Biology of diabetes explored

Type 2 diabetes may be caused by “a chain reaction which destroys vital insulin-producing cells”, BBC News reported. The website said that a “malfunctioning protein” called amyloid could trigger the condition, in which the body loses its ability to control blood sugar levels.

The news is based on a laboratory study that investigated a series of complex chemical reactions affecting cells involved in type 2 diabetes, the more common form of diabetes. It has discovered a series of complex processes that might trigger the formation of amyloid deposits in the cells of the pancreas. These deposits damage the cells that produce insulin, a hormone that the body uses to regulate blood sugar.

News reports also suggested that it may eventually be possible to interrupt these processes and stop the disease from progressing. Any such developments are a long way off and it is too soon to claim that a cause or cure for diabetes has been found. Nevertheless, this early research is an important exploration of the processes behind type 2 diabetes.

Where did the story come from?

The study was carried out by researchers from Trinity College in Dublin and other academic and medical institutions around the world. It was funded by Australia’s National Health and Medical Research Council, the Science Foundation Ireland, the US Department of Veterans Affairs and the US National Institutes of Health. The study was published in the peer-reviewed medical journal Nature Immunology.

BBC News covered the research well, and although it did not provide much detail of its methodology, it put the study in context by explaining type 2 diabetes and highlighting the scale of problem in the UK.

What kind of research was this?

This laboratory research investigated the complex chemical pathways involved in type 2 diabetes.

Type 2 diabetes is characterised by high levels of glucose in the blood. It occurs when not enough insulin is produced by the body or when the body’s cells do not react to insulin. The condition, which typically develops later in life, is usually managed with a combination of dietary changes and oral medication. Type 2 diabetes differs from type 1 diabetes, which begins in childhood or young adulthood and requires insulin injections to control blood sugar levels.

Previous studies have suggested that IL-1beta, a chemical involved in inflammatory reactions, is important in the disease process for both type 1 and type 2 diabetes. Raised levels of IL-1beta are a risk factor for both types of diabetes but the events that lead to higher levels of IL-1beta in type 2 diabetes are not clear.

In this study, researchers investigated the complex chain of reactions behind the increased levels of IL-1beta in type 2 diabetes. Some studies have revealed parts of the chemical pathways involved, identifying sets of chemicals that need to be secreted to trigger the production of IL-1beta. Key to the process is a collection of proteins known as the inflammasome, which is itself activated by a range of other chemicals.

In this laboratory study, the researchers investigated whether there was a particular chemical that could activate these inflammasome proteins in people with type 2 diabetes. They worked on the principal that a compound called islet amyloid polypeptide (IAPP) may be responsible for the activation of IL-1beta through the inflammasome. IAPP, also called amylin, is known to be deposited in pancreatic cells and to play a part in the loss of the pancreas’ insulin-producing cells, the islet or beta cells.

What did the research involve?

The methods to investigate the details of chemical reactions happening in cells are necessarily complex. Here, researchers investigated the ability of human IAPP to stimulate the production of IL-1beta in cells derived from bone marrow. They then investigated what was happening in the chemical processes preceding this reaction to try to get an understanding of the complex chain of reactions leading to the production of IL-1beta. They found that another chemical called glyburide inhibited the activation of the inflammasome proteins.

The researchers wanted to study these reactions in a living system, so they used mice. However, the mouse form of IAPP does not produce pancreas-damaging amyloid so the researchers used genetically modified mice that produced a human form of IAPP. When these mice are fed a high-fat diet, amyloid is deposited in the pancreas cells, leading to damage to the insulin-producing cells.

The researchers fed these mice a high-fat diet for a year and then assessed whether IL-1beta was present in the cells in the pancreas.

What were the basic results?

The study found that human IAPP could stimulate the production of IL-1beta in cells from bone marrow. Studying the preceding reactions revealed that IAPP activates several enzymes, specifically the inflammasome complex of proteins. By examining these pathways, the researchers were able to determine which part of IAPP began the series of reactions that ultimately activated the inflammasome.

The results of these tests suggest that macrophages (cells that engulf foreign material) may be responsible because they produce IL-1beta when they take up IAPP.

Tests in mice then showed that human IAPP promoted the manufacture of IL-1beta in the pancreas.

How did the researchers interpret the results?

The study has shown that amyloid, a molecule that is deposited in the pancreas in type 2 diabetes, stimulated the processing of a chemical called IL-1beta. In turn, this caused the death of insulin-producing islet cells.

The authors say that they have identified a “previously unknown mechanism” in the development of type 2 diabetes.

Conclusion

This laboratory study has delved deep into the complex associations between different chemicals that have a known link to type 2 diabetes.

However, there is still uncertainty over whether the amyloid deposits seen in type 2 diabetes are a cause or effect of the condition, in other words whether diabetes causes amyloid deposits or amyloid deposits lead to diabetes. This study was not intended to confirm which of the two factors triggers the other, so it is too soon to suggest that the amyloid protein “may spark” the disease, as BBC News did.

Nevertheless, the researchers say that the build-up of IL-1beta seems to aid the progressive loss of the function of cells that produce insulin. This discovery is important and will lead to further research. The implications for the treatment of type 2 diabetes are not yet clear as this is early research and the development of treatments from this type of chemical research is long and unpredictable. However, it does start with these types of studies, and more research in this area will undoubtedly follow.