Type 1 Diabetes: Etiology, Immunology, and Therapeutic Strategies
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease in which destruction or damaging of the beta-cells in the islets of Langerhans results in insulin deficiency and hyperglycemia. We only know for sure that autoimmunity is the predominant effector mechanism of T1D, but may not be its primary cause. T1D precipitates in genetically susceptible individuals, very likely as a result of an environmental trigger. Current genetic data point towards the following genes as susceptibility genes: HLA, insulin, PTPN22, IL2Ra, and CTLA4. Epidemiological and other studies suggest a triggering role for enteroviruses, while other microorganisms might provide protection. Efficacious prevention of T1D will require detection of the earliest events in the process. So far, autoantibodies are most widely used as serum biomarker, but T-cell readouts and metabolome studies might strengthen and bring forward diagnosis. Current preventive clinical trials mostly focus on environmental triggers. Therapeutic trials test the efficacy of antigen-specific and antigen-nonspecific immune interventions, but also include restoration of the affected beta-cell mass by islet transplantation, neogenesis and regeneration, and combinations thereof. In this comprehensive review, we explain the genetic, environmental, and immunological data underlying the prevention and intervention strategies to constrain T1D.
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Many practical and intellectual advances have been made since the first immune-based therapies, including improved metabolic testing, better understanding of disease pathogenesis, and availability of immune markers.
“Many practical and intellectual advances have been made since then, including improved metabolic testing, better understanding of disease pathogenesis, and availability of immune markers.126”
From Type 1 diabetes (2014) · cites this paper as [126]
Cites
Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses
Kato, H., Takeuchi, O., Sato, S., Yoneyama, M., Yamamoto, M., Matsui, K., Uematsu, S., Jung, A., Kawai, T., Ishii, K. J., et al. (2006) · Nature · doi:10.1038/nature04734 · Cited by 3,888 · see citing works
Lymphoproliferative Disorders with Early Lethality in Mice Deficient in <i>Ctla-4</i>
Waterhouse, P., Penninger, J. M., Timms, E., Wakeham, A., Shahinian, A., Lee, K. P., Thompson, C. B., Griesser, H., & Mak, T. W. (1995) · Science · doi:10.1126/science.270.5238.985 · Cited by 2,766 · see citing works
Innate immunity and intestinal microbiota in the development of Type 1 diabetes
Wen, L., Ley, R. E., Volchkov, P. Y., Stranges, P. B., Avanesyan, L., Stonebraker, A. C., Hu, C., Wong, F. S., Szot, G. L., Bluestone, J. A., et al. (2008) · Nature · doi:10.1038/nature07336 · Cited by 1,921 · see citing works
Kroon, E., Martinson, L. A., Kadoya, K., Bang, A. G., Kelly, O. G., Eliazer, S., Young, H., Richardson, M., Smart, N. G., Cunningham, J., et al. (2008) · Nature Biotechnology · doi:10.1038/nbt1393 · Cited by 1,843 · cited 3× · see citing works
“This can be done by differentiation of embryonic stem (ES) cells (234) or pluripotent stem (IPS) cells (487), or the “reprogramming” of cells from their initial phenotype into beta-like cells (494).”
BackgroundRobust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes
Finland, G. O. T. 1. D. I., Todd, J. A., the Wellcome Trust Case Control Consortium, Walker, N. M., Cooper, J. D., Smyth, D. J., Downes, K., Plagnol, V., Bailey, R., Nejentsev, S., et al. (2007) · Nature Genetics · doi:10.1038/ng2068 · Cited by 1,456 · see citing works
Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants
Wellcome Trust Case Control Consortium, & The Australo-Anglo-American Spondylitis Consortium (TASC) (2007) · Nature Genetics · doi:10.1038/ng.2007.17 · Cited by 1,374 · see citing works
Rituximab, B-lymphocyte depletion, and preservation of beta-cell function
Pescovitz, M. D., Greenbaum, C. J., Krause-Steinrauf, H., Becker, D. J., Gitelman, S. E., Goland, R., Gottlieb, P. A., Marks, J. B., McGee, P. F., Moran, A. M., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0904452 · Cited by 1,093 · see citing works
Nejentsev, S., Walker, N., Riches, D., Egholm, M., & Todd, J. A. (2009) · Science · doi:10.1126/science.1167728 · Cited by 958 · see citing works
Pugliese, A., Zeller, M., Fernandez, A., Zalcberg, L. J., Bartlett, R. J., Ricordi, C., Pietropaolo, M., Eisenbarth, G. S., Bennett, S. T., & Patel, D. D. (1997) · Nature Genetics · doi:10.1038/ng0397-293 · Cited by 945 · see citing works
HLA DR-DQ Haplotypes and Genotypes and Type 1 Diabetes Risk
Erlich, H., Valdes, A. M., Noble, J., Carlson, J. A., Varney, M., Concannon, P., Mychaleckyj, J. C., Todd, J. A., Bonella, P., Fear, A. L., et al. (2008) · Diabetes · doi:10.2337/db07-1331 · Cited by 790 · cited 2× · see citing works
“The DRB1*1501DQA1*0102-DQB1*0602 haplotype, found in 20% of the population but only 1% of patients, confers dominant protection against T1D (134).”
BackgroundEffects of Oral Insulin in Relatives of Patients With Type 1 Diabetes
The Diabetes Prevention Trial-Type 1 Study Group (2005) · Diabetes Care · doi:10.2337/diacare.28.5.1068 · Cited by 668 · see citing works
A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene
Hakonarson, H., Grant, S. F. A., Bradfield, J. P., Marchand, L., Kim, C. E., Glessner, J. T., Grabs, R., Casalunovo, T., Taback, S. P., Frackelton, E. C., et al. (2007) · Nature · doi:10.1038/nature06010 · Cited by 542 · see citing works
GAD treatment and insulin secretion in recent-onset type 1 diabetes
Ludvigsson, J., Faresjö, M., Hjorth, M., Axelsson, S., Chéramy, M., Pihl, M., Vaarala, O., Forsander, G., Ivarsson, S., Johansson, C., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0804328 · Cited by 520 · see citing works
Defective regulatory and effector T cell functions in patients with FOXP3 mutations
Bacchetta, R. (2006) · Journal of Clinical Investigation · doi:10.1172/jci25112 · Cited by 511 · see citing works
Atkinson, M. A., Bowman, M. A., Campbell, L., Darrow, B. L., Kaufman, D. L., & Maclaren, N. K. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117567 · Cited by 448 · see citing works
Näntö-Salonen, K., Kupila, A., Simell, S., Siljander, H., Salonsaari, T., Hekkala, A., Korhonen, S., Erkkola, R., Sipilä, J. I., Haavisto, L., et al. (2008) · The Lancet · doi:10.1016/s0140-6736(08)61309-4 · Cited by 382 · see citing works
Concordance for islet autoimmunity among monozygotic twins
Redondo, M. J., Jeffrey, J., Fain, P. R., Eisenbarth, G. S., & Orban, T. (2008) · New England Journal of Medicine · doi:10.1056/nejmc0805398 · Cited by 353 · see citing works
Type 1 diabetes associated autoimmunity: natural history, genetic associations and screening
Barker, J. M. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-1679 · Cited by 350 · see citing works
Association between adherence and glycemic control in pediatric type 1 diabetes: a meta-analysis
Hood, K. K., Peterson, C. M., Rohan, J. M., & Drotar, D. (2009) · Pediatrics · doi:10.1542/peds.2009-0207 · Cited by 347 · see citing works
Redondo, M. J., Yu, L., Hawa, M., Mackenzie, T., Pyke, D. A., Eisenbarth, G. S., & Leslie, R. D. G. (2001) · Diabetologia · doi:10.1007/s001250051626 · Cited by 322 · see citing works
Gillespie, K. M., Bain, S. C., Barnett, A. H., Bingley, P. J., Christie, M. R., Gill, G. V., & Gale, E. A. (2004) · The Lancet · doi:10.1016/s0140-6736(04)17357-1 · Cited by 304 · see citing works
Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes
Agardh, C.-D., Cilio, C. M., Lethagen, Å., Lynch, K., Leslie, R. D. G., Palmér, M., Harris, R. A., Robertson, J. A., & Lernmark, Å. (2005) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2004.12.003 · Cited by 226 · see citing works
Exendin-4 modulates diabetes onset in nonobese diabetic mice
Hadjiyanni, I., Baggio, L. L., Poussier, P., & Drucker, D. J. (2008) · Endocrinology · doi:10.1210/en.2007-1137 · Cited by 110 · see citing works
Dai, Y. D., Marrero, I. G., Gros, P., Zaghouani, H., Wicker, L. S., & Sercarz, E. E. (2009) · Diabetes · doi:10.2337/db07-1608 · Cited by 41 · see citing works
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Sorted by citations
Atkinson, M. A., Eisenbarth, G. S., & Michels, A. W. (2014) · The Lancet · doi:10.1016/s0140-6736(13)60591-7 · Cited by 2,713 · see citing works
Regulation of tumour necrosis factor signalling: live or let die
Brenner, D., Blaser, H., & Mak, T. W. (2015) · Nature Reviews Immunology · doi:10.1038/nri3834 · Cited by 998 · see citing works
Animal models of human disease: challenges in enabling translation
McGonigle, P., & Ruggeri, B. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.08.006 · Cited by 610 · see citing works
Understanding and treating the inflammatory adverse events of cancer immunotherapy
Dougan, M., Luoma, A. M., Dougan, S. K., & Wucherpfennig, K. W. (2021) · Cell · doi:10.1016/j.cell.2021.02.011 · Cited by 319 · see citing works
Benner, C., van der Meulen, T., Cacéres, E., Tigyi, K., Donaldson, C. J., & Huising, M. O. (2014) · BMC Genomics · doi:10.1186/1471-2164-15-620 · Cited by 302 · see citing works
Campbell‐Thompson, M., Wasserfall, C., Kaddis, J., Albanese‐O'Neill, A., Staeva, T., Nierras, C., Moraski, J., Rowe, P., Gianani, R., Eisenbarth, G., et al. (2012) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.2316 · Cited by 236 · see citing works
Kwon, H., Kim, M., Seo, Y., Moon, Y. S., Lee, H. J., Lee, K., & Lee, H. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2017.11.034 · Cited by 208 · see citing works
Early prediction of autoimmune (type 1) diabetes.
Regnell, S. E., & Lernmark, Å. (2017) · Diabetologia · doi:10.1007/s00125-017-4308-1 · Cited by 195 · see citing works
Current understandings of the pathogenesis of type 1 diabetes: genetics to environment
Giwa, A. M., Ahmed, R., Omidian, Z., Majety, N., Karakus, K. E., Omer, S. M., Donner, T., & Hamad, A. R. A. (2020) · World Journal of Diabetes · doi:10.4239/wjd.v11.i1.13 · Cited by 137 · see citing works
Toyokuni, S. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.10.401 · Cited by 102 · see citing works
Combination immunotherapy for type 1 diabetes
Bone, R. N., & Evans-Molina, C. (2017) · Current Diabetes Reports · doi:10.1007/s11892-017-0878-z · Cited by 41 · see citing works
Recent advances in understanding type 1 diabetes
Christoffersson, G., Rodriguez-Calvo, T., & von Herrath, M. (2016) · F1000Research · doi:10.12688/f1000research.7356.1 · Cited by 32 · see citing works
- Authors
- Van Belle, T. L., Coppieters, K. T., & Von Herrath, M. G.
- Affiliations
- Center for Type 1 Diabetes Research, La Jolla Institute for Allergy and Immunology, La Jolla, California
- La Jolla Institute for Immunology (US)
- ORCID
- Coppieters, Ken T.
- Venue
- Physiological Reviews
- Publisher
- American Physiological Society
- Published
- 2011-01
- Volume
- 91
- Issue
- 1
- Pages
- 79-118
- ISSN
- 0031-9333 (ISSN-L)
- 1522-1210
- OpenAlex
- W2129387684
- Cited by
- 1,022
- References
- 24
- Citations by year
- 2026: 18 · 2025: 34 · 2024: 34 · 2023: 53 · 2022: 50 · 2021: 51 · 2020: 65 · 2019: 54 · 2018: 70 · 2017: 82 · 2016: 88 · 2015: 94 · 2014: 105 · 2013: 93 · 2012: 92
- FWCI
- 11.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Physiological Reviews (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Funders
- American Diabetes Association
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (P01 AI-58105, P01AI058105)
- National Institute of Diabetes and Digestive and Kidney Diseases (U01-DK-78013, U01DK078013)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- type 1 diabetes, autoimmunity, beta cell destruction, pancreatic islets, HLA, genetic susceptibility, PTPN22, IL2RA, CTLA-4, enterovirus, environmental triggers, autoantibodies, biomarkers, metabolomics, prevention, antigen-specific immunotherapy, islet transplantation, beta cell regeneration, neogenesis
- MeSH terms
- Animals, Clinical Trials as Topic, Diabetes Mellitus, Type 1, Humans, Prediabetic State, Primary Prevention, Genetic Predisposition to Disease
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