Decreased GLUT2 and glucose uptake contribute to insulin secretion defects in MODY3/HNF1A hiPSC-derived mutant β cells.

Autor: Low BSJ; Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Lim CS; Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.; Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore., Ding SSL; Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore., Tan YS; Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore., Ng NHJ; Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore., Krishnan VG; Molecular Engineering Lab (MEL), IMCB, A*STAR, Singapore, Singapore., Ang SF; Khoo Teck Puat Hospital, Singapore, Singapore., Neo CWY; Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Verma CS; Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.; Department of Biological Sciences, National University of Singapore, Singapore, Singapore.; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore., Hoon S; Molecular Engineering Lab (MEL), IMCB, A*STAR, Singapore, Singapore., Lim SC; Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.; Khoo Teck Puat Hospital, Singapore, Singapore., Tai ES; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Teo AKK; Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore. ateo@imcb.a-star.edu.sg.; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. ateo@imcb.a-star.edu.sg.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 May 25; Vol. 12 (1), pp. 3133. Date of Electronic Publication: 2021 May 25.
DOI: 10.1038/s41467-021-22843-4
Abstrakt: Heterozygous HNF1A gene mutations can cause maturity onset diabetes of the young 3 (MODY3), characterized by insulin secretion defects. However, specific mechanisms of MODY3 in humans remain unclear due to lack of access to diseased human pancreatic cells. Here, we utilize MODY3 patient-derived human induced pluripotent stem cells (hiPSCs) to study the effect(s) of a causal HNF1A +/H126D mutation on pancreatic function. Molecular dynamics simulations predict that the H126D mutation could compromise DNA binding and gene target transcription. Genome-wide RNA-Seq and ChIP-Seq analyses on MODY3 hiPSC-derived endocrine progenitors reveal numerous HNF1A gene targets affected by the mutation. We find decreased glucose transporter GLUT2 expression, which is associated with reduced glucose uptake and ATP production in the MODY3 hiPSC-derived β-like cells. Overall, our findings reveal the importance of HNF1A in regulating GLUT2 and several genes involved in insulin secretion that can account for the insulin secretory defect clinically observed in MODY3 patients.
Databáze: MEDLINE
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