Insulin is a hormone made in the pancreas, and it has a critical role in controlling the levels of a sugar, glucose, in the blood. In the various forms of diabetes, people have problems producing or responding to the hormone, and at least 422 million people are affected by the disease. Although that has made insulin the subject of a tremendous amount of research, scientists are still learning more about it. New work by scientists at the Department of Biomedical Sciences, University of Copenhagen has identified a molecule that is essential to ensuring that the insulin hormone is folded into its functional shape. This work, which has been reported in Diabetes, may help generate new treatments for disorders like hyperinsulinemia, in which the blood contains too much insulin, or potentially, diabetes.
“We hope this new discovery will guide the development of novel drugs. Understanding the biological processes behind the production of insulin in the cells will enable us to modify the processes. We thus hope we will be able to inhibit overproduction of insulin as it occurs in children and adults with hyperinsulinemia,” said the senior study author, Associate Professor Michal Tomasz Marzec of the Department of Biomedical Sciences at the University of Copenhagen.
Functional insulin is made in the body from proinsulin, which is a molecule that has to be folded and processed correctly by other proteins so it will fulfill its biological roles. This work showed that a protein called GRP94 is essential to the folding process.
“Even though proinsulin has a relatively short sequence, it still needs help acquiring the right structure to become mature, functional insulin. However, several other studies have shown that proinsulin can be folded without help from proteins in artificial cell-free conditions. Yet, our study conducted in live cells shows that proinsulin is not folded correctly and does not acquire the right structure without help from GRP94,” explained Marzec.
In this work, the researchers disrupted the activity of the GRP94 protein in cells and found that proinsulin was improperly folded. Beta cells, which are pancreatic cells that are the source of insulin, did not release enough insulin when GRP94 levels were reduced. However, that reduction did not cause the cells to die; they appeared normal.
“This is surprising, because one would anticipate that the beta cells would die from stress when huge amounts of misfolded proinsulin accumulate inside the cells,” noted Marzec. “It is like removing the bearing beam without weakening the construction. This indicates that the GRP94 protein plays a very specialized function and that beta cells are well-prepared to mount effective responses to deal with consequences of misfolding of proinsulin. We are currently working to understand these responses and their biological and pathological consequences.”
The researchers are hopeful that their study will eventually help scientists to gain control of the process of converting proinsulin to insulin. It may be possible to treat hyperinsulinemia by inhibiting insulin production at that point. The work may also offer new insight into diabetes.
“In the long term we also hope we will be able to increase the production of insulin, ease the large production burden of beta cells in connection with type 2 diabetes and to maintain their secretion function for longer, without the need for insulin injections,” said Marzec.