Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes
The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susc...
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| Published in | Diabetes care Vol. 43; no. 1; pp. 5 - 12 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Diabetes Association
01.01.2020
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0149-5992 1935-5548 1935-5548 |
| DOI | 10.2337/dc19-0880 |
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| Abstract | The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the “single disease” approach appears untenable, as does the notion of individualizing each single patient’s care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management. |
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| AbstractList | The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the "single disease" approach appears untenable, as does the notion of individualizing each single patient's care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management. The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the "single disease" approach appears untenable, as does the notion of individualizing each single patient's care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the "single disease" approach appears untenable, as does the notion of individualizing each single patient's care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management. |
| Author | Brusko, Todd M. Oram, Richard A. Roep, Bart O. Schatz, Desmond Hessner, Martin J. Greenbaum, Carla J. Krischer, Jeffrey P. Pastinen, Tomi Battaglia, Manuela Evans-Molina, Carmella Becker, Dorothy Bingley, Polly J. Gitelman, Stephen E. Qian, Xiaoning Lundgren, Markus Peakman, Mark Jacobsen, Laura Ahmed, Simi Long, S. Alice Anderson, Mark S. DiMeglio, Linda A. Atkinson, Mark A. Skibinski, David Morgan, Noel G. Redondo, Maria J. Knip, Mikael McKinney, Eoin F. Peters, Michael C. Petrelli, Alessandra Herold, Kevan C. Bosi, Emanuele Gottlieb, Peter A. |
| Author_xml | – sequence: 1 givenname: Manuela orcidid: 0000-0003-4535-3152 surname: Battaglia fullname: Battaglia, Manuela organization: San Raffaele Diabetes Research Institute, IRCCS San Raffaele Hospital, Milan, Italy – sequence: 2 givenname: Simi surname: Ahmed fullname: Ahmed, Simi organization: JDRF, New York, NY – sequence: 3 givenname: Mark S. surname: Anderson fullname: Anderson, Mark S. organization: Diabetes Center, University of California, San Francisco, San Francisco, CA – sequence: 4 givenname: Mark A. surname: Atkinson fullname: Atkinson, Mark A. organization: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL – sequence: 5 givenname: Dorothy surname: Becker fullname: Becker, Dorothy organization: Division of Endocrinology and Diabetes, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA – sequence: 6 givenname: Polly J. surname: Bingley fullname: Bingley, Polly J. organization: Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K – sequence: 7 givenname: Emanuele surname: Bosi fullname: Bosi, Emanuele organization: San Raffaele Diabetes Research Institute, IRCCS San Raffaele Hospital, Milan, Italy, Vita-Salute San Raffaele University, Milan, Italy, and Department of Internal Medicine, IRCCS San Raffaele Hospital, Milan, Italy – sequence: 8 givenname: Todd M. orcidid: 0000-0003-2878-9296 surname: Brusko fullname: Brusko, Todd M. organization: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL – sequence: 9 givenname: Linda A. orcidid: 0000-0002-8033-6078 surname: DiMeglio fullname: DiMeglio, Linda A. organization: Division of Pediatric Endocrinology and Diabetology and Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN – sequence: 10 givenname: Carmella orcidid: 0000-0001-7764-8663 surname: Evans-Molina fullname: Evans-Molina, Carmella organization: Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN – sequence: 11 givenname: Stephen E. surname: Gitelman fullname: Gitelman, Stephen E. organization: Division of Pediatric Endocrinology and Diabetes, University of California, San Francisco, San Francisco, CA – sequence: 12 givenname: Carla J. orcidid: 0000-0003-4451-9800 surname: Greenbaum fullname: Greenbaum, Carla J. organization: Diabetes Program, Benaroya Research Institute, Seattle, WA – sequence: 13 givenname: Peter A. surname: Gottlieb fullname: Gottlieb, Peter A. organization: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO – sequence: 14 givenname: Kevan C. orcidid: 0000-0003-1534-6613 surname: Herold fullname: Herold, Kevan C. organization: Department of Immunobiology, Yale University, New Haven, CT – sequence: 15 givenname: Martin J. orcidid: 0000-0001-9941-0314 surname: Hessner fullname: Hessner, Martin J. organization: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI – sequence: 16 givenname: Mikael orcidid: 0000-0003-0474-0033 surname: Knip fullname: Knip, Mikael organization: Children’s Hospital, University of Helsinki and Helsinki University Hospital, Clinical and Molecular Metabolism Research Program, University of Helsinki, Helsinki, Finland – sequence: 17 givenname: Laura orcidid: 0000-0002-5144-7836 surname: Jacobsen fullname: Jacobsen, Laura organization: Department of Pediatrics, University of Florida, Gainesville, FL – sequence: 18 givenname: Jeffrey P. surname: Krischer fullname: Krischer, Jeffrey P. organization: Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL – sequence: 19 givenname: S. Alice orcidid: 0000-0002-0281-1240 surname: Long fullname: Long, S. Alice organization: Diabetes Program, Benaroya Research Institute, Seattle, WA – sequence: 20 givenname: Markus surname: Lundgren fullname: Lundgren, Markus organization: Department of Clinical Sciences, Clinical Research Centre, Faculty of Medicine, Lund University, and Skåne University Hospital, Malmö, Sweden – sequence: 21 givenname: Eoin F. surname: McKinney fullname: McKinney, Eoin F. organization: Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, U.K – sequence: 22 givenname: Noel G. orcidid: 0000-0003-1537-8113 surname: Morgan fullname: Morgan, Noel G. organization: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K., University of Exeter Medical School and Royal Devon and Exeter Hospital, Exeter, U.K – sequence: 23 givenname: Richard A. orcidid: 0000-0003-3581-8980 surname: Oram fullname: Oram, Richard A. organization: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, U.K., NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, U.K., Academic Renal Unit, Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K – sequence: 24 givenname: Tomi surname: Pastinen fullname: Pastinen, Tomi organization: Center for Pediatric Genomic Medicine, Children’s Mercy Kansas City, Kansas City, MO – sequence: 25 givenname: Michael C. surname: Peters fullname: Peters, Michael C. organization: Division of Pulmonary and Critical Care Medicine, Department of Medicine, and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA – sequence: 26 givenname: Alessandra surname: Petrelli fullname: Petrelli, Alessandra organization: San Raffaele Diabetes Research Institute, IRCCS San Raffaele Hospital, Milan, Italy – sequence: 27 givenname: Xiaoning surname: Qian fullname: Qian, Xiaoning organization: Department of Electrical and Computer Engineering, TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering, Texas A&M University, College Station, TX – sequence: 28 givenname: Maria J. orcidid: 0000-0001-5871-4645 surname: Redondo fullname: Redondo, Maria J. organization: Baylor College of Medicine, Texas Children’s Hospital, Houston, TX – sequence: 29 givenname: Bart O. orcidid: 0000-0003-1616-8337 surname: Roep fullname: Roep, Bart O. organization: Department of Diabetes Immunology, Diabetes & Metabolism Research Institute, Beckman Research Institute, National Medical Center, City of Hope, Duarte, CA, Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands – sequence: 30 givenname: Desmond surname: Schatz fullname: Schatz, Desmond organization: Department of Pediatrics, University of Florida, Gainesville, FL – sequence: 31 givenname: David surname: Skibinski fullname: Skibinski, David organization: Diabetes Program, Benaroya Research Institute, Seattle, WA – sequence: 32 givenname: Mark surname: Peakman fullname: Peakman, Mark organization: Peter Gorer Department of Immunobiology, Faculty of Life Sciences and Medicine, King's College London, London, U.K., King’s Health Partners Institute of Diabetes, Obesity and Endocrinology, London, U.K |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/31753960$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | Biological Variation, Population - physiology Blood Glucose - metabolism Clinical Medicine Clinical trials Diabetes Diabetes mellitus Diabetes mellitus (insulin dependent) Diabetes Mellitus, Type 1 - blood Diabetes Mellitus, Type 1 - classification Diabetes Mellitus, Type 1 - pathology Diabetes Mellitus, Type 1 - therapy Disease Progression Endocrinology and Diabetes Endokrinologi och diabetes Glucose monitoring Heterogeneity Humans Insulin Insulin - metabolism Klinisk medicin Medical and Health Sciences Medicin och hälsovetenskap Medicine Pathogenesis Phenotype Phenotypes Precision medicine Precision Medicine - methods Precision Medicine - trends s in Care Translation |
| Title | Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes |
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