This page contains a Flash digital edition of a book.
Eisenbarth_edit_Cardiology_book_temp 22/12/2009 10:15 Page 83
Type 1 Diabetes—Pathogenesis, Prediction, and Prevention
solution to the disease. Currently, efforts are under way to prevent beta- considered for participation in NIH-sponsored trials (either new onset or
cell loss or replace lost cells via beta-cell regeneration or transplantation pre-diabetic) by contacting Trialnet (1-800-HALT-DM1).
of islets. Subjects who undergo islet cell transplant often initially develop
insulin independence and markedly improved glucose levels. However, Conclusion
these benefits are short-lived with a significant number losing insulin There has been great progress in understanding type 1 diabetes in the
independence over long-term (two- and five-year) follow-up. There last two decades. We can predict disease through genetic testing of
remains some benefit with improved blood glucose control and prevention alleles of genes in the MHC region combined with analysis of islet
of severe hypoglycemia, however.
81
Toxicity of immunosuppressive autoantibodies and metabolic function. The realization that type 1
regimens and failure of islet grafts with time suggest that for most patients diabetes is an autoimmune disorder associated with a series of
complications of therapy outweigh the benefits, and for now islet additional autoimmune diseases, many with shared genetic loci
transplantation is still in development.
82
(e.g. celiac disease, Addison’s disease, thyroid autoimmunity), has led
many centers to screen for these associated disorders. Current
It was reported more than 20 years ago that horse anti-thymocyte knowledge has also led to progress in trials of preventive therapies
globulin or cyclosporine therapy prolongs the honeymoon phase in new- through manipulation of the immune response. It is hoped that in the
onset diabetic patients.
83,84
Since the initial publications, many therapies years to come diabetes will be a preventable disease and the results of
have been studied to modulate the immune system both generally as current phase III clinical trials will hopefully inform clinical care. n
well as through targeting specific antigens. General immunosupression is
a poor option for treatment and prevention of diabetes, given the very
Peter R Baker II, MD, is a Fellow in Clinical Genetics and
high cost–benefit ratio. Trials using oral insulin (through the National
Metabolism at the University of Colorado Denver. His
Institutes of Health [NIH] Diabetes Prevention Trial) to stimulate current role includes research in immunogenetics as it
self-tolerance in the subgroup of individuals with high levels of anti-
relates to autoimmune disease in the Eisenbarth lab at the
Barbara Davis Center for Childhood Diabetes via a grant
insulin antibodies showed some promise only in individuals with high
funded by the Pediatric Scientist Development Program.
levels of insulin autoantibodies by delaying the onset of diabetes. In He is a board-certified pediatrician, and is a member of
several well-powered studies, however, the onset of disease could not be
the American Academy of Pediatrics (AAP) and the Society
for Inherited Metabolic Disorders (SIMD).
prevented overall.
69,85–89
Other promising therapies include vaccination
with GAD65 (a known target of anti-islet antibodies) and monoclonal
George S Eisenbarth, MD, PhD, is Executive Director of
antibody therapy with anti-CD3 and anti-CD20.
89–91
Again, long-term arrest
the Barbara Davis Center for Childhood Diabetes and a
of disease progression has not been found with these therapies. While
Professor of Pediatrics, Medicine, and Immunology at the
antigen-specific therapies are safer than broad immunomodulation,
University of Colorado Denver. He was the recipient of the
Banting Award in 2009 for his research on the prediction
there is less evidence for efficacy. Still, there is optimism and ongoing
and prevention of type I (insulin-dependent) diabetes. This
research devoted to this area. Several phase III trials are either under way
includes the immunogenetics of type I diabetes, focusing
or planned with goals to delay loss of beta cells after onset of
on the activation and natural history of specific patterns of
autoimmunity in genetically susceptible individuals.
hyperglycemia or in autoantibody-positive high-risk individuals. In North
America, individuals can be screened for islet autoantibodies and
1. Gillespie KM, Bain SC, Barnett AH, et al., The rising Responses against islet antigens in NOD mice are diabetes in the nonobese diabetic mouse, Proc Natl Acad Sci
incidence of childhood type 1 diabetes and reduced prevented by tolerance to proinsulin but not IGRP, J Clin U S A, 2003;100:10376–81.
contribution of high-risk HLA haplotypes, Lancet, Invest, 2006;116:3258–65. 16. Jasinski JM, Yu L, Nakayama M, et al., Transgenic insulin
2004;364:1699–1700. 9. Nakayama M, Abiru N, Moriyama H, et al., Prime role for an (B:9-23) T-cell receptor mice develop autoimmune diabetes
2. U.S. Department of Health and Human Services NIoH 2008 insulin epitope in the development of type 1 diabetes in dependent upon RAG genotype, H-2g7 homozygosity, and
National Institute of Diabetes and Digestive and Kidney NOD mice, Nature, 2005;435:220–23. insulin 2 gene knockout, Diabetes, 2006;55:1978–84.
Diseases: National Diabetes Statistics, 2007 fact sheet. 10. Peng JT, Wong FS, Du W, et al., Insulin Reactive T Regulatory 17. Mathews CE, Pietropaolo SL, Pietropaolo M, Reduced
3. Dunger DB, Sperling MA, Acerini CL, et al., European Cell TCR Transgenic NOD Mouse, Diabetes, 2005;54(Suppl. 1): thymic expression of islet antigen contributes to loss of
Society for Paediatric Endocrinology/Lawson Wilkins A93. self-tolerance, Ann N Y Acad Sci, 2003;1005:412–17.
Pediatric Endocrine Society consensus statement on 11. Solvason N, Lou YP, Peters W, et al., Improved efficacy of a 18. Nakayama M, Babaya N, Miao D, Thymic expression of
diabetic ketoacidosis in children and adolescents, Pediatrics, tolerizing DNA vaccine for reversal of hyperglycemia mutated B16:A preproinsulin messenger RNA does not
2004;113:e133–40. through enhancement of gene expression and localization reverse acceleration of NOD diabetes associated with
4. Eisenbarth SC, Homann D, Primer immunology and to intracellular sites, J Immunol, 2008;181:8298–8307. insulin 2 (thymic expressed insulin) knockout, J Autoimmun,
autoimmunity. In: Eisenbarth GS (ed.), Type I Diabetes: 12. Suri A, Levisetti MG, Unanue ER, Do the peptide-binding 2005;25:193–8.
Molecular, Cellular and Clinical Immunology, 2006. Online edition properties of diabetogenic class II molecules explain 19. Hernandez Prada JA, Ferreira AJ, Katovich MJ, Structure-
Version 3.0, updated August 2008. Available at: autoreactivity? Curr Opin Immunol, 2008;20:105–10. based identification of small-molecule angiotensin-
www.uchsc.edu/misc/diabetes/books.html 13. Thebault-Baumont K, Dubois-LaForgue D, Krief P, converting enzyme 2 activators as novel antihypertensive
5. Simone EA, Yu L, Wegmann DR, Eisenbarth GS, T cell Acceleration of type 1 diabetes mellitus in proinsulin 2- agents, Hypertension, 2008;51:1312–17.
receptor gene polymorphisms associated with anti-insulin, deficient NOD mice, J Clin Invest, 2003;111:851–7. 20. Kobayashi M, Jasinski J, Liu E, et al., Conserved T cell
autoimmune T cells in diabetes-prone NOD mice, 14. Fukushima K, Abiru N, Nagayama Y, Combined insulin B:9- receptor alpha-chain induces insulin autoantibodies, Proc
J Autoimmun, 1997;10:317–21. 23 self-peptide and polyinosinic-polycytidylic acid Natl Acad Sci U S A, 2008;105:10090–94.
6. Homann D, Eisenbarth GS, An immunologic homunculus for accelerate insulitis but inhibit development of diabetes by 21. Burton AR, Vincent E, Arnold PY, et al., On the pathogenicity
type 1 diabetes, J Clin Invest, 2006;116:1212–15. increasing the proportion of CD4+Foxp3+ regulatory T cells of autoantigen-specific T-cell receptors, Diabetes,
7. Jaeckel E, Lipes MA, von Boehmer H, Recessive tolerance in the islets in non-obese diabetic mice, Biochem Biophys Res 2008;57:1321–30.
to preproinsulin 2 reduces but does not abolish type 1 Commun, 2008;367:719–24. 22. Corper AL, Stratmann T, Apostolopoulos V, et al., A
diabetes, Nat Immunol, 2004;5:1028–35. 15. Moriyama H, Abiru N, Paronen J, et al., Evidence for a structural framework for deciphering the link between I-
8. Krishnamurthy B, Dudek NL, McKenzie MD, et al., primary islet autoantigen (preproinsulin 1) for insulitis and Ag7 and autoimmune diabetes, Science, 2000;288:505–11.
US ENDOCRINOLOGY 83
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92  |  Page 93  |  Page 94  |  Page 95  |  Page 96  |  Page 97  |  Page 98  |  Page 99  |  Page 100  |  Page 101  |  Page 102  |  Page 103  |  Page 104  |  Page 105  |  Page 106  |  Page 107  |  Page 108  |  Page 109  |  Page 110  |  Page 111  |  Page 112  |  Page 113  |  Page 114  |  Page 115  |  Page 116  |  Page 117  |  Page 118  |  Page 119  |  Page 120  |  Page 121  |  Page 122  |  Page 123  |  Page 124
Produced with Yudu - www.yudu.com