Insulin-Dependent Diabetes Mellitus
An Autoimmune Disease
Introduction
Insulin-dependent diabetes mellitus (IDDM), commonly referred to as
type-I diabetes, is a condition caused when an autoimmune response induces
the death of insulin-secreting b cells in the
pancreas. Insulin (see Figure 1) is the protein
that is responsible for transporting glucose (secreted by pancreatic a
cells)
from the blood into the cells, where the glucose is metabolized for energy.
When b cells are killed the body has no way
of producing insulin, so glucose levels in the blood are unable to be controlled,
leading to hyperglycemia, or high blood glucose level. Longterm complications
of hyperglycemia include cardiovascular, kidney, and eye diseases, as well
as various nervous system disorders. (diabetes.com,
2000)
Causes
IDDM tends to run in families, and there is substantial evidence that
genetics plays a significant role in causing the disease. However,
studies have shown that the concordance rate for IDDM among monozygotic
twins is less than 50 percent, meaning that environmental factors must
also play a significant role. (Tisch et al.,
1996). The fact that both environment and genetics contribute
to IDDM has led to the assumption that the autoimmune response causing
insulitis and autoantibody release (see pathogenesis
below) is generally triggered by an environmental stimulus, but occurs
primarily in those who are genetically predisposed to the disease.
Genetic susceptibility to IDDM, as with most autoimmune diseases, is believed to be primarily related to the MHC genotype. The MHC II genes that appear to play the most significant role in IDDM susceptibility are found at the HLA-DR locus, which is linked tightly to HLA-DQ. The two alleles HLA-DR3 and HLA-DR4 seem to be the strongest genetic causes of IDDM, since nearly all diabetics express at least one, or more often both of these alleles. Conversely, a third allele, HLA-DR2, is commonly expressed in non-diabetic individuals, but very seldom appears among diabetics, which suggests that this allele helps prevent IDDM. The HLA-A, HLA-B, and HLA-C genes encoding MHC I are also believed to be associated with IDDM. Both CD8 and CD4 T cells have been shown to play significant roles in mediating the IDDM autoimmune response, so it is reasonable that the genetic source is associated with genes encoding MHC I and MHC II, the molecules with which CD8 and CD4 T cells interact, respectively. (Janeway et al., 1999) A figure showing a map of the human MHC complex, with labeled IDDM-associated loci, can be found at <http://www.harrisonsonline.com/marketing/sample/entrypages/public/ch334/334_fig1.htm>.
Although IDDM susceptibility has an apparent genetic origin, what exactly
is responsible for stimulating the autoimmune response remains unclear.
The most common examples of the various possible external factors that
have been shown to trigger a response leading to IDDM include:
can be induced by IFN-g, which could be present due to a viral infection. This theory therefore works in conjunction with the virus theory, claiming that infant exposure to cow's milk elicits antibodies capable of attacking b cells later in life following a viral infection. (Harrison's Online, 2000)
Pathogenesis
The two distinctive features of IDDM are the infiltration of pancreatic
islets by macrophages and lymphocytes, a condition known as insulitis (see
Figure
2), and the presence of autoantibodies in the serum. (Haskins
et
al., 1996) Both of these events serve as markers for the
prediabetic phase of IDDM.
More than a dozen islet-cell proteins that elicit antibody responses in type-I diabetics have been identified, and the presence of these autoantigens (and/or their corresponding autoantibodies) serve as important diagnostic tools for early identification of IDDM. Among the apparently more significant autoantigens are:
- 37k antigen--The antibodies to this autoantigen are found in over half of all type-I diabetics, and these autoantibodies are unique to diabetes and are not found in patients suffering from other endocrine-related autoimmune diseases.
- b-granule antigen--This autoantigen has not been completely identified yet, but it is known the be the target for the Th1 T cell clones derived from NOD mice.
- P69
- Insulin
- GAD--Glutamic acid decarboxylase (GAD) exists in two isoforms of 65kD (GAD65) and 67kD (GAD67).
Insulitis, also referred to as isletitus, occurs when macrophages and
activated T cells invade the islets of
Langerhans in the pancreas and attack the insulin-secreting b
cells. Insulitis occurs during the prediabetic phase, ultimately
leading to the complete depletion of b cells
which is characteristic of IDDM. Analysis of pancreatic islets during
this stage has revealed the presence of both CD4 and CD8 T cells, and tests
have indicated that both are necessary to induce b
cell autoimmunity, but the role of CD4 is more clearly understood.
One relatively new strategy used to examine the respective roles of CD4
and CD8 T cells in insulitis has been to create T cell clones of
T cell lines derived from the islets of nonobese diabetic (NOD) mice.
Through adoptive-transfer experiments it has been possible to identify
specific T cells as diabetogenic, or able to induce diabetes in healthy
animals. Studies using this method concluded that although CD8 T
cells are generally present and active in the b
cell autoimmune response, these cytotoxic T cells usually failed to induce
diabetes in the absence of CD4, specifically Th1 T cells. CD4 T cells
generally appeared to be responsible for initiating the autoimmune response
and recruiting other cells, including CD8 T cells, to the pancreas, which
explains the dependency of cytotoxic T cells on Th1 cells. In some
cases, the particular antigen specificities of the T cell clones have been
identified, making it possible to study the diabetogenicity of T cell clones
specific to proteins such as GAD and insulin, as well as other pancreatic
proteins. (Haskins et al., 1996)
In one study by Zekzer et al.,
a line of CD4 Th1 T cell clones specific to GAD65 were derived from NOD
mice that developed diabetes in response to purified GAD injection.
These Th1 cells, called 5A T cells, were shown to induce insulitis spontaneously
in NOD mice through adoptive transfer. (Zekzer
et
al., 1998) Another related study by Tian
et
al. demonstrated that a single intranasal administration of GAD65
peptides to NOD mice elicited a Th2 rather than Th1 response. The
fact that these NOD mice did not develop IDDM suggests that the Th1 autoimmune
response was inhibited by stimulating a dominantly Th2 GAD-specific T cell
population. (Tian
et al., 1996)
Although these studies provide strong evidence that GAD-reactive Th1 cells
are capable of inducing b cell autoimmunity in genetically predisposed
NOD mice, there is no evidence establishing that autoreactive Th1 cells
are limited to GAD specificity. (Zekzer
et
al., 1998)
Several studies have demonstrated an important role of many apoptotic pathways, specifically Fas/Fas Ligand (FasL), perforin, and TNF-a pathways, in the T cell-induced apoptosis of b cells. A study by Su et al., using a population of mutated Fas-deficient NOD mice (NOD-lpr/lpr), demonstrated that NOD mice that do not express Fas fail to develop IDDM. This study also showed that NOD-lpr/lpr mice were also resistant to adoptive transfer of diabetogenic T cells, suggesting that the Fas/FasL apoptotic pathway is the primary method of killing b cells. (Su et al., 2000) A related study suggested that the cytokines IL-a, IL-1b, and IFN-g somehow prime b cells to be destroyed by CD4 T cells. Amrani et al. identified a diabetogenic b cell-specific T cell receptor (4.1-TCR) capable of inducing apoptosis of b cells via the Fas/FasL pathway, and demonstrated the importance of these cytokines, as well as Fas, by observing that cytokine-treated NOD-lpr/lpr mice introduced with 4.1-TCR T cells failed to develop IDDM, as did untreated NOD mice. Cytokine-treated NOD mice, on the other hand, quickly developed IDDM. The study suggests that the Fas/FasL pathway is the initial process of inducing b cell apoptosis, but is followed later by perforin-mediated CD8 cytotoxicity. (Amrani et al., 2000) This suggestion is consistent with the earlier mentioned studies which demonstrated that CD4 T cell infiltration into the islets preceded that of CD8 T cells.
Despite the vast amount of research that has been done exploring the mechanisms which lead to IDDM, we have only reached the tip of the iceberg. The fact that so many different proteins and pathways have been demonstrated to be relevant to the development of IDDM suggests that it may take significantly more time and effort until a clear understanding of the pathogenesis of this disease. The complexity of the disease is further amplified by the likelihood that there are many different causes possibly leading to a multitude of various mechanisms by which autoimmunity is induced and b cells are killed.
Treatment
Since it remains unclear what causes the autoimmune response leading
eventually to IDDM, and it is almost certain that there are numerous such
causes, we are still quite far away from developing effective means of
preventing the onset of IDDM. However, recent studies with pancreatic
stem cells have shown a lot of promise to providing a possible cure for
type-I diabetic individuals with fully depleted b
cell populations. Experiments have been conducted in which pancreatic
islet stem cells were removed from NOD mice that had not yet developed
IDDM. These stem cells were cultured and differentiated into a population
of mature, insulin-producing islets of Langerhans. The cells, when
inserted into fully diabetic NOD mice, seemed to reverse diabetes since
these mice continued to be able to produce insulin in response to glucose
after being gradually weaned off of insulin injections. A similar
process could be used for humans, in which pancreatic tissue taken from
cadavers could be cultured and transplanted into type-I diabetic patients.
(Berger, 2000) This possibility, however,
brings up the issue of possible graft rejection. Transplantation
creates the need for immunosuppressant drugs, such as cyclosporin, to prevent
rejection, and there is significant controversy over whether it is worthwhile
to compromise the effectiveness of the immune system in general to attain
good blood glucose control. IDDM is presently treated very effectively
with regular routine of insulin injections (usually 1-2 injections per
day), blood glucose monitoring, and balanced diet. These daily
routine treatments allow type-I diabetics to lead a fairly normal lifestyle,
and when blood glucose levels are closely monitored and controlled with
insulin injections, the risk of complications caused by hyperglycemia is
greatly reduced. Transplantation may present a cure, but there is
reason to believe that immunosuppresants may present more health risks
than well-controlled IDDM, especially as methods for maintaining normal
blood glucose levels continue to improve. (Harrison's
Online, 2000)
Figure 1: Chime figure of an R6 Human Insulin Hexamer. The figure shows 6 insulin proteins, each consisting of two peptide chains linked by 2 disulfide bonds. Image obtained from the National Center for Biotechnology Information (NCBI) <http://www.ncbi.nlm.nih.gov/Structure/>
Figure 2: This is an insulitis of an islet of Langerhans in a patient who will eventually develop type I diabetes mellitus. The presence of the lymphocytic infiltrates in this edematous islet suggests an autoimmune mechanism for this process. The destruction of the islets leads to an absolute lack of insulin that characterizes type I diabetes mellitus. Image and text used by permission from Edward C. Klatt, MD. <http://www-medlib.med.utah.edu/WebPath/ENDOHTML/ENDO040.html>
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IFN-g mark b cells
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