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09 Sep 2017

Type 1 diabetes: Releasing the 'insulin handbrake' could make transplants a reality for thousands

A Garvan-led research team has shown that a new therapeutic approach can enhance insulin secretion by the pancreas, and has the potential to improve islet cell transplants in individuals with type 1 diabetes

An Australian study has found a new way to boost insulin production by the pancreas. The findings, just published in the journal Nature Communications, could one day make islet transplants a realistic and life-changing treatment option for over 100,000 Australians currently living with type 1 diabetes, as well as for millions worldwide.

By blocking a protein called Y1 receptor in human pancreas islet cells, researchers found that they were able to enhance insulin secretion. They went on to show that, in diabetic mice, blocking Y1 made transplants much more effective. Importantly, five times fewer cells were needed for transplant when Y1 receptor was blocked.

Professor Herbert Herzog and Associate Professor Shane Grey, of the Garvan Institute of Medical Research in Sydney, led the study with Dr Kim Loh, from St Vincent’s Institute of Medical Research in Melbourne (SVI), and Garvan’s Dr Yanchuan Shi and Stacey Walters. The collaboration brought together experts from Garvan’s Divisions of Neuroscience, Immunology, and Diabetes and Metabolism, as well as from SVI, and from Jichi University in Japan.

Prof Herzog’s team discovered that the Y1 receptor – which is known to help regulate appetite and energy expenditure in the body – can also switch off insulin release from islet cells in the pancreas. Importantly, when they treated mouse islet cells with a molecule designed to specifically block Y1 receptor, the switch was completely inactivated, and insulin release was restored.

“The involvement of Y1 receptor in pancreas activity is a very exciting finding,” says Prof Herzog.

“We are seeing for the first time that Y1 receptor acts like an ‘insulin handbrake’ to help get the right levels of insulin released according to a body’s needs,” explains Dr Shi.

A/Prof Grey adds, “For many years, diabetes researchers have been trying to make islet cells produce more insulin – with Y1 receptor, we now have a very promising target for therapies that could do just that.”

Type 1 diabetes is an autoimmune condition, where the body attacks the pancreas, destroying the insulin-producing islet cells. It develops most often in childhood, with the highest rate of new cases found in children under the age of 14.

Clinically, type 1 diabetes is managed with daily insulin injections throughout an individual’s lifetime. However, continuous monitoring is required to avoid the dangers of both high and low glucose levels, and there are many associated complications that can significantly affect a person’s quality of life, including risk of eye disease, progressive nerve damage, kidney deterioration and heart disease.

“The holy grail for type 1 diabetes research is to enable people to manage their insulin levels without needing daily treatment and monitoring," says A/Prof Grey.

Islet cell transplants from deceased donors offer a solution – but for most people, including children, the need for lifelong immunosuppressive medication following a transplant means that it is currently only a treatment option for special cases. Furthermore, donor islets are in short supply.

An additional limitation is the number of islet cells needed. Each individual usually needs multiple transplants from two or three donors in order to become ‘insulin independent’.

“So if we could boost the function of the transplanted islets in the first place, it might be possible to transplant fewer islets for each person, with better success, and many more people would benefit from this life-changing treatment,” says A/Prof Grey.

The new findings could be the key.

The researchers first compared blood sugar levels in diabetic mice transplanted with 60 or 300 mouse islets. In the mice with 300 islets, but not in those with 60, blood sugar was normalised. Importantly however, 60 islets were enough to normalise blood sugar when a molecule that blocks the Y1 receptor was administered.

“The success of these transplants using such a tiny number of islets was amazing,” Ms Walters says.

Next, the researchers studied human islets obtained from SVI’s Islet Transplant Program.

“We found that human islets were able to release substantially more insulin when the Y1 receptor is blocked,” says Dr Loh.

“When we then transplanted human islets into diabetic mice, we could correct blood sugar levels more rapidly when they were also with the Y1 receptor blocker.”

A/Prof Grey continues, “If this approach works as successfully in people, this could make islet cell transplants feasible for a great many more patients.”

“And with fewer donors required for each individual, the immunological complications would also be reduced, which may lower the level of immunosuppressive medication required post-transplant.”

This type of treatment may have other clinical applications too.

Dr Shi explains, “Newly diagnosed type I diabetic patients often experience a so called “honeymoon period,” where the islet cells are not completely destroyed and the remaining cells function well enough to maintain normal glucose level. During this stage, individuals are symptom-free. Blocking Y1 receptor at this period offers the potential to either slow down or arrest the ongoing destruction of the remaining beta cells, prolonging this symptom-free time.”

Prof Herzog says, “We also looked at mice with reduced islet cell function that were susceptible to hyperglycaemia – similar to what is happening in people who are newly diagnosed with type 1 diabetes. In these mice, blocking the Y1 receptor improved glucose tolerance and markedly delayed the onset of hyperglycaemia.”

“If these results translate into the clinic, we could effectively delay the onset of full blown type 1 diabetes for thousands of kids, for a considerable period of time. The longer these kids get to live without all the complications of diabetes, the better,” says A/Prof Grey.

“Importantly, insulin deregulation can also occur in other conditions, including type 2 diabetes – so therapies that target Y1 receptor might also be beneficial to improve insulin production and glucose metabolism in individuals with type 2 diabetes,” says Prof Herzog.

“This therapeutic approach could be life altering for a lot of people.”

Dr Loh says the team are extremely grateful to the people who donate their pancreatic islets for research.

“These discoveries wouldn’t happen without their generosity,” he says.

Read more about SVI's part in the study.