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Type 1 Diabetes
Type 1 Diabetes—Pathogenesis, Prediction, and Prevention
Peter R Baker II, MD
1
and George S Eisenbarth, MD, PhD
2
1. Fellow, Clinical Genetics and Metabolism, University of Colorado Denver;
2. Executive Director, Barbara Davis Center for Childhood Diabetes, University of Colorado Denver
Abstract
Type 1 diabetes affects over 1.4 million people in the US, with a rising incidence in many western nations. It is clear that there is a strong
hereditary component and that autoimmunity plays a large role in disease pathogenesis. In the last two decades novel technologies have been
developed to study the genetics, biochemistry, and molecular pathology of type 1 diabetes. These, in turn, have allowed for early recognition of
disease as well as the potential for prevention trials and early insulin treatment. This article highlights the prediction of type 1 diabetes risk and
developing immunotherapeutic concepts.
Keywords
Autoimmune polyendocrine syndrome (APS), autoantibodies, autoimmunity, environmental risk, genome-wide association study, human leukocyte
antigen (HLA), insulin, major histocompatability complex (MHC), pancreatic beta cells, trimolecular complex
Disclosure: The authors have no conflicts of interest to declare.
Acknowledgments: This work was supported by the National Institutes of Health (DK32083, DK057538, UO1DK062418, DK32493), Autoimmunity Prevention Center (AI050864),
Diabetes Endocrine Research Center (P30 DK57516), Clinical Research Centers (MO1 RR00069, MO1 RR00051), the Immune Tolerance Network (AI15416), the American Diabetes
Association, the Juvenile Diabetes Research Foundation, the Children’s Diabetes Foundation, and the Brehm Coalition. Peter R Baker II, MD, is a Fellow of the Pediatric Scientist
Development Program. The project described was supported by Award K12-HD000850 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Received: October 12, 2009 Accepted: November 23, 2009
Correspondence: George S Eisenbarth, MD, PhD, Barbara Davis Center for Childhood Diabetes, 1775 Ursula St, Room 4201E, Building M20, PO Box 6511, Box B140, Aurora,
CO 80045-6511. E: George.Eisenbarth@ucdenver.edu
Type 1 diabetes has become one of the most studied polygenic obese diabetic (NOD) mouse (which has many similarities to human type
disorders. It effects over 1.4 million people in the US, with a rising 1 diabetes), the pathogenesis of autoimmune beta-cell destruction is
incidence in many western nations.
1,2
It is clear that there is a strong becoming clearer. Central to T-cell response, including autoimmune
hereditary component in the development of disease, with siblings at responses, are components of the trimolecular complex. For CD4-
higher risk than offspring and both at higher risk than the general positive T cells this complex consists of the T-cell receptor (TCR), an
population. It is also clear that autoimmunity plays a large role in disease antigenic peptide, and a human leukocyte antigen (HLA) molecule on
pathogenesis. Development is insidious and chronic, but the initial antigen-presenting cells (APCs) (e.g. the NOD mouse I-Ag7, homologous
presentation is often acute (hyperglycemia, ketoacidosis, and cerebral to HLA class II DQ of humans).
edema) and can be deadly as it is often unexpected.
3
Figure 1 illustrates the trimolecular complex, which can be likened to a
In the last two decades novel technologies have been developed to hotdog (the peptide), bun (class II or class I molecules of the major
study the genetics, biochemistry, and molecular pathology of type 1 histocompatability complex or MHC), and barbecue instruments (the
diabetes. These, in turn, have allowed for early recognition of disease, as TCR). The peptide sequence being presented to the TCR sits in the
well as the potential for prevention trials and early insulin treatment. In groove of class II or class I molecules on the surface of an APC. The TCR
this article we will highlight the prediction of type 1 diabetes risk and is then able to recognize it, bind to it (with varying affinity dependent on
developing immunotherapeutic concepts. molecular shape and charge), and mount an immune response. The TCR
is crucial for T-cell selection in the thymus as well as immune targeting
Immunology and Pathophysiology of of peptides by mature T-lymphocytes. The receptor structure includes
Type 1 Diabetes variable alpha and beta chains, both with germline-encoded V and J
An overwhelming amount of evidence in the last several decades points sequences. These segment sequences are ‘randomly’ combined to form
to type 1 diabetes being an autoimmune, specifically T-cell-mediated, literally billions of different TCRs that recognize specific antigenic
disease. Through study of multiple animal models, including the non- sequences.
4,5
When an antigenic peptide is presented by thymic
© TOUCH BRIEFINGS 2009 79
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