Defining the role of dedifferentiation as a primary mechanism of beta-cell dysfunction in Type 2 diabetes
The insulin-producing beta cells in the pancreas usually cease to function in Type 2 diabetes. Rather than dying off, this may be because the cells transform and lose their identity. Professor James Shaw’s student will track the development of human beta cells in the lab to uncover the mechanisms involved in this identity loss.
Background to research
Type 2 diabetes gets steadily worse as insulin-producing beta cells in the pancreas cease to function. Previously it was thought that this was a result of beta cells dying off due to the high glucose and fat levels seen in Type 2 diabetes. However, examination of autopsy tissue from people with the condition does not support this theory – as only modest reductions in beta cell numbers are seen. The rapid recovery of beta cell function and remission of Type 2 diabetes in people who have lost weight using a low calorie diet also challenges this idea. Recent studies in mice suggest that, rather than dying outright, beta cells change identity and lose the machinery necessary to produce insulin. Professor James Shaw and his team in Newcastle believe that this identity transformation, rather than being part of an irreversible process, provides beta-cells with a 'hideaway' that protects them from death through stress and overwork caused by high glucose and fat levels.
With support from Diabetes UK, Professor James Shaw’s student will track the development of human beta cells in the lab to find out what happens when they lose their identity. They will also uncover the mechanisms and molecular triggers involved in this process. First, genetic engineering will be used to label each cell with a fluorescent marker so that they can be tracked even when they transform. Conditions that mimic those in Type 2 diabetes will then be used to encourage the cells to transform and the chemical signalling pathways that drive this transformation will be determined. These pathways will then be examined further in islets from people with Type 2 diabetes.
Potential benefit to people with diabetes
Most current therapies for Type 2 diabetes do not address the key problem of beta cell dysfunction. Identifying the chemical pathways that cause insulin-producing beta cells to transform and lose their identity could help the researchers to identify targets for new Type 2 diabetes drugs. These could be used to maintain and restore beta cell numbers in the pancreas by preventing or reversing this transformation, and could undergo clinical trials 3-5 years after this study is complete.