Despite decades of research, the underlying mechanisms causing type
1 diabetes—characterised by complete insulin dependence of the
subjects—remain largely unknown. The disease, in almost all cases,
has an autoimmune aetiology, based on autopsy, and more recently
biopsy, of the pancreas showing infiltrates of immune cells,
particularly CD8+ T lymphocytes, the sensitivity of the disease to
immunosuppression, the presence of autoantibodies to islet proteins,
including insulin itself and the enzyme glutamic acid decarboxylase,
and the genetic association of type 1 diabetes with the HLA region on
chromosome 6p21. In addition, two accurate animal models of the
disease exist, in the mouse and in the rat, both strongly supporting
the autoimmune nature of the disease and its association 
with immune
response genes within the HLA gene complex.
In humans it appears that T lymphocytes, in collaboration with
other cells of the immune system (particularly cells that can present
foreign and self protein fragments to T cells, including macrophages,
B lymphocytes, and dendritic cells) home to the pancreas, invading the
insulin-producing islets, which are mostly composed of ß cells,
producing an irreversible immune destruction of the ß cells. One way
to identify the mechanisms and pathways involved in this remarkably
specific immune inflammatory destruction is to identify the genes that
predispose and protect from type 1 diabetes. Type 1 diabetes is
clustered in families and often occurs with other autoimmune diseases,
such as autoimmune thyroid disease (Graves' disease), and rheumatoid
arthritis. One major reason for the clustering of type 1 diabetes in
disease is the association of the disease with the HLA class II genes.
These genes encode molecules that orchestrate T-cell development and
T-cell responses both to foreign antigens during infection, and during
the education of the T-cell immune system during the establishment and
maintenance of immune tolerance. Immune tolerance is when the body's
immune system does not attack self proteins and tissues. Only when
individuals carry certain genotypes at the HLA class II genes does the
immune system have a tendency to lose tolerance to certain ß-cell
proteins and provide the possibility of islet infiltration and ß-cell
destruction.
However, we know that allelic variation in these HLA class II genes is
not sufficient to explain the disease, and other genes across the
genome are involved. So far we only know of two of these. The insulin
gene itself, for which it appears that a polymorphism that affects
expression of insulin in the thymus, which is the organ in the body
that prevents autoimmune disease by establishing and maintaining
T-cell tolerance, might provide protection against type 1 diabetes by
increasing the level of immune tolerance to insulin and its
precursors. This is only a model, but it is consistent with studies in
the animal models. The third gene, which remains to be fully
characterised, probably maps close to the T-cell regulation gene, CTLA4.
CTLA-4 is a key molecule in the control of T-cell tolerance, in the
proliferation and programmed cell death of T cells. It appears, as for
the insulin gene, that the defect might lie in the expression of
CTLA-4. This proposed mechanism again is consistent with findings from
animal models of the disease and autoimmunity.
With rapid advances in the human genome project and the collection
of large sample sizes for the study of the genetics of type 1 diabetes
we can expect more rapid characterisation of the genes and their
variants involved. Because the genetic approach identifies primary
determinants of the disease it should be possible in the next few
years to identify which pathways and mechanisms are involved and how
they interact. The goal of our research is to focus on those pathways
discovered that might be targets for therapy, to alter the process of
autoimmune disease. Type 1 diabetes probably begins, in most cases, in
the first two years of life. Not only are many genes involved but
unknown, and probably many, environmental factors involving diet and
infection during the life of an individual determine the outcome of
the genetic programme. This complex interaction between genes and
environment remains a very significant challenge for the study of type
1 diabetes and of other common, complex, and multifactorial diseases.
Dr. John Todd
University of Cambridge
Department of Medical Genetics
Cambridge, England
n this essay, one of the most-cited scientists in diabetes
research in the past decade, Dr. John Todd, relates the progress that
has been made in elucidating the causes and prevention of type 1
diabetes in recent years. In our Special Topics analysis of diabetes
research, Dr. Todd ranks at #2, with 76 papers meeting the search
criteria cited a total of 4,002 times. Two of his papers also made the
top 25 papers list in this analysis. Dr. Todd’s work is
well-represented in the 
Web product, with papers
in the fields of Molecular Biology & Genetics, Clinical Medicine,
and Immunology, as well as in the Multidisciplinary field. Dr. Todd is
Professor of Medical Genetics and Director of the Wellcome Trust
Diabetes and Inflammation Laboratory at the University of Cambridge in
England