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

Blaise Su Jun Low, Chang Siang Lim, Shirley Suet Lee Ding, Yaw Sing Tan, Natasha Hui Jin Ng, Vidhya Gomathi Krishnan, Su Fen Ang, Claire Wen Ying Neo, Chandra S. Verma, Shawn Hoon, Su Chi Lim, E. Shyong Tai and Adrian Kee Keong Teo ()
Additional contact information
Blaise Su Jun Low: Agency for Science, Technology and Research (A*STAR)
Chang Siang Lim: Agency for Science, Technology and Research (A*STAR)
Shirley Suet Lee Ding: Agency for Science, Technology and Research (A*STAR)
Yaw Sing Tan: Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR)
Natasha Hui Jin Ng: Agency for Science, Technology and Research (A*STAR)
Vidhya Gomathi Krishnan: Molecular Engineering Lab (MEL), IMCB, A*STAR
Su Fen Ang: Khoo Teck Puat Hospital
Claire Wen Ying Neo: Agency for Science, Technology and Research (A*STAR)
Chandra S. Verma: Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR)
Shawn Hoon: Molecular Engineering Lab (MEL), IMCB, A*STAR
Su Chi Lim: National University of Singapore
E. Shyong Tai: National University of Singapore
Adrian Kee Keong Teo: Agency for Science, Technology and Research (A*STAR)

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-22843-4

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