Loss of functional β-cell mass is the key mechanism leading to the two main forms of diabetes mellitus — type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Understanding the mechanisms behind β-cell failure is critical to prevent or revert disease. Basic pathogenic differences exist in the two forms of diabetes mellitus; T1DM is immune mediated and T2DM is mediated by metabolic mechanisms. These mechanisms differentially affect early β-cell dysfunction and eventual fate. Over the past decade, major advances have been made in the field, mostly delivered by studies on β-cells in human disease. These advances include studies of islet morphology and human β-cell gene expression in T1DM and T2DM, the identification and characterization of the role of T1DM and T2DM candidate genes at the β-cell level and the endoplasmic reticulum stress signalling that contributes to β-cell failure in T1DM (mostly IRE1 driven) and T2DM (mostly PERK–eIF2α dependent). Here, we review these new findings, focusing on studies performed on human β-cells or on samples obtained from patients with diabetes mellitus.
Pancreatic β-cell dysfunction and cell death are key processes in the development of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM).
The pathogenesis of T1DM and T2DM is fundamentally distinct, differentially impacting early β-cell dysfunction (immune mediated versus metabolic in T1DM and T2DM, respectively) and cell fate (massive versus mild-to-moderate β-cell loss).
Pancreatic islet cells have unexpected plasticity; however, the magnitude and clinical relevance of this phenomenon in humans remains to be determined.
A substantial fraction of T1DM-associated genetic variants act at the β-cell level but only become manifest upon immune-mediated islet cell perturbations, whereas T2DM genetic signals largely regulate β-cell development and function.
In T1DM (and potentially in other autoimmune diseases), enhancers pre-bound by tissue-specific transcription factors seemingly facilitate cell type-specific responses to ubiquitous pro-inflammatory signals, which could explain the tissue selectivity in autoimmune attack.
Endoplasmic reticulum stress affects β-cells in both T1DM and T2DM; however, the signalling differs, with predominantly IRE1-mediated β-cell damage in T1DM and PERK–eIF2α-mediated β-cell damage in T2DM.
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We thank M. Colli, ULB Center for Diabetes Research, for preparing Fig. 1 and M. Ramos-Rodríguez, IGTP, for preparing part of Fig. 2. D.L.E. acknowledges the support of a grant from the Welbio-FNRS (Fonds National de la Recherche Scientifique), Belgium, the Dutch Diabetes Fonds (DDFR), Holland, and start up-funds from the Indiana Biosciences Research Institute (IBRI), Indianapolis, Indiana, USA. D.L.E. and M.C. acknowledge the support of joint grants from the European Union’s Horizon 2020 research and innovation programme, project T2DSystems, under grant agreement No 667191; Brussels Capital Region-Innoviris project Diatype; the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115797 (INNODIA), supported by the European Union’s Horizon 2020 research and innovation programme, and EFPIA, JDRF and The Leona M. and Harry B. Helmsley Charitable Trust; and the Innovative Medicines Initiative 2 Joint Undertaking Rhapsody, under grant agreement No. 115881, supported by the European Union’s Horizon 2020 Research and Innovation Programme, EFPIA and the Swiss State Secretariat for Education‚ Research and Innovation (SERI) under contract number 16.0097. M.C. acknowledges the support of the FNRS, Belgium. L.P. acknowledges the support of grants from the Spanish Ministry of Economy and Competitiveness (SAF2017-86242-R), Marató TV3 (201624.10), EFSD/JDRF/Lilly Programme on Type 1 Diabetes Research and the further support of ISCIII (PIE16/00011).
Relevant publications were identified by searching the PubMed database (Jan 1, 2005 to October 30, 2019) using combinations of the following terms: “pancreatic beta cells”, “pancreatic islets”, “insulin release”, “insulin secretion”, “diabetes”, “type 1 diabetes”, “type 2 diabetes”, “pathogenesis”, “histology”, “transcriptome”, “genetics”, “candidate genes”, “islet gene regulation”, “islet epigenomics”, “endoplasmic reticulum stress” and “apoptosis”. We preferentially selected publications in the past 5 years, plus earlier key publications for citation. A manual search of some references cited in these papers or in relevant articles related to the role of pancreatic β-cells in the pathogenesis of diabetes was also done. All selected papers were English-language, full-text articles. Review articles are often cited to provide the readers with additional references. Many of the references identified could not be included owing to space restrictions.
The authors declare no competing interests.
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TIGER (the Translational Human Pancreatic Islet Genotype Tissue-Expression Resource): http://tiger.bsc.es/
Antigens that have not been previously presented or recognized by the immune system. They can be formed as a result in changes in transcription, translation or post-translational events.
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Eizirik, D.L., Pasquali, L. & Cnop, M. Pancreatic β-cells in type 1 and type 2 diabetes mellitus: different pathways to failure. Nat Rev Endocrinol 16, 349–362 (2020). https://doi.org/10.1038/s41574-020-0355-7
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