute to human type 1 diabetes.”
Lernmark is senior author of a paper describing the findings,
published in the July 2002 issue of Genome Research. The research was
supported by the National Institute of Allergy and Infectious
Disease, one of the National Institutes of Health. The work is a
collaboration in rat genomics with others throughout the United
States.
Type 1 diabetes affects up to 1 percent of humans, many fewer than
type 2 diabetes. The two types of diabetes also differ in why the
body doesn’t metabolize blood glucose (sugar) using the hormone
insulin. Researchers have spent the last two decades studying a
particular breed of rat, known as the BB rat, which develops type 1
diabetes naturally and dies unless given insulin. In the current
study, the researchers have succeeded in using positional cloning to
identify a new gene, dubbed Ian5 (pronounced “I A N 5″), with a
mutation that causes the deletion of a protein that is found in,
among other places, the thymus. The thymus is an organ that lies
behind the breastbone and in which lymphocytes (white blood cells)
mature and multiply.
To understand why that’s important, one needs to understand the type
1 diabetes disease process. Inside the bodies of both humans and
rats, bone marrow produces white blood cells, or lymphocytes, such as
T cells, that leave the marrow and travel to the thymus for filtering
and processing. The thymus filters and rejects T cells that would
harm the body. In a process that is less understood, a healthy thymus
incubates T cells that will be released into the body to fight
infections.
In type 1 diabetes, something goes wrong with this process. The
thymus releases T cells that “think” that insulin-producing cells in
the pancreas represent an infection that needs to be destroyed. In
fact, the insulin-producing cells in the pancreas are necessary to
life. When the T cells attack and destroy those insulin-producing
cells in the pancreas, the body has to get insulin from another
source. This condition is called type 1 diabetes, and human patients
as well as BB rats require daily insulin from outside the body to
survive.
Obviously, says Dr. Armand J. MacMurray of the University of
Washington, “Something in the immune system is going wrong. No one is
sure exactly what.” But now that the researchers have identified a
specific gene that is causing an immune system defect, MacMurry
says, “we can try to understand how that gene is acting in its
particular context in the immune system normally. That will help us
understand what is happening abnormally that is predisposing the rats
to the disease, and then see what we can learn about any similar
process within humans.”
Besides studying the exact function of the Ian5 gene and its protein,
researchers will try to find out if there are any people with type 1
diabetes who have variants of the Ian5 gene. They have already
determined that humans have an Ian5 gene in the same relative
location on chromosome 7 that corresponds to the rat gene’s position
on its chromosome 4.
The researchers hope that a better understanding of the gene and the
function of the thymus could help find answers for diabetes. “One
hypothesis is that Ian5, in its regular form, allows T cells to
mature properly in the thymus. But perhaps because of this gross
defect in the gene, the thymus allows the creation of the defective T
cells that are at the root of diabetes,” MacMurray says.
Copyright (c) 2002 Acurian Inc. All Rights Reserved.
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