Inflammation puts insulin production on hold – University of Copenhagen

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14 November 2018

Inflammation puts insulin production on hold

Research result

When people become overweight and develop type 2 diabetes, the body goes into a state of chronic sterile infection. Researchers from Department of Biomedical Sciences have discovered that inflammation increases the degradation of messenger RNA, which instructs the cells to produce insulin. The researchers hope this new knowledge can lead to the development of new drugs capable of restarting the production of insulin in patients with type 2 diabetes.

At least 250.00 Danes suffer from diabetes. About 80 percent of those have type 2 diabetes, where the reduced production of insulin is incapable of meeting the body’s increased need, for example in connection with overweight. Overweight also results in a state of chronic sterile infection in the body, also called inflammation.

Researchers from Thomas Mandrup-Poulsen's research group have now for the first time ever discovered that the inflammation causes insulin-producing cells in the body to degrade their so-called messenger RNA. And that inhibits the production of insulin. 

Under normal circumstances the messenger RNA tells the cells to produce insulin. It ‘copies’ the layout of our DNA, which tells the cells which proteins to produce. But when the messenger RNA is degraded due to inflammation it is no longer capable of passing on this information.

’Inflammation can force the cells to produce substances that damage the cells. Therefore, the cells try to protect themselves by degrading the harmful RNA molecules. Even though this defence mechanism is useful in the immediate situation, it is problematic in the long term, because it also leads to the degradation of the beneficial RNA molecules. We believe this mechanism contributes to the missing insulin production causing type 2 diabetes’, says the main author of the study, Professor Thomas Mandrup-Poulsen.

So as long as the body experiences inflammation, the cells pay a price for protecting themselves by putting the insulin production on hold.

New Discovery of Cell Function 
Back in 1986 Thomas Mandrup-Poulsen and his team were the first to show that inflammation damages the insulin-producing cells. But at the time they were unfamiliar with the underlying processes.

‘We have known for a long time that inflammation damages the function and survival of the cells. But this is the first time someone has shown in a cell that inflammatory signals regulate the expression of the RNA degradation system. It is an important new discovery concerning the function of the cell’, he says.

The researchers have done tests on insulin-producing cell lines and insulin-producing tissue from healthy, diseased humans who have donated their body to research.

In petri dishes they added a combination of transmitter substances used by the body to signal inflammation. Using molecular-biological techniques they learned that inflammation increases the production of the cells’ degradation systems, and that it affected the cells’ insulin production and survival.

Inhibitor Can Restart the Production of Insulin
The researchers will use this new knowledge to develop medicine preventing the degradation of the insulin messenger RNA caused by the chronic state of infection seen in connection with overweight and type 2 diabetes.

’If we inhibit the degradation it helps the cell increase the level of insulin messenger RNA. This way the insulin-producing cells are once again told to produce insulin, even though their natural defence response would be to go into hibernation while fighting the inflammation’, Thomas Mandrup-Poulsen explains.

Medicine capable of kick-starting the insulin production in patients with type 2 diabetes will not be available for some time, though. 

’So far we have only done tests on cells from animals and healthy people. We have not looked at cells from patients with diabetes or studied the system in animal models, and we need to do this before we can do clinical tests and start thinking about developing drugs. It is a long process’, says Thomas Mandrup-Poulsen.

The study is funded by the Danish Diabetes Academy (DDA), Zealand Pharma A/S, the Augustinus Foundation, the Bjarne Jensen Foundation and the Department of Biomedical Sciences at the University of Copenhagen.

Read the entire study ‘The No-Go and Nonsense-Mediated RNA Decay Pathways are Regulated by Inflammatory Cytokines in Insulin-Producing Cells and Human Islets and Determine β–Cell Insulin Biosynthesis and Survival’ in the Diabetes journal.