PDX1LOW MAFALOW β-cells contribute to islet function and insulin release
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Colleges, School and Institutes
Transcriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH β-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the β-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in β-cell maturity, might be important for the maintenance of islet function.
Funding Information: G.A.R. has received grant funding from Servier and is a consultant for Sun Pharma. The remaining authors declare no competing interests. Funding Information: We thank Dr. Jocelyn E. Manning Fox and Prof. Patrick E. MacDonald for provision of human islets via the Alberta Diabetes Institute IsletCore at the University of Alberta in Edmonton with the assistance of the Human Organ Procurement and Exchange (HOPE) program, Trillium Gift of Life Network (TGLN) and other Canadian organ procurement organizations. We are grateful to the European Consortium for Islet Transplantation (ECIT), which was supported by JDRF award 31-2008-416 (ECIT Islet for Basic Research program). D.J.H. was supported by a Diabetes UK R.D. Lawrence (12/0004431) Fellowship, a Wellcome Trust Institutional Support Award, and MRC (MR/N00275X/1 and MR/S025618/1) and Diabetes UK (17/0005681) Project Grants. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (Starting Grant 715884 to D.J.H.). G.A.R. was supported by Wellcome Trust Senior Investigator (WT098424AIA) and Investigator (212625/Z/18/Z) Awards, MRC Programme Grants (MR/R022259/1, MR/ J0003042/1, MR/L020149/1) and Experimental Challenge Grant (DIVA, MR/L02036X/ 1), MRC (MR/N00275X/1), Diabetes UK (BDA/11/0004210, BDA/15/0005275, BDA 16/ 0005485) and Imperial Confidence in Concept (ICiC) Grants. This project has received funding from the European Union’s Horizon 2020 research and innovation programme via the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115881 (RHAPSODY) to G.A.R. L.P. provided human islets through collaboration with the Diabetes Research Institute, IRCCS San Raffaele Scientific Institute (Milan), within the European Consortium for Islet Transplantation islet distribution program for basic research supported by JDRF (1-RSC-2014-90-I-X). We thank the Microscopy and Imaging Services (MISBU) in the Tech Hub facility at Birmingham University for support and maintenance of microscopes.
|Number of pages||19|
|Publication status||Published - 29 Jan 2021|
- Animals, Calcium/metabolism, Cells, Cultured, Diabetes Mellitus, Type 2/metabolism, Female, Gene Knock-In Techniques, Homeodomain Proteins/genetics, Humans, Insulin Secretion/physiology, Insulin-Secreting Cells/metabolism, Maf Transcription Factors, Large/genetics, Male, Mice, Mice, Transgenic, Models, Animal, Primary Cell Culture, Trans-Activators/genetics