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Diabetes Care. 2019 Nov 21. pii: dc190880. doi: 10.2337/dc19-0880. [Epub ahead of print]

Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes.

Author information

1
San Raffaele Diabetes Research Institute, IRCCS San Raffaele Hospital, Milano, Italy battaglia.manuela@icloud.com.
2
JDRF, New York, NY.
3
Diabetes Center, University of California, San Francisco, San Francisco, CA.
4
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL.
5
Division of Endocrinology and Diabetes, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA.
6
Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K.
7
San Raffaele Diabetes Research Institute, IRCCS San Raffaele Hospital, Milano, Italy.
8
Vita-Salute San Raffaele University, Milan, Italy, and Department of Internal Medicine, IRCCS San Raffaele Hospital, Milan, Italy.
9
Division of Pediatric Endocrinology/Diabetology and Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, IN.
10
Herman B Wells Center for Pediatric Diabetes Research, Indiana University School of Medicine, Indianapolis, IN.
11
Division of Pediatric Endocrinology and Diabetes, University of California, San Francisco, San Francisco, CA.
12
Diabetes Program, Benaroya Research Institute, Seattle, WA.
13
Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.
14
Department of Immunobiology, Yale University, New Haven, CT.
15
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.
16
Children's Hospital, University of Helsinki, Research Program for Clinical and Molecular Metabolism, Helsinki University Hospital, Helsinki, Finland.
17
Department of Pediatrics, University of Florida, Gainesville, FL.
18
Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL.
19
Department of Clinical Sciences, Clinical Research Centre, Faculty of Medicine, Lund University, and Skåne University Hospital, Malmö, Sweden.
20
Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, U.K.
21
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K.
22
University of Exeter Medical School and Royal Devon and Exeter Hospital, Exeter, U.K.
23
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, U.K.
24
NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, U.K.
25
Academic Renal Unit, Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K.
26
Center for Pediatric Genomic Medicine, Children's Mercy Kansas City, Kansas City, MO.
27
Division of Pulmonary and Critical Care Medicine, Department of Medicine, and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA.
28
Department of Electrical and Computer Engineering, TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering, Texas A&M University, College Station, TX.
29
Baylor College of Medicine, Texas Children's Hospital, Houston, TX.
30
Department of Diabetes Immunology, Diabetes & Metabolism Research Institute, Beckman Research Institute, National Medical Center, City of Hope, Duarte, CA.
31
Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
32
Peter Gorer Department of Immunobiology, Faculty of Life Sciences and Medicine, King's College London, London, U.K. mark.peakman@kcl.ac.uk.
33
King's Health Partners' Institute of Diabetes, Obesity and Endocrinology, London, U.K.

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.

PMID:
31753960
DOI:
10.2337/dc19-0880

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