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Insulin may ward off infections

University Health Network researchers find insulin could play a role in the immune system

Insulin may ward off infections

It was Frederick Banting’s co-discovery of how to extract insulin in the early 1920s at U of T that continues to save millions of lives across the globe, providing hope to patients suffering from diabetes who, in previous years, had none.

For Dr. Sue Tsai and Dr. Dan Winer at the University Health Network (UHN), insulin is the gift that keeps on giving.

“In [our] field a lot of people are looking at how obesity causes inflammation,” said Tsai. “But no one really knows it affects the immune system when it comes to infectious diseases, or cancer, because so many things are altered [and] your hormones are all dysregulated.”

Insulin’s role in diabetes is well-researched, but little is known about the role it has in regulating T cell function and what leads T cells to stop responding to insulin.

Tsai wanted to determine what factors cause obese individuals to have a reduced response to vaccinations, develop more infections, and be more likely to develop cancer.

They narrowed their target to insulin, because individuals become resistant to it when they become obese.

Tsai, a postdoctoral fellow at UHN, and Winer, an Assistant Professor in U of T’s Department of Laboratory Medicine and Pathology, have uncovered an insulin signalling pathway that elicits a response from infection-fighting T cells when they are activated.

Insulin, a pancreatic hormone, promotes glucose uptake via downstream signalling pathways. These pathways involve the binding of the insulin hormone to an insulin receptor (INSR).

Immune cells, such as B cells and T cells, that protect the body against infection also possess this receptor. Tsai and Winer hypothesized that the binding of this receptor would stimulate T cell activation and proliferation, leading to a strong and immediate immune response.

In their study, Tsai and her colleagues compared T cell function in mice without the INSR to those with the receptor.

“We found that T cells [without INSR] become less functional, and when we give the mice influenza [H1N1], they do worse,” explained Tsai. “They lose more weight and then they have a weaker immune response against the influenza.”

INSR played an integral role in maximizing the potential function of the T cells in mice by increasing their nutrient uptake and in turn generating energy through ATP production during inflammation and infection.

The researchers’ findings provide some reasoning as to why vaccines in obese individuals may not be as effective. Many obese individuals are insulin-resistant and, as shown in this study, could therefore have a weaker T cell response.

T cells are integral to the efficacy of a vaccine, as they recruit infection-fighting antibodies and aid in immunological memory.

Tsai hopes to continue exploring the link between insulin and immunity, and is currently investigating insulin signalling in B cells. She believes the findings of these studies could have wide-ranging applications.

“The most obvious thing is influenza vaccines. How can we develop a vaccine, and what additional signals can we add to the vaccine to get them to work better in individuals who are insulin resistant?” said Tsai.

“Also, tumour immunotherapies. Do obese people respond to these therapies differently than non-obese people and does insulin resistance play a role in that?”

In the future, the insulin signaling pathway could also be used to study and find ways to ‘boost’ the immune system and develop vaccines that would work more effectively in obese individuals.

Tsai’s findings were published in Cell Metabolism last month, almost a century after the discovery of insulin.

Experiments Explained: How U of T researchers discovered insulin

In 1922, Fredrick Banting and Charles Best found the key to extending the lives of diabetics

Experiments Explained: How U of T researchers discovered insulin

Experiments Explained is The Varsity’s Science subsection featuring notable findings in history. Our goal is to showcase the experiments that shaped our understanding of science today.

Step into the Macleod Auditorium in the Medical Sciences Building, and you will find a display dedicated to the discovery of insulin — perhaps the most well-known success story to come out of U of T medical research.

Before the discovery of insulin, type 1 diabetes was a death sentence. Patients died of either the disease or the treatment, a starvation diet that restricted children to as little as 500 calories a day, for which there was meagre evidence of benefit.

In 1920, Canadian physician Frederick Banting jotted down 24 words: “Ligate pancreatic ducts of dogs. Keep dogs alive till acini degenerate leaving Islets. Try to isolate the internal secretion of these to relieve glycosurea.”

In other words, diabetes — which Banting equated with glycosuria because diabetics excreted the sugar glucose in their urine — had been traced to the pancreas, the hockey stick-shaped organ tucked behind the stomach. More specifically, it had been linked to dysfunction of the islets of Langerhans, clumps of cells found throughout the pancreas.

Previous attempts to isolate the component ­— something healthy people had and type 1 diabetics lacked — secreted by these islets ultimately failed.

Banting theorized that the previous experiments did not work because the pancreas secreted juice, composed of digestive enzymes, and destroyed the anti-diabetic secretions before they could be isolated.

Hence his plan: “ligate [cut] pancreatic ducts of dogs” to stop them from producing the digestive juice, then collect the secretions from the islets. Armed with this idea, Banting moved to Toronto, where U of T professor John Macleod equipped him with a laboratory and an assistant, medical student Charles Best.

In May 1921, Banting and Best began their experiments. They removed the pancreata of some dogs to induce diabetes, and cut pancreatic ducts in others so they could extract islet secretions.

They then injected the secretions from the second group into the now-diabetic first group, monitoring their blood and urine sugar levels as well as their lifespans. The dogs survived.

The islet extract — first called isletin, later renamed insulin — alleviated their symptoms.

Macleod, finally convinced of their success after asking them to repeat their experiments, brought in Bertram Collip to help the team purify the extract. By then, they had switched from dog pancreata to cows, simply because they needed more extract than dogs could provide.

While Banting’s initial idea to cut pancreatic ducts was unsuccessful, the team had succeeded in isolating insulin.

In January 1922, the team administered insulin to 14-year-old Leonard Thompson — the first person to receive insulin. At the time, Thompson weighed a mere 65 pounds and was on the brink of death. Following the treatment, Thompson’s condition improved. He lived another 13 years. Others in similar conditions also improved after being treated with insulin.

During the same year, the experimental cure reached the United States and clinical trials launched in North America in July of the same year. By the end of the year, insulin production started in Europe. In 1923, Banting and Macleod received the 1923 Nobel Prize in Physiology or Medicine for their discovery of insulin. Banting shared his prize money with Best while Macleod shared his with Collip.

To this day, insulin makes diabetes — although an incurable condition — manageable for those living with it.

The naming of Macleod Auditorium and its tribute to Banting, Best, and Collip serve not only to commemorate a moment in U of T medical history, but also to celebrate a scientific breakthrough that continues to save lives.