Human alpha cell transcriptomic signatures of types 1 and 2 diabetes highlight disease-specific dysfunction pathways
Year: 2022
Type: article
Abstract: Glucagon secretion is perturbed in both type 1 and type 2 diabetes (T1D, T2D) the pathophysiological changes at the level of individual pancreatic alpha cells are still largely obscure. Using recently-curated single-cell RNA data from human donors with either T1D or T2D and appropriate controls, we leveraged alpha cell transcriptomic alterations consistent with both common and discrete pathways. Firstly, altered expression of genes associated with alpha cell identity ( ARX, MAFB ) was common to both diseases. In contrast, increased expression of cytokine-regulated genes and genes involved in glucagon biosynthesis and processing were apparent in T1D, whereas mitochondrial genes associated with reactive oxygen species generation ( COX7B, NQO2 ) were dysregulated in alpha cells from T2D patients. Conversely, T1D alpha cells displayed alterations in genes associated with autoimmune-induced ER stress ( ERLEC1, HSP90 ) whilst those from T2D patients showed changes in glycolytic and citrate cycle genes ( LDH, PDHB, PDK4 ) which were unaffected in T1D. These findings suggest that despite some similarities related to loss-of-function, the alterations of alpha cells present important disease-specific signatures, suggesting that they are secondary to the main pathogenic events characteristic to each disease, namely immune-mediated-or metabolic-mediated-stress in respectively T1D and T2D.
Source: iScience
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,000
Funders: University of Pennsylvania, Leona M. and Harry B. Helmsley Charitable Trust, Wellcome Trust, European Federation of Pharmaceutical Industries and Associations, Gouvernement Wallon, Human Islet Research Network, Région de Bruxelles-Capitale, Waalse Gewest, European Commission, Fonds De La Recherche Scientifique - FNRS, Diabetes Fonds, Innoviris, Université de Montréal, Innovative Medicines Initiative, Walloon excellence in life sciences and biotechnology, National Institutes of Health, HORIZON EUROPE Framework Programme, Medical Research Council, Biotechnology and Biological Sciences Research Council, Staatssekretariat für Bildung, Forschung und Innovation, National Institute of Diabetes and Digestive and Kidney Diseases
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OpenAlex ID: W4294550826