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ResearchIn-Press PreviewAutoimmunityCell biologyEndocrinology
Open Access | 
10.1172/JCI195267
Altered immune and metabolic molecular pathways drive islet cell dysfunction in human type 1 diabetes
Theodore dos Santos,1 Xiao-Qing Dai,1 Robert C. Jones,2 Aliya F. Spigelman,1 Hannah M. Mummey,3 Jessica D. Ewald,4 Cara E. Ellis,1 James G. Lyon,5 Nancy Smith,1 Austin Bautista,6 Jocelyn E. Manning Fox,1 Norma F. Neff,7 Angela M. Detweiler,7 Michelle Tan,7 Rafael Arrojo e Drigo,8 Jianguo Xia,9 Joan Camunas-Soler,10 Kyle J. Gaulton,11 Stephen R. Quake,12 and Patrick E. MacDonald6
1Department of Pharmacology, University of Alberta, Edmonton, Canada
2Department of Bioengineering, Stanford University, Stanford, United States of America
3Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, United States of America
4European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
5Department of Pharmacology, Unviersity of Alberta, Edmonton, Canada
6Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
7Chan Zuckerberg Biohub, San Francisco, United States of America
8Department of Molecular Physiology and Biophysics, Vanderbilt, Nashville, United States of America
9Department of Microbiology & Immunology, McGill University, Montreal, Canada
10Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, United States of America
11Department of Pediatrics, University of California San Diego, La Jolla, United States of America
12Department of Bioengineering, Stanford University, Stanford, United States of America
Find articles by dos Santos, T. in: PubMed | Google Scholar
1Department of Pharmacology, University of Alberta, Edmonton, Canada
2Department of Bioengineering, Stanford University, Stanford, United States of America
3Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, United States of America
4European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
5Department of Pharmacology, Unviersity of Alberta, Edmonton, Canada
6Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
7Chan Zuckerberg Biohub, San Francisco, United States of America
8Department of Molecular Physiology and Biophysics, Vanderbilt, Nashville, United States of America
9Department of Microbiology & Immunology, McGill University, Montreal, Canada
10Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, United States of America
11Department of Pediatrics, University of California San Diego, La Jolla, United States of America
12Department of Bioengineering, Stanford University, Stanford, United States of America
Find articles by Dai, X. in: PubMed | Google Scholar
1Department of Pharmacology, University of Alberta, Edmonton, Canada
2Department of Bioengineering, Stanford University, Stanford, United States of America
3Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, United States of America
4European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
5Department of Pharmacology, Unviersity of Alberta, Edmonton, Canada
6Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
7Chan Zuckerberg Biohub, San Francisco, United States of America
8Department of Molecular Physiology and Biophysics, Vanderbilt, Nashville, United States of America
9Department of Microbiology & Immunology, McGill University, Montreal, Canada
10Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, United States of America
11Department of Pediatrics, University of California San Diego, La Jolla, United States of America
12Department of Bioengineering, Stanford University, Stanford, United States of America
Find articles by Jones, R. in: PubMed | Google Scholar
1Department of Pharmacology, University of Alberta, Edmonton, Canada
2Department of Bioengineering, Stanford University, Stanford, United States of America
3Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, United States of America
4European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
5Department of Pharmacology, Unviersity of Alberta, Edmonton, Canada
6Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
7Chan Zuckerberg Biohub, San Francisco, United States of America
8Department of Molecular Physiology and Biophysics, Vanderbilt, Nashville, United States of America
9Department of Microbiology & Immunology, McGill University, Montreal, Canada
10Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, United States of America
11Department of Pediatrics, University of California San Diego, La Jolla, United States of America
12Department of Bioengineering, Stanford University, Stanford, United States of America
Find articles by Spigelman, A. in: PubMed | Google Scholar
1Department of Pharmacology, University of Alberta, Edmonton, Canada
2Department of Bioengineering, Stanford University, Stanford, United States of America
3Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, United States of America
4European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
5Department of Pharmacology, Unviersity of Alberta, Edmonton, Canada
6Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
7Chan Zuckerberg Biohub, San Francisco, United States of America
8Department of Molecular Physiology and Biophysics, Vanderbilt, Nashville, United States of America
9Department of Microbiology & Immunology, McGill University, Montreal, Canada
10Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, United States of America
11Department of Pediatrics, University of California San Diego, La Jolla, United States of America
12Department of Bioengineering, Stanford University, Stanford, United States of America
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1Department of Pharmacology, University of Alberta, Edmonton, Canada
2Department of Bioengineering, Stanford University, Stanford, United States of America
3Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, United States of America
4European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
5Department of Pharmacology, Unviersity of Alberta, Edmonton, Canada
6Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
7Chan Zuckerberg Biohub, San Francisco, United States of America
8Department of Molecular Physiology and Biophysics, Vanderbilt, Nashville, United States of America
9Department of Microbiology & Immunology, McGill University, Montreal, Canada
10Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, United States of America
11Department of Pediatrics, University of California San Diego, La Jolla, United States of America
12Department of Bioengineering, Stanford University, Stanford, United States of America
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1Department of Pharmacology, University of Alberta, Edmonton, Canada
2Department of Bioengineering, Stanford University, Stanford, United States of America
3Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, United States of America
4European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
5Department of Pharmacology, Unviersity of Alberta, Edmonton, Canada
6Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
7Chan Zuckerberg Biohub, San Francisco, United States of America
8Department of Molecular Physiology and Biophysics, Vanderbilt, Nashville, United States of America
9Department of Microbiology & Immunology, McGill University, Montreal, Canada
10Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, United States of America
11Department of Pediatrics, University of California San Diego, La Jolla, United States of America
12Department of Bioengineering, Stanford University, Stanford, United States of America
Find articles by Ellis, C. in: PubMed | Google Scholar
1Department of Pharmacology, University of Alberta, Edmonton, Canada
2Department of Bioengineering, Stanford University, Stanford, United States of America
3Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, United States of America
4European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
5Department of Pharmacology, Unviersity of Alberta, Edmonton, Canada
6Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
7Chan Zuckerberg Biohub, San Francisco, United States of America
8Department of Molecular Physiology and Biophysics, Vanderbilt, Nashville, United States of America
9Department of Microbiology & Immunology, McGill University, Montreal, Canada
10Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, United States of America
11Department of Pediatrics, University of California San Diego, La Jolla, United States of America
12Department of Bioengineering, Stanford University, Stanford, United States of America
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1Department of Pharmacology, University of Alberta, Edmonton, Canada
2Department of Bioengineering, Stanford University, Stanford, United States of America
3Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, United States of America
4European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
5Department of Pharmacology, Unviersity of Alberta, Edmonton, Canada
6Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
7Chan Zuckerberg Biohub, San Francisco, United States of America
8Department of Molecular Physiology and Biophysics, Vanderbilt, Nashville, United States of America
9Department of Microbiology & Immunology, McGill University, Montreal, Canada
10Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, United States of America
11Department of Pediatrics, University of California San Diego, La Jolla, United States of America
12Department of Bioengineering, Stanford University, Stanford, United States of America
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1Department of Pharmacology, University of Alberta, Edmonton, Canada
2Department of Bioengineering, Stanford University, Stanford, United States of America
3Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, United States of America
4European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
5Department of Pharmacology, Unviersity of Alberta, Edmonton, Canada
6Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
7Chan Zuckerberg Biohub, San Francisco, United States of America
8Department of Molecular Physiology and Biophysics, Vanderbilt, Nashville, United States of America
9Department of Microbiology & Immunology, McGill University, Montreal, Canada
10Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, United States of America
11Department of Pediatrics, University of California San Diego, La Jolla, United States of America
12Department of Bioengineering, Stanford University, Stanford, United States of America
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1Department of Pharmacology, University of Alberta, Edmonton, Canada
2Department of Bioengineering, Stanford University, Stanford, United States of America
3Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, United States of America
4European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
5Department of Pharmacology, Unviersity of Alberta, Edmonton, Canada
6Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
7Chan Zuckerberg Biohub, San Francisco, United States of America
8Department of Molecular Physiology and Biophysics, Vanderbilt, Nashville, United States of America
9Department of Microbiology & Immunology, McGill University, Montreal, Canada
10Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, United States of America
11Department of Pediatrics, University of California San Diego, La Jolla, United States of America
12Department of Bioengineering, Stanford University, Stanford, United States of America
Find articles by Manning Fox, J. in: PubMed | Google Scholar
1Department of Pharmacology, University of Alberta, Edmonton, Canada
2Department of Bioengineering, Stanford University, Stanford, United States of America
3Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, United States of America
4European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
5Department of Pharmacology, Unviersity of Alberta, Edmonton, Canada
6Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
7Chan Zuckerberg Biohub, San Francisco, United States of America
8Department of Molecular Physiology and Biophysics, Vanderbilt, Nashville, United States of America
9Department of Microbiology & Immunology, McGill University, Montreal, Canada
10Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, United States of America
11Department of Pediatrics, University of California San Diego, La Jolla, United States of America
12Department of Bioengineering, Stanford University, Stanford, United States of America
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1Department of Pharmacology, University of Alberta, Edmonton, Canada
2Department of Bioengineering, Stanford University, Stanford, United States of America
3Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, United States of America
4European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
5Department of Pharmacology, Unviersity of Alberta, Edmonton, Canada
6Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
7Chan Zuckerberg Biohub, San Francisco, United States of America
8Department of Molecular Physiology and Biophysics, Vanderbilt, Nashville, United States of America
9Department of Microbiology & Immunology, McGill University, Montreal, Canada
10Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, United States of America
11Department of Pediatrics, University of California San Diego, La Jolla, United States of America
12Department of Bioengineering, Stanford University, Stanford, United States of America
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1Department of Pharmacology, University of Alberta, Edmonton, Canada
2Department of Bioengineering, Stanford University, Stanford, United States of America
3Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, United States of America
4European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
5Department of Pharmacology, Unviersity of Alberta, Edmonton, Canada
6Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
7Chan Zuckerberg Biohub, San Francisco, United States of America
8Department of Molecular Physiology and Biophysics, Vanderbilt, Nashville, United States of America
9Department of Microbiology & Immunology, McGill University, Montreal, Canada
10Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, United States of America
11Department of Pediatrics, University of California San Diego, La Jolla, United States of America
12Department of Bioengineering, Stanford University, Stanford, United States of America
Find articles by Tan, M. in: PubMed | Google Scholar
1Department of Pharmacology, University of Alberta, Edmonton, Canada
2Department of Bioengineering, Stanford University, Stanford, United States of America
3Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, United States of America
4European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
5Department of Pharmacology, Unviersity of Alberta, Edmonton, Canada
6Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
7Chan Zuckerberg Biohub, San Francisco, United States of America
8Department of Molecular Physiology and Biophysics, Vanderbilt, Nashville, United States of America
9Department of Microbiology & Immunology, McGill University, Montreal, Canada
10Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, United States of America
11Department of Pediatrics, University of California San Diego, La Jolla, United States of America
12Department of Bioengineering, Stanford University, Stanford, United States of America
Find articles by Arrojo e Drigo, R. in: PubMed | Google Scholar
1Department of Pharmacology, University of Alberta, Edmonton, Canada
2Department of Bioengineering, Stanford University, Stanford, United States of America
3Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, United States of America
4European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
5Department of Pharmacology, Unviersity of Alberta, Edmonton, Canada
6Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
7Chan Zuckerberg Biohub, San Francisco, United States of America
8Department of Molecular Physiology and Biophysics, Vanderbilt, Nashville, United States of America
9Department of Microbiology & Immunology, McGill University, Montreal, Canada
10Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, United States of America
11Department of Pediatrics, University of California San Diego, La Jolla, United States of America
12Department of Bioengineering, Stanford University, Stanford, United States of America
Find articles by Xia, J. in: PubMed | Google Scholar
1Department of Pharmacology, University of Alberta, Edmonton, Canada
2Department of Bioengineering, Stanford University, Stanford, United States of America
3Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, United States of America
4European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
5Department of Pharmacology, Unviersity of Alberta, Edmonton, Canada
6Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
7Chan Zuckerberg Biohub, San Francisco, United States of America
8Department of Molecular Physiology and Biophysics, Vanderbilt, Nashville, United States of America
9Department of Microbiology & Immunology, McGill University, Montreal, Canada
10Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, United States of America
11Department of Pediatrics, University of California San Diego, La Jolla, United States of America
12Department of Bioengineering, Stanford University, Stanford, United States of America
Find articles by Camunas-Soler, J. in: PubMed | Google Scholar
1Department of Pharmacology, University of Alberta, Edmonton, Canada
2Department of Bioengineering, Stanford University, Stanford, United States of America
3Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, United States of America
4European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
5Department of Pharmacology, Unviersity of Alberta, Edmonton, Canada
6Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
7Chan Zuckerberg Biohub, San Francisco, United States of America
8Department of Molecular Physiology and Biophysics, Vanderbilt, Nashville, United States of America
9Department of Microbiology & Immunology, McGill University, Montreal, Canada
10Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, United States of America
11Department of Pediatrics, University of California San Diego, La Jolla, United States of America
12Department of Bioengineering, Stanford University, Stanford, United States of America
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Gaulton, K.
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1Department of Pharmacology, University of Alberta, Edmonton, Canada
2Department of Bioengineering, Stanford University, Stanford, United States of America
3Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, United States of America
4European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
5Department of Pharmacology, Unviersity of Alberta, Edmonton, Canada
6Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
7Chan Zuckerberg Biohub, San Francisco, United States of America
8Department of Molecular Physiology and Biophysics, Vanderbilt, Nashville, United States of America
9Department of Microbiology & Immunology, McGill University, Montreal, Canada
10Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, United States of America
11Department of Pediatrics, University of California San Diego, La Jolla, United States of America
12Department of Bioengineering, Stanford University, Stanford, United States of America
Find articles by Quake, S. in: PubMed | Google Scholar
1Department of Pharmacology, University of Alberta, Edmonton, Canada
2Department of Bioengineering, Stanford University, Stanford, United States of America
3Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, United States of America
4European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
5Department of Pharmacology, Unviersity of Alberta, Edmonton, Canada
6Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
7Chan Zuckerberg Biohub, San Francisco, United States of America
8Department of Molecular Physiology and Biophysics, Vanderbilt, Nashville, United States of America
9Department of Microbiology & Immunology, McGill University, Montreal, Canada
10Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, United States of America
11Department of Pediatrics, University of California San Diego, La Jolla, United States of America
12Department of Bioengineering, Stanford University, Stanford, United States of America
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MacDonald, P.
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Published September 30, 2025 - More info
Copyright © 2025, dos Santos et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)