Research: New insight on pre-diabetes insulin production

LKCMedicine-led study discovers that macrophages are key to increase insulin production

Amanda Lee, Senior Assistant Manager (Media), Communications and Outreach

An international research team led by LKCMedicine Assistant Professor of Metabolic Disease Yusuf Ali, has found that a type of immune cell is capable of promoting insulin production during the pre-diabetes phase.

The discovery comes after a five-year study scrutinised a certain type of immune cell known as "pancreatic islet resident macrophage". The role of islet macrophages during the pre-diabetes phase had been an enigma for awhile. This study found that the increase in islet macrophages during pre-diabetes was associated with increased islet blood vessel formation and this allowed the islet to remodel to further increase the supply of insulin during pre-diabetes.

The research team believe that the macrophages could be harnessed through new targeted treatments to help prevent Type 2 pre-diabetic patients from turning fully diabetic.

Pre-diabetes is a telltale sign as it is when a person's blood glucose levels are higher than normal, but not high enough to be considered as diabetes.

Located in various organs such as the heart, liver and lungs, resident macrophages are large, specialised cells that identify, envelop and destroy cells. Within the pancreas there are numerous cell clusters shaped as "islands" known as islets, and within each islet, resident macrophages reside closely to "beta cells" – key cells responsible for the synthesis and secretion of insulin, a hormone which helps regulate blood sugar levels. 

"There are currently more than 300,000 people in Singapore and many more around the world who are living and coping with Type 2 diabetes. However, even more people are living in the pre-diabetes phase and if we could detect it early, it would be much easier to reverse any negative progression of the condition," said Asst Prof Ali.

The research team also comprises scientists from the NTU School of Biological Sciences, the Singapore Eye Research Institute (SERI), The Rolf Luft Research Centre for Diabetes and Endocrinology, Karolinska Institute in Sweden and the Department of Medicine of the Universitätsklinikum Carl Gustav Carus in Germany.

Their findings were published in the peer-reviewed journal, American Journal of Physiology – Endocrinology and Metabolism on 1 October 2019. It is supported by SERI which helped with image acquisition of how islets behaved in a living body, and SingHealth Duke-NUS Transplant Centre for the provision of human islets.

In pre-diabetic patients, cells in the muscles, body fat and liver start resisting the signals from insulin to remove glucose from the bloodstream, and the beta cells respond to this by increasing insulin secretion. This is further supported by an increase in the islet mass and number of beta cells in a process called "islet remodelling".

For the study, the team used pre-diabetes mice models and human insulin-producing cell preparations in the laboratory, to show that the findings are translatable for humans. This was conducted in line with Singapore's research ethical permits and reporting guidelines.

Acknowledging the support of the research agencies in Singapore and individuals who donated their bodies to science after they had passed away, Asst Prof Yusuf said, "We took years to validate this study using human islet preparations and we are appreciative of our clinical partners SERI and SingHealth, and especially to the people who donated their organs for research."

Over a 16-week period, macrophages near beta cells multiplied through cell division. When the scientists removed this subset of macrophages, islet remodelling and insulin levels fell, causing a transition from the pre-diabetes phase into full Type 2 diabetes.

From the findings, the team believe that pancreatic islet macrophages could be successfully manipulated through new targeted treatments during the pre-diabetes phase. By doing so, it will increase the supply of insulin secretion and reduce the progression to the full-blown diabetes phase.

Asst Prof Yusuf said, "The pre-diabetes phase varies from individual to individual. Some get pre-diabetes in a matter of months and develop full-blown diabetes, while others live with pre-diabetes for years. Building on our discovery, we now hope to fully uncover the role islet macrophages play and hopefully find ways to delay or reverse the progression of diabetes."

The scientists hope to conduct deeper research in macrophage subsets, to spur better targeted drugs and treatments for pre-diabetic patients in order to potentially reverse their aliment.

Dr Daniel Chew, Head & Senior Consultant Department of Endocrinology at Tan Tock Seng Hospital who was not involved in the study, said in the course of the development of Type 2 diabetes, insulin secreting beta cells initially respond to the challenge of insulin resistance by producing more insulin. However, the beta cells "fail" and produce less insulin, he noted.

"This research explores a novel mechanism for the compensatory phase of this phenomenon, sometimes called Starling's Law of the pancreas. The investigators have demonstrated the importance of vascular remodelling of the pancreatic islets in which the beta cells reside and provide strong evidence that it is aided by resident macrophages (immune regulatory cells). Further elucidation of the mechanism by which macrophages enhance beta cell function could lead to novel therapies for prevention and treatment of Type 2 diabetes," said Dr Chew.