In brief

Researchers found that while type 2 diabetes disrupted PAX6 and other related proteins responsible for secreting insulin from pancreatic beta cells, a PAX6-restoring gene therapy rebalanced the system.

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Gene therapy restores broken insulin pump

2 Aug 2022

A breakthrough discovery describes key molecular players involved in insulin secretion, paving the way for a new class of gene therapies targeting type 2 diabetes.

What has a head, body, and tail and is linked to one of Singapore’s most pressing public health threats? The pancreas—a flat, roughly hand-length organ that churns out insulin to balance blood sugar levels in our bodies. Type 2 diabetes is linked to “tired” pancreatic beta cells that no longer make enough insulin as a result of chronically unhealthy lifestyles.

Restoring the function of these dysfunctional beta cells has remained a challenge, given that many of the molecular events governing insulin secretion remain an enigma. For example, scientists don’t quite understand how beta cells pump out insulin molecules, although they hypothesise it relies heavily on a cellular process called exocytosis.

“Since insulin granule exocytosis is the final and a common step of insulin secretion, we are particularly interested in studying the regulation of insulin exocytosis,” said Wing Yan So, a Research Scientist at A*STAR’s Institute of Molecular and Cell Biology (IMCB). Together with her team leader Weiping Han, a Research Director at IMCB, So and a team of experts zeroed in on a protein called PAX6, a transcription factor known to be crucial for orchestrating pancreatic development and function.

The scientists developed a lab-based cell culture model of the human pancreas for their study, which allowed them to selectively turn PAX6 and its related proteins on and off. This enabled them to map the dynamic cascade of molecular interactions involved in insulin exocytosis in high resolution.

The team found that it all begins with PAX6, which sets off a domino effect, activating downstream activation of other transcription factors, such as CREB. This flurry of molecular activity culminates in the expression of Munc18-1 and Munc18-2, transport proteins that work to ferry insulin out of beta cells.

The researchers also found that simulated diabetic conditions upended this delicate PAX6/CREB/Munc18-1/2 axis, which significantly reduced insulin secretion. Following up on this breakthrough result, the team explored a potential solution: a gene therapy that restores balance to the exocytosis axis.

They created a genetically engineered adenovirus that acts as a harmless vector, delivering a specialised gene therapy that restores PAX6 function. They then tested the experimental therapy in a mouse model of type 2 diabetes and found that it helped boost PAX6 expression in beta cells, thereby revitalising insulin secretion.

“Our results shed light onto the pathophysiological role of PAX6 in type 2 diabetes,” So and Han said, adding that their team is now focused on building on this new body of knowledge to support the development of next-generation gene therapy for diabetes.

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

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So, W.Y., Liu, W.N., Teo, A.K.K., Rutter, G.A., and Han, W. Paired box 6 programs essential exocytotic genes in the regulation of glucose-stimulated insulin secretion and glucose homeostasis, Science Translational Medicine 13:eabb1038 (2021) | article

About the Researchers

Weiping Han obtained his PhD degree from Cornell University and did postdoctoral work at the University of Pittsburgh and HHMI/UT Southwestern Medical Center. In 2005, he moved to Singapore to set up a research program in the Laboratory of Metabolic Medicine (LMM) at the Singapore Bioimaging Consortium (SBIC). Currently, he is Divisional Director at A*STAR’s Institute of Molecular and Cell Biology (IMCB), and Professor at the National University of Singapore (NUS) and Duke-NUS Medical School.
Wing Yan So obtained her PhD degree from The Chinese University of Hong Kong before moving to Singapore. She is currently a Research Scientist in the Laboratory of Metabolic Medicine (LMM) at A*STAR’s Institute of Molecular and Cell Biology (IMCB).

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