Amyloid could “directly poison” pancreas cells. Shedding light on how a malfunctioning protein helps trigger Type 2 diabetes could one day offer the chance to halt the damage, say scientists….
The presence of amyloid protein may produce a chain reaction which destroys vital insulin-producing cells. Researchers based in Dublin, Ireland, writing in the Nature Immunology, say future drugs could target this process. Amyloid is implicated in many other diseases, most notably Alzheimer’s.
Scientists at Trinity College Dublin have discovered what could be the underlying basis for Type 2 diabetes, a debilitating disease where people stop responding to insulin. The TCD team has found that the peptide hormone, Islet Amyloid Polypeptide (IAPP), which gets deposited in the pancreas in Type 2 diabetes, is the trigger for a protein complex called the inflammasome. This in turn leads to the production of the pro-inflammatory agent IL-1beta, which is already being targeted in several clinical trials.
“We’ve found what might be the ‘straw that breaks the camel’s back’ in Type 2 diabetes,” says Dr. Seth Masters, lead author on the publication. “IL-1beta is known to be important in the disease and we have found what might be the key mechanism leading to its over-production.” The work provides a deeper insight into the disease process.
“Current treatments are somewhat effective but there is a pressing need for newer therapeutic approaches,” says Professor of Biochemistry, Luke O’Neill, who heads the group at TCD. “IL-1beta is being explored by several drug companies and results are promising. Our work confirms the importance of IL-1beta in the disease and also points to Nlrp3 as a new target to go after.”
Insulin is made in “beta cells” in the pancreas, and scientists first noticed “deposits” of the amyloid protein in pancreatic tissue of some people with Type 2 diabetes some years ago.
It was thought that amyloid could be poisoning the cells directly, but the latest research offers an additional explanation. It found that a type of immune cell called a macrophage, whose normal role is to get rid of debris in the cell, reacted abnormally when it ingested amyloid.
It triggered activity in other cells nicknamed “angry macrophages,” which in turn released proteins that cause inflammation. The inflammation then destroys the vital beta cells, and the ability to produce insulin is reduced.
Opsona Therapeutics, co-founded by Luke O’Neill, has an active program in this area. The work is likely to spur further efforts to develop drugs that interfere with this process. “Mechanistic insights such as the one we have made are very important for the effort to develop new therapies. There is real optimism that much better treatments for Type 2 diabetes will emerge from this area,” says Prof. O’Neill.
The researchers said that they hoped the finding would “spur new research” to target the mechanisms of the disease.
Dr. Eric Hewitt, a researcher into amyloid-related disease at Leeds University, U.K., said the paper was “interesting,” and could help explain why the presence of amyloid deposits, or the process that laid them down, could be so damaging. “It suggests we are looking at a very complex disease — we know that amyloid is present in some Type 2 diabetics, but not others…. What we have is a second indirect mechanism which can lead to the destruction of beta cells, and this could be helpful when looking at other diseases which may involve amyloid, such as Alzheimer’s…. It does offer a possible opportunity to interrupt this mechanism at some point in the future and perhaps stop the disease from progressing.”