Super-connected “leader” cells coordinate insulin response in animals

Beta cells, which produce insulin, on the pancreas' surface

New research into how insulin-secreting cells regulate responses to rising blood glucose levels could help us to understand how diabetes develops.

In collaboration with the Technische Universität Dresden (TUD), an Imperial-led study has revealed how the responses of highly-connected clusters of pancreatic beta cells – which produce and release insulin in the body – are coordinated by small teams of “leader” or “hub” cells when blood glucose levels rise. The paper, published today in Nature Metabolism, describes an innovative imaging technique which allowed researchers to observe beta cells’ hierarchical relationship in live animals for the first time. 

Although the biochemistry of individual beta cells is well understood, it was previously unclear as to how clusters (known as islets) worked together to regulate their responses to glucose. Based on observations of these islets in mice and fish, researchers now know that insulin release is coordinated by a select group of hub cells. This could be significant in understanding why insulin responses falter in patients with diabetes.

In vivo investigations

Research led by Imperial’s Professor Guy Rutter previously demonstrated the presence of hub cells by studying electrical signals sent between beta cells within islets in the lab. Building on these findings, the study team set out to investigate whether this could also be observed in living animals.  

To do this, lead researcher Dr Victoria Salem worked with Professor Rutter to refine a novel imaging technique to carry out the study. As a practical alternative to imaging the entire pancreas in vivo, the team was able to observe human beta cell islets in action by grafting them into the anterior eye chamber of a mouse.

“This is a very simple procedure that doesn’t cause the animal any distress. The transplanted islets can be imaged many times over their lifetime as the animal is gently kept under anaesthesia,” explains Dr Salem.

“This approach allowed us to visualise the behaviour of the islets at different circulating glucose levels in a system that mirrors the endogenous pancreas. Most importantly, it enables us to repeat the experiments over time.”

By using high-speed 3D imaging and novel analytical approaches, researchers revealed that small teams of hub cells coordinated responses within the engrafted islets. Critically, they also found that coordination was impaired in human islets taken from subjects with diabetes.

Building the case

In addition to investigating how the engrafted islets behaved in a mammalian model, the team worked in close partnership with TUD researchers Luis Delgadillo Silva and Dr Nikolay Ninov to image islets in situ in zebrafish. Researchers again found that when blood glucose levels increased, well-connected beta cells responded in a coordinated fashion. Significantly, the team also observed that when hub cells were selectively deleted, the level of coordination in subsequent responses to glucose was disrupted.

To further investigate the role of leader cells as “pacemakers” within islets, researchers worked closely with Professor Walter Distaso (Imperial College Business School), who performed a mathematical causality analysis of the beta cells observed in the mice islets. The analysis confirmed that the visually-identified hub cells were causally related to the activity of the follower cells in the islet.

Furthermore, following transcriptomic analysis performed in collaboration with Dr Timothy Pullen (King’s College London / Imperial College London) and Dr Sumeet Pal Singh (TUD), the team was also able to demonstrate that beta cells taken from both the zebrafish and mouse islets contained a unique genetic signature. The analysis showed that hub cells are more metabolically active, and less focussed on secreting insulin. 

Next steps

The findings raise a number of important questions that, if answered, could help us to better understand why beta cells sometimes fail to release insulin in response to rising blood glucose levels.

“For now, we have established the existence of functionally relevant leader or hub cells in the living animal. The next step is to understand how important they are in the development of diabetes,” explains Dr Salem.

“For instance, if these cells become impaired, does this lead to the rapid progression of islet failure? Can they be targeted to work more efficiently with drugs? The stability of hub cells is another critical question: are these cells present from birth, or do they appear (and disappear) over time?”

“It’s important for us to understand if hub cells are vulnerable to damage as diabetes develops and, crucially, whether they can be targeted to maintain strong and healthy insulin responses to help cure the disease.”

"Leader β cells coordinate Ca2+ dynamics across pancreatic islets in vivo" by Victoria Salem, Luis Delgadillo Silva et al. is published in Nature Metabolism. DOI 10.1038/s42255-019-0075-2.

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