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By understanding how the liver and pancreas develop in human embryos, researchers hope to better inform precision medicine approaches for diabetes.

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Getting to the roots of early-onset diabetes

23 Aug 2019

Mutations in the gene HNF4A impair liver and pancreas development, indicating that maturity-onset diabetes of the young starts much earlier than initially thought.

For diabetic patients, carefully controlling sugar intake is not an option, but a necessity. A subset of diabetic patients suffer from maturity-onset diabetes of the young 1 (MODY1), a condition that typically manifests before 25 years of age.

Scientists know that MODY1 is caused by mutations in a single gene, HNF4A, leading to impaired insulin production by β cells of the pancreas. Insulin is the key molecule regulating glucose levels in the body.

“However, the molecular underpinnings of the pancreatic β cell defects in MODY1 patients remain poorly understood,” said Adrian Teo of A*STAR’s Institute of Molecular and Cell Biology (IMCB).

In this study, Teo's team mapped the downstream consequences of HNF4A disruption to shed light on how MODY1 develops and progresses.

“As mouse models with Hnf4a heterozygous gene mutations do not develop diabetes, unlike humans, we had to utilize patient-derived human stem cells in our study,” explained study first author Natasha Ng, a postdoctoral research fellow on Teo’s team.

The team derived nine human induced pluripotent stem cell (hiPSC) lines from two MODY1 patients who each had one mutant copy (HNF4A p.Ile271fs) and one normal copy of the HNF4A gene, and from two healthy members of the same family. The hiPSCs were then differentiated into foregut endoderm and human pancreatic precursors—the parts of human embryos that eventually give rise to the pancreas and liver.

The researchers observed that human pancreatic precursors from MODY1 patient-derived hiPSCs had significantly lower expression of the HNF4A protein than equivalent cells from normal patients. They also noted that the HNF4A protein normally resides in the nucleus of cells, but mutant HNF4A protein was found in the cytoplasm instead. Furthermore, several markers characteristic of early pancreas and liver differentiation were downregulated, whereas a group of hindgut-specifying genes, known as HOX genes, were upregulated.

“These effects could result from the loss of transactivation of specific target genes due to reduced HNF4A function, subsequently impairing proper liver and pancreas development. These findings highlight that MODY1 is a developmental disease that begins in the foregut endoderm and extends to its derivative tissues, such as the pancreas and the liver,” said Teo, adding that the study could inform precision medicine approaches for MODY1 patients.

Going forward, the team intends to identify the downstream gene targets of HNF4A and a closely related gene—HNF1A—which is implicated in MODY3, the most common form of monogenic diabetes. “This work is also applicable in the context of type 2 diabetes (T2D), as both genes have been associated with T2D risk,” said Teo.

The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB).

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References

Ng, N. H. J., Jasmen, J. B., Lim, C. S., Lau, H. H., Krishnan, V. G. et al. HNF4A Haploinsufficiency in MODY1 Abrogates Liver and Pancreas Differentiation from Patient-Derived Induced Pluripotent Stem Cells. iScience 16,192-205 (2019) | article

About the Researcher

Adrian Teo Kee Keong

Principal Investigator

Institute of Molecular and Cell Biology
Adrian Teo Kee Keong pursued his PhD degree at the University of Cambridge, UK, and returned to Singapore in 2010, joining A*STAR’s Institute of Medical Biology (IMB) as a postdoctoral fellow. In 2011, he moved to the Joslin Diabetes Center at Harvard Medical School, US, under the Juvenile Diabetes Research Foundation fellowship and secured two Harvard Stem Cell Institute seed grants to pursue research on human pluripotent stem cells for in vitro disease modeling of diabetes. Adrian is currently a Principal Investigator at the Institute of Molecular and Cell Biology (IMCB), A*STAR; an Assistant Professor at the Yong Loo Lin School of Medicine, National University of Singapore; and an Adjunct Assistant Professor at the School of Biological Sciences, Nanyang Technological University, Singapore.

This article was made for A*STAR Research by Wildtype Media Group