Chapter I. Pathogenesis
| Rev Diabet Stud,
2012,
9(4):137-147 |
DOI 10.1900/RDS.2012.9.137 |
Genetic Analysis of Type 1 Diabetes: Embryonic Stem Cells as New Tools to Unlock Biological Mechanisms in Type 1 Diabetes
Nick Holmes, Anne Cooke
Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK
Address correspondence to: Nick Holmes, e-mail nh106@cam.ac.uk
Abstract
The nonobese diabetic (NOD) mouse has provided an important animal model for studying the mechanism and genetics of type 1 diabetes over the past 30 years. Arguably, the bio-breeding (BB) rat model may be an even closer phenotypic mimic of the typical human disease. A large number of distinct genetic traits which influence diabetes development have been defined through an extraordinary effort, most conspicuously in the mouse model. However, in both NOD and BB models the lack of availability of robust means for experimental genetic manipulation has restricted our understanding of the mechanisms underlying this spontaneous autoimmune disease. Recent developments in the derivation of embryonic stem (ES) cells have the potential to transform this picture. We argue here that targeting of NOD strain ES cells can bring much needed certainty to our present understanding of the genetics of type 1 diabetes in the NOD mouse. In addition, ES cells can play important roles in the future, in both the NOD mouse and BB rat models, through the generation of new tools to investigate the mechanisms by which genetic variation acts to promote diabetes.
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| Rev Diabet Stud,
2012,
9(4):148-168 |
DOI 10.1900/RDS.2012.9.148 |
Pathogenic Mechanisms in Type 1 Diabetes: The Islet is Both Target and Driver of Disease
Kate L. Graham1, Robyn M. Sutherland2,3, Stuart I. Mannering1,4, Yuxing Zhao1, Jonathan Chee1,4, Balasubramanian Krishnamurthy1,4, Helen E. Thomas1,4, Andrew M. Lew2,3, Thomas W.H. Kay1,4
1St. Vincent´s Institute of Medical Research, Fitzroy, Victoria, Australia
2The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
3Department of Medical Biology, The University of Melbourne, Victoria, Australia
4Department of Medicine, The University of Melbourne, St. Vincent´s Hospital, Fitzroy, Victoria Australia
Address correspondence to: Thomas Kay, St Vincent's Institute, 41 Victoria Parade, Fitzroy, VIC, 3065, Australia, e-mail tkay@svi.edu.au
Abstract
Recent advances in our understanding of the pathogenesis of type 1 diabetes have occurred in all steps of the disease. This review outlines the pathogenic mechanisms utilized by the immune system to mediate destruction of the pancreatic beta-cells. The autoimmune response against beta-cells appears to begin in the pancreatic lymph node where T cells, which have escaped negative selection in the thymus, first meet beta-cell antigens presented by dendritic cells. Proinsulin is an important antigen in early diabetes. T cells migrate to the islets via the circulation and establish insulitis initially around the islets. T cells within insulitis are specific for islet antigens rather than bystanders. Pathogenic CD4+ T cells may recognize peptides from proinsulin which are produced locally within the islet. CD8+ T cells differentiate into effector T cells in islets and then kill beta-cells, primarily via the perforin-granzyme pathway. Cytokines do not appear to be important cytotoxic molecules in vivo. Maturation of the immune response within the islet is now understood to contribute to diabetes, and highlights the islet as both driver and target of the disease. The majority of our knowledge of these pathogenic processes is derived from the NOD mouse model, although some processes are mirrored in the human disease. However, more work is required to translate the data from the NOD mouse to our understanding of human diabetes pathogenesis. New technology, especially MHC tetramers and modern imaging, will enhance our understanding of the pathogenic mechanisms.
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| Rev Diabet Stud,
2012,
9(4):169-187 |
DOI 10.1900/RDS.2012.9.169 |
Comparative Genetics: Synergizing Human and NOD Mouse Studies for Identifying Genetic Causation of Type 1 Diabetes
John P. Driver1, Yi-Guang Chen2, Clayton E. Mathews3
1Department of Animal Science, University of Florida, Gainesville, FL 32610, USA
2Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA
3Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA
Address correspondence to: Clayton E. Mathews, 1600 SW Archer Road, Room R4-204, P.O. Box 100275, Gainesville, FL 32610-0275, USA, e-mail clayton.mathews@pathology.ufl.edu
Abstract
Although once widely anticipated to unlock how human type 1 diabetes (T1D) develops, extensive study of the nonobese diabetic (NOD) mouse has failed to yield effective treatments for patients with the disease. This has led many to question the usefulness of this animal model. While criticism about the differences between NOD and human T1D is legitimate, in many cases disease in both species results from perturbations modulated by the same genes or different genes that function within the same biological pathways. Like in humans, unusual polymorphisms within an MHC class II molecule contributes the most T1D risk in NOD mice. This insight supports the validity of this model and suggests the NOD has been improperly utilized to study how to cure or prevent disease in patients. Indeed, clinical trials are far from administering T1D therapeutics to humans at the same concentration ranges and pathological states that inhibit disease in NOD mice. Until these obstacles are overcome it is premature to label the NOD mouse a poor surrogate to test agents that cure or prevent T1D. An additional criticism of the NOD mouse is the past difficulty in identifying genes underlying T1D using conventional mapping studies. However, most of the few diabetogenic alleles identified to date appear relevant to the human disorder. This suggests that rather than abandoning genetic studies in NOD mice, future efforts should focus on improving the efficiency with which diabetes susceptibility genes are detected. The current review highlights why the NOD mouse remains a relevant and valuable tool to understand the genes and their interactions that promote autoimmune diabetes and therapeutics that inhibit this disease. It also describes a new range of technologies that will likely transform how the NOD mouse is used to uncover the genetic causes of T1D for years to come.
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| Rev Diabet Stud,
2012,
9(4):188-200 |
DOI 10.1900/RDS.2012.9.188 |
Protein Tyrosine Phosphatases and Type 1 Diabetes: Genetic and Functional Implications of PTPN2 and PTPN22
Karen Cerosaletti, Jane H. Buckner
Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA
Address correspondence to: Jane H. Buckner, Associate Director, Benaroya Research Institute, Director, Translational Research, Benaroya Research Institute at Virginia Mason, 1201 9th Ave, Seattle, WA 98101, USA, e-mail jbuckner@benaroyaresearch.org
Abstract
Protein tyrosine phosphatases (PTPs) play a central role in modulating the transduction of cellular signals, including the cells of the immune system. Several PTPs, PTPN22, PTPN2, and UBASH3A, have been associated with risk of type 1 diabetes (T1D) by genome wide association studies. Based on the current understanding of PTPs, it is clear that these variants impact antigen receptor signaling and cytokine signaling. This impact likely contributes to the development and progression of autoimmunity through multiple mechanisms, including failures of central and peripheral tolerance and the promotion of proinflammatory T cell responses. In this review, we discuss the genetic and functional implications of two of these PTPs, PTPN22 and PTPN2, in the development of T1D. We describe the known roles of these proteins in immune function, and how the expression and function of these proteins is altered by the genetic variants associated with T1D. Yet, there are still controversies in the field that require further study and the development of new approaches to extend our understanding of these PTP variants, with the goal of using the information gained to improve our ability to predict and cure T1D.
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| Rev Diabet Stud,
2012,
9(4):201-223 |
DOI 10.1900/RDS.2012.9.201 |
From Markers to Molecular Mechanisms: Type 1 Diabetes in the Post-GWAS Era
Alan G. Baxter, Margaret A. Jordan
Comparative Genomics Centre, Molecular Sciences Building 21, James Cook University, Townsville QLD 4811, Australia
Address correspondence to: Alan G. Baxter, e-mail alan.baxter@jcu.edu.au
Abstract
By the year 2000, a draft of the human genome sequence was completed. Millions of single-nucleotide polymorphisms (SNPs) had been deposited into public databases, and high throughput technologies were under development for SNP genotyping. At that time, it was predicted that large case control association studies would provide far better resolution and power than genome-wide linkage studies. Type 1 diabetes was one of the first phenotypes to be examined by genome-wide association studies (GWAS), and to date over 50 genomic regions have been associated with the disease. In general, the great majority of these loci individually contribute a relatively small degree of risk, and most loci lie outside of coding sequences. The identification of molecular mechanisms from these genomic data therefore remains a significant challenge. Here, we summarize genetic candidate, linkage, and association studies of type 1 diabetes and discuss a potential strategy to identify mechanisms of disease from genomic data.
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| Rev Diabet Stud,
2012,
9(4):224-235 |
DOI 10.1900/RDS.2012.9.224 |
Novel Biomarkers in Type 1 Diabetes
Yulan Jin, Jin-Xiong She
Center for Biotechnology and Genomic Medicine and Department of Pathology, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA
Address correspondence to: Jin-Xiong She, Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University,1120 15th Street, Augusta, GA 30912, USA, e-mail: jshe@gru.edu
Abstract
Biomarkers are useful tools for research into type 1 diabetes (T1D) for a number of purposes, including elucidation of disease pathogenesis, risk prediction, and therapeutic monitoring. Susceptibility genes and islet autoantibodies are currently the most useful biomarkers for T1D risk prediction. However, these markers do not fully meet the needs of scientists and physicians for several reasons. First, improvement of the specificity and sensitivity is still desirable to achieve better positive predictive values. Second, autoantibodies appear relatively late in the disease process, thus limiting their value in early disease prediction. Third, the currently available biomarkers are not useful for assessing therapeutic outcomes because some are not involved in the disease process (autoantibodies) and others do not change during disease progression (susceptibility genes). Therefore, considerable effort has been devoted to the discovery of novel T1D biomarkers in the last three decades. The advent of high-throughput technologies for genetic, transcriptomic, and proteomic studies has allowed genome-wide examinations of genetic polymorphisms, global gene changes, and protein expression changes in T1D patients and prediabetic subjects. These large-scale studies resulted in the discovery of a large number of susceptibility genes and changes in gene and protein expression. While these studies have provided a number of novel biomarker candidates, their clinical benefits remain to be evaluated in prospective studies, and no new "star biomarker" has been identified until now. Previous studies suggest that significant improvements in study design and analytical methodologies have to be made to identify clinically relevant biomarkers. In this review, we discuss progress, opportunities, challenges, and future directions in the development of T1D biomarkers, mainly by focusing on the genetic, transcriptomic, and proteomic aspects.
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| Rev Diabet Stud,
2012,
9(4):236-247 |
DOI 10.1900/RDS.2012.9.236 |
Metabolomics in the Studies of Islet Autoimmunity and Type 1 Diabetes
Matej Oresic
VTT Technical Research Centre of Finland, Tietotie 2, Espoo, FIN-02044 VTT, Finland
Abstract
The metabolome is sensitive to genetic and environmental factors contributing to complex diseases such as type 1 diabetes (T1D). Metabolomics is the study of biochemical and physiological processes involving metabolites. It is therefore one of the key platforms for the discovery and study of pathophysiological phenomena leading to T1D and the development of T1D-associated complications. Although the application of metabolomics in T1D research is still rare, metabolomic research has already advanced across the full spectrum, from disease progression to the development of diabetic complications. Metabolomic studies in T1D have contributed to an improved etiopathogenic understanding and demonstrated their potential in the clinic. For example, metabolomic data from recent T1D studies suggest that a specific metabolic profile, or metabotype, precedes islet autoimmunity and the development of overt T1D. These early metabolic changes are attributed to many biochemical pathways, thus suggesting a systemic change in metabolism which may be inborn. Based on this evidence, the role of the metabolome in the progression to T1D is therefore to facilitate specific biochemical processes associated with T1D, and to contribute to the development of a vulnerable state in which disease is more likely to be triggered. This may have important implications for the understanding of T1D pathophysiology and early disease detection and prevention.
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