Strategic Research Centre: How CF exocrine pancreatic disease may lead to CF related diabetes

Recent research suggests that cystic fibrosis-related diabetes (CFRD) is caused by damage to the digestive-juice-producing part of the pancreas, triggering things to go wrong in the insulin-producing ‘beta’ cells in another part of the pancreas. Researchers will investigate how the damage to insulin-producing cells occurs and the best ways to measure it in people with cystic fibrosis.

Summary

Insulin is an important hormone that helps to regulate the amount of sugar in the blood. In CFRD, the body can’t release enough insulin from where it is made in the pancreas. The body also responds differently to the insulin that is released, which means that the sugar levels in the blood aren’t regulated properly. The signs and symptoms of CFRD share similarities to both Type 1 and Type 2 diabetes, but CFRD is a distinct condition, with a different underlying cause.

In a recently published paper from a previous Strategic Research Centre (SRC) on CFRD, Professor James Shaw and colleagues suggested that chemical signals from the CF-damaged, exocrine (digestive juice-producing) cells of the pancreas are linked to the development of CFRD.

The aim of this SRC is to focus on the action of these chemical signals in the development of CFRD. The researchers will look at: how the signals move from the exocrine parts of the pancreas to the insulin-producing cells, which signals cause the most damage and whether these signals can be measured in the blood of people with cystic fibrosis. Understanding more about these signals could lead to entirely new approaches to treating CFRD in the future, avoiding the need for insulin injections.

More detail on the specific aims within this SRC are given below.

Aim 1: Can early signs of insulin-producing-cell damage be detected in the blood?

When different parts of the body become stressed or damaged, they release stress signals into the blood. Researchers can link the type of stress signal found in the blood to specific types of damage, and the levels of stress signal can indicate the extent of the damage. These stress signals can give a unique ‘fingerprint’ for different diseases. For doctors, measuring stress signals in the blood could be an indirect way of monitoring disease onset and disease progression. For people with the condition blood tests are a less invasive way of monitoring their disease.

Earlier research has shown that this approach may be feasible to monitor CF-related diabetes. This analysis could also help researchers find out more about its causes. Researchers working on the SRC will take blood samples from people with CF and analyse the stress signals in the blood that come from the pancreas. They hope that they’ll be able to identify a pattern of signals that are specifically linked to damage to insulin-producing cells in the pancreas, as a way to assess early signs of CF-related diabetes.

Aim 2: What do different ways of measuring pancreatic function tell us about the cause and progression of CF-related diabetes?

Within this aim of the SRC, for the first time, researchers will be able to link data from several new methods of measuring pancreas function and data obtained from existing, more established methods, to give new insights into the cause and progression of CF-related diabetes. State of the art, newly-developed MRI methods will be used alongside analysis of pancreatic signals in the blood and more general tests of pancreas and gut function in people with CF over time.

People taking part in the study will have different types and levels of pancreas damage, different CF genotypes and, if appropriate for their genotype, will be taking different CFTR modulators. Knowing what to measure and when will enable researchers to spot earlier signs of CFRD than are currently measured and work out possible to prevent it from occurring.

Aim 3: What changes are seen across the pancreas as CFRD develops?

In CFRD the insulin-producing cells within the pancreas may be changing their function to stop insulin production. Scientists think that this change in cell function is triggered by signals from the damaged digestive-juice-producing cells within the pancreas.

A detailed examination of different types of cell in post-mortem pancreas tissue from people with CF will allow the researchers within this SRC to understand more about how these changes in cell function happen. They have access to two well-established biobanks and will benefit from expertise in the most up-to-date and thorough methods for confidently identifying the numbers, locations and functions of different types of cell, and the presence of any damage-causing signals within these cells.

 By analysing tissue from people who had different types and extent of pancreatic damage, they’ll be able to piece together how CFRD develops over time and the signals that trigger these changes.

Aim 4: Which signals trigger the change in properties of insulin-producing cells?

Using human pancreas cells growing the lab, the researchers have developed a way to mimic the stressed conditions seen in CF-related diabetes. They will analyse which signals are produced from these cells, and compare the signals produced by the lab-grown pancreas cells with the pancreas signals that other researchers within the SRC have detected in the blood of people with CF-related diabetes.

The researchers believe that the signals released by the digestive-juice-producing cells in the pancreas during CFRD are triggering inflammation. To test this, and explore a potential new way of treating CFRD, they will investigate whether known anti-inflammatory drugs are effective at blocking the activity of these signals. If successful, these drugs would allow more insulin to be produced, which would reduce the impact of CF-related diabetes.

Aim 5: How do these stress signals actually trigger the effects on insulin-producing cells?

If insulin-producing cells in CFRD are damaged from being exposed to stress signals from other parts of the pancreas, then ‘treating’ healthy, human pancreas cells with these stress signals should trigger CFRD-like changes. The researchers will use the stress signals from the blood of people with CF and add them to healthy human pancreas cells growing in the lab. The results would further confirm the role of these signals in causing CFRD.

Alongside these studies, researchers will study these stress signals in detail, to understand how they are exerting their effects. Such a detailed understanding will inform the development of future therapies to minimise these effects.

Principal investigator: Professor James Shaw, University of Newcastle

Co-investigators:

• Dr Mike Gray, University of Newcastle
• Dr Shafagh Waters, Sydney Children’s Hospital
• Dr Daniel Faurholt-Jepsen, Rigshospitalet, Copenhagen
• Dr Kieren Hollingsworth, University of Newcastle
• Prof Roy Taylor, University of Newcastle
• Prof Peter Hegyi, University of Pécs, Hungary
• Dr Andrea Parniczky, National Institute of Paediatrics, Budapest
• Prof Gunter Kloppel, Technical University of Munich, Germany
• Prof Lena Eliasson, Lund University Sweden
• Dr Imogen Felton, Royal Brompton and Harefield NHS Foundation Trust, London
• Dr Catriona Kelly, University of Ulster

Our investment in CF-related diabetes research

In June 2020 we published a Research in focus report on CF-related diabetes. The report explains the impact CF-related diabetes has on the lives of people with CF, what we’ve learnt from our funding, and how this SRC builds on the knowledge gained so far.