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Browsing by Author "Morgan, Noel G."
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Item Altered β-Cell Prohormone Processing and Secretion in Type 1 Diabetes(American Diabetes Association, 2021) Rodriguez-Calvo, Teresa; Chen, Yi-Chun; Verchere, C. Bruce; Haataja, Leena; Arvan, Peter; Leete, Pia; Richardson, Sarah J.; Morgan, Noel G.; Qian, Wei-Jun; Pugliese, Alberto; Atkinson, Mark; Evans-Molina, Carmella; Sims, Emily K.; Pediatrics, School of MedicineAnalysis of data from clinical cohorts, and more recently from human pancreatic tissue, indicates that reduced prohormone processing is an early and persistent finding in type 1 diabetes. In this article, we review the current state of knowledge regarding alterations in islet prohormone expression and processing in type 1 diabetes and consider the clinical impact of these findings. Lingering questions, including pathologic etiologies and consequences of altered prohormone expression and secretion in type 1 diabetes, and the natural history of circulating prohormone production in health and disease, are considered. Finally, key next steps required to move forward in this area are outlined, including longitudinal testing of relevant clinical populations, studies that probe the genetics of altered prohormone processing, the need for combined functional and histologic testing of human pancreatic tissues, continued interrogation of the intersection between prohormone processing and autoimmunity, and optimal approaches for analysis. Successful resolution of these questions may offer the potential to use altered prohormone processing as a biomarker to inform therapeutic strategies aimed at personalized intervention during the natural history of type 1 diabetes and as a pathogenic anchor for identification of potential disease-specific endotypes.Item Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes(American Diabetes Association, 2020-01) Battaglia, Manuela; Ahmed, Simi; Anderson, Mark S.; Atkinson, Mark A.; Becker, Dorothy; Bingley, Polly J.; Bosi, Emanuele; Brusko, Todd M.; DiMeglio, Linda A.; Evans-Molina, Carmella; Gitelman, Stephen E.; Greenbaum, Carla J.; Gottlieb, Peter A.; Herold, Kevan C.; Hessner, Martin J.; Knip, Mikael; Jacobsen, Laura; Krischer, Jeffrey P.; Long, S. Alice; Lundgren, Markus; McKinney, Eoin F.; Morgan, Noel G.; Oram, Richard A.; Pastinen, Tomi; Peters, Michael C.; Petrelli, Alessandra; Qian, Xiaoning; Redondo, Maria J.; Roep, Bart O.; Schatz, Desmond; Skibinski, David; Peakman, Mark; Pediatrics, School of MedicineThe 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.