Decreased GLUT2 and glucose uptake contribute to insulin secretion defects in MODY3/HNF1A hiPSC-derived mutant \u03b2 cells

Blaise Su Jun Low,E Shyong Tai,Yaw Sing Tan,Chang Siang Lim,Shawn Hoon,Vidhya Gomathi Krishnan,Su Chi Lim,Claire Wen Ying Neo,Su Fen Ang,Natasha Hui Jin Ng,Chandra S Verma,Adrian Kee Keong Teo,Shirley Suet Lee Ding

doi:10.1038/s41467-021-22843-4

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.

Highlights

Heterozygous HNF1A gene mutations can cause maturity onset diabetes of the young 3 (MODY3), characterized by insulin secretion defects
We leverage on MODY3-human induced pluripotent stem cells (hiPSCs) disease modeling by generating patient-specific induced pluripotent stem-cell lines from two Singaporean MODY3 patients harboring a unique HNF1A+/H126D mutation[11], and differentiate them towards the pancreatic lineage in order to study its effect on insulin secretion in human pancreatic β cells
We find that the HNF1A mutation results in a loss of binding and decreased expression of genes involved in pancreas development, β cell survival, insulin secretion, insulin resistance and type 2 diabetes (T2D)

Summary

Introduction

Heterozygous HNF1A gene mutations can cause maturity onset diabetes of the young 3 (MODY3), characterized by insulin secretion defects. Insulin secretory defects and higher blood glucose concentrations are found to occur only in Hnf1α−/− homozygous knockout mice but not in Hnf1α+/− heterozygous mice[7] This is in contrast to the MODY3 pathology in humans whereby all known cases are caused by autosomal dominant HNF1A+/− heterozygous mutations[8]. The study revealed that HNF1A deletion resulted in pancreatic developmental and metabolic defects, as well as dysregulation of glycolysis and mitochondrial respiration While these studies have implicated HNF1A mutations in reduced ATP production and defective mitochondrial respiration, the effects of HNF1A mutations on the rest of the stimulus-secretion coupling pathway— glucose uptake, KATP channel and voltage-gated Ca2+ signaling— in human β cells remain largely unexplored. We comprehensively demonstrate that the HNF1A mutation causes GLUT2 deficiency that is associated with reduced glucose uptake and ATP production This may partly account for the lack of insulin secretion in MODY3 patients. We propose that a modulation of glucose uptake or ADP to ATP conversion may be a viable means to reinstate the insulin secretory capacity of these dysfunctional β cells

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Conclusion