Results from a study led by researchers at the Garvan Institute of Medical Research in Australia show how treatment with anti-inflammatory steroids can affect a gene called RELA and trigger diabetes symptoms.
The results of the research, published in the journal Diabetologia, suggest that RELA plays a joint role in controlling inflammation and insulin secretion, which is why people treated with anti-inflammatory drugs such as corticosteroids can develop diabetes as a result.
“Our discovery sheds new light on a complex network of factors governing glucose metabolism and how it can go awry in diabetes,” said Shane Grey, lead author of the paper and Head of the Transplant Immunology Lab at Garvan, in a press statement.
“Steroids are known to help prevent inflammation by targeting RELA. Our finding that RELA also coordinates the expression of genes in the pancreas that are essential for glucose control and preventing diabetes therefore has major implications for understanding and preventing steroid-induced diabetes, which could be achieved using treatment strategies that prevent inflammation without targeting RELA.”
To investigate links between inflammation and insulin secretion, Grey and colleagues created mouse models with a non-functional mouse equivalent of the RELA gene, as well as models with deletions of other genes thought to be relevant for the same inflammatory and metabolic pathways.
RELA encodes transcription factor p65 (also known as nuclear factor NF-kappa-B p65 subunit) and contributes to the formation of NF kappa-beta, another transcription factor that plays an important role in the immune system.
As expected, the researchers observed that mice without a functional Rela gene did not show immune-regulatory activity related to the gene. However, there was an additional effect on blood glucose levels in these animals.
“When we removed RELA from the system, we found that our models became pre-diabetic. We found this was due to impaired insulin secretion in the beta cells of the pancreas,” said first author Nathan Zammit, a visiting scientist at the Garvan Institute.
On further investigation in the lab, the team found that the RELA gene plays an important role in maintaining normal glucose homeostasis. The pancreatic beta cells of the mice with no functional Rela gene failed to secrete insulin in response to glucose in a similar fashion to that seen in patients with type 2 or steroid-induced diabetes.
Notably, the scientists also checked other NF kappa-beta signalling pathways and it appeared that only RELA was specifically required to maintain insulin secretion function.
“We found that the protein RELA produces directly switches on a genetic program required for cells in the pancreas to produce insulin,” explained Zammit. “This indicated that even though inflammation and diabetes are known to be linked, RELA regulates blood sugar and inflammation completely independently. Our findings suggest that RELA plays an essential role in keeping blood-sugar levels normal, even when there is no inflammation.”
Although this research is at an early stage and requires further validation, the findings could help people impacted by steroid-induced diabetes. If drugs that impact the RELA pathway can be avoided then patients could receive necessary anti-inflammatory medication, without developing diabetic symptoms as a result.
“By understanding how insulin-producing cells and systems in the pancreas are regulated by RELA, it may be possible to balance the inhibition of inflammation without disrupting the function of insulin-producing cells. This could lead to the development of medications that reduce inflammation without bringing on steroid-induced diabetes as a side effect,” said Grey.
