Making waves with macrophages

NTU Singapore scientists discover new key to promote insulin production in pre-diabetes patients

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SINGAPORE—With obesity on the rise worldwide, Nanyang Technological University (NTU) scientists have discovered that a type of immune cell known as “pancreatic islet macrophage” is capable of promoting insulin production during the pre-diabetes phase, before the full-blown disease takes hold. The NTU team’s findings are published in the peer-reviewed journal American Journal of Physiology–Endocrinology and Metabolism, and supported by the Singapore Eye Research Institute, which provided the advanced imaging equipment for the research.
Although macrophages were not previously known to produce or regulate insulin, and had often been overlooked in diabetes research, the NTU team believed that the macrophages could be harnessed through new targeted treatments to help prevent type 2 pre-diabetic patients from suffering the physical complications and medical expenses of becoming fully diabetic.
Working with an international team of scientists, a five-year study was led by Yusuf Ali, assistant professor of metabolic disease molecular and cellular dysfunction from NTU’s Lee Kong Chian School of Medicine.
“There are currently more than 300,000 people in Singapore—and many more around the world—living and coping with type 2 diabetes,” Ali says. “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.”
Located in various organs such as the heart, lungs and liver, macrophages are large, specialized cells that identify, envelope and even destroy certain cells. Pancreatic islet macrophages reside closely to beta cells in the pancreas, key cells responsible for the synthesis and secretion of insulin.
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 beta cells by increasing insulin secretion, Ali explains. This is further supported by an increase in the mass and number of beta cells in a process called “islet remodeling.”
Ali and his team used pre-diabetes mouse models, as well as human insulin-producing cell preparations, in the laboratory to show that the findings are translatable for humans, he says. This was conducted in accordance with Singapore’s research ethical permits and reporting guidelines.
Over the course of 16 weeks, macrophages near beta cells multiplied through cell division, according to the paper. When the scientists removed this subset of macrophages, islet remodeling and insulin levels fell, causing a transition from the pre-diabetes phase into full type 2 diabetes.
The NTU scientists believe the results of the study indicate that pancreatic islet macrophages could be successfully manipulated through new targeted treatments during the pre-diabetes phase in order to increase the supply of insulin secretion and reduce the progression of the pre-diabetes phase.
“The length of time of the pre-diabetes phase varies from individual to individual,” Ali notes. “Some get pre-diabetes and in a matter of months will 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 Singapore Ministry of Health, in consultation with the World Health Organization, sometimes refer to pre-diabetes as impaired glucose tolerance or impaired fasting glucose, or both, depending on the type of test used for detection and diagnosis.
According to Ali, there are no clear symptoms of pre-diabetes. The only reliable method of diagnosis is to have blood tests done.
“It is possible to reverse out of pre-diabetes with a few changes to one’s lifestyle, which includes exercising, dietary changes, and of course, NTU’s research, which found a way to potentially increase insulin production,” says Ali.
“Lastly, the long-term goal of this research is to come up with targeted treatments for pre-diabetes patients,” he adds.
Dr. Daniel Chew, head and senior consultant, Department of Endocrinology at Tan Tock Seng Hospital, who was not involved in the study, said, “In the course of development of type 2 diabetes, initially insulin secreting beta cells respond to the challenge of insulin resistance by producing more insulin, but later they ‘fail’ and produce less insulin.”
This research explores a novel mechanism for the compensatory phase of this phenomenon, sometimes called Starling’s Law of the pancreas, Chew commented. The investigators have demonstrated the importance of vascular remodeling of the pancreatic islets in which the beta cells reside, and provide strong evidence that it is aided by resident macrophages (immune regulatory cells).
The paper, entitled “Islet macrophages are associated with islet vascular remodeling and compensatory hyperinsulinemia during diabetes,” was published Oct. 1, 2019.

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