The beta cell whisperer gene

Diabetes affects millions of people worldwide. The widespread disease occurs when the body either produces too little insulin - a hormone that regulates blood sugar levels - or when the body is unable to utilise the insulin produced effectively. If the number of beta cells is too low or they are not functioning properly, not enough insulin is secreted. In order to release insulin in a coordinated manner, the beta cells communicate with each other. An international team of researchers from the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, the Paul Langerhans Institute Dresden (PLID) and the Universities of Oulu (Finland) and Copenhagen (Denmark) has now shown that the Wnt4 gene in the beta cells ensures that they recognise glucose and release the hormone insulin. This enables other cells in the body to store glucose. These findings could contribute to the development of replacement beta cells for diabetes therapy in the future.

At birth, a baby begins to accept food and convert it into energy. Many nutrients can be converted into sugar (glucose) and released into the bloodstream. A higher blood sugar level signals the beta cells in the pancreas to release insulin, which transports the blood sugar into the cells to be used or stored as energy. In the different phases of life, however, the beta cells that react to food have to adapt to different foods and needs. In a study recently published in Nature Communications, Anne Grapin-Botton, Director at the MPI-CBG, and her team in Dresden and at the Novo Nordisk Foundation Centre for Stem Cell Biology in Copenhagen, Denmark, together with colleagues at the MPI-CBG, have investigated how beta cells adapt to different foods;nemark, together with colleagues at the Carl Gustav Carus Medical Faculty of the Technical University of Dresden, have discovered that the Wnt4 gene becomes active in beta cells when they mature in early life after birth.

How it all began

The journey to discover the role of Wnt4 in the development of the pancreas began in the 1990s at Harvard University when Anne Grapin-Botton, then a postdoctoral researcher, was working with Seppo Vainio, now head of a research unit at the University of Oulu. „I remember that when I was researching Wnt4 in kidney development, we were already speculating that this signalling might also play a role in pancreatic development“, says Seppo Vainio. At that time, however, the researchers lacked the appropriate methods. More than 20 years later, postdoctoral researcher Keiichi Katsumoto wanted to find out in Anne Grapin-Botton's laboratory what role the Wnt4 gene plays in the development of the pancreas. In the meantime, the Vainio laboratory in Oulu had further developed the mouse models: „With these capabilities, we were able to investigate the role of Wnt4 in pancreas development and physiology together with Anne Grapin-Botton's research laboratory“, says Seppo Vainio.

Fascinating communication between beta cells

Keiichi Katsumoto describes what he observed: „We found that the Wnt4 gene is produced in beta cells during cell maturation. The cells that start to produce Wnt4 stop proliferating and become more functional. We have seen that with less Wnt4, the beta cell secretes less insulin. The team found that although the beta cells were able to recognise sugar in the blood, they secreted less insulin in response to glucose.“

„When we observed that mice without the Wnt4 gene developed diabetes, we knew we had found something important, but we didn't know how it worked“, says Anne Grapin-Botton, who led the study. „We knew from work in other organs, particularly from our collaborator Seppo Vainio and his colleagues, that this gene is a signal that is sent from one cell to another. It was exciting to discover the communication between beta cells in the pancreas, their conservation across multiple species and the mechanisms by which it works. It was particularly exciting to see the profound metabolic changes that this communication causes in the beta cells. However, we do not yet know whether the beta cells release Wnt4 constantly or under certain circumstances. We want to investigate this in the future.“

„The results also suggest that the increase in Wnt4 shortly after birth allows beta cells to mature“, says Katsumoto. Our next step is to understand why Wnt4 is produced as the cells mature.

These results could support the development of replacement beta cells for diabetes therapy, to which Wnt4 is added to support maturation.

Source: Max Planck Institute of Molecular Cell Biology and Genetics. In: idw from 02 November 2022