It has been 44 years since Ana Osborne passed out one morning before school and woke up four hours later, bewildered. After dragging herself to the doctor and being ordered to get to a hospital immediately, the 18-year-old was diagnosed with Type 1 diabetes and told that her very survival would depend on frequent injections of life-saving insulin. An early routine involved poking her finger with a lancet, putting a drop of blood on a test strip to check her blood sugar level, and then using a syringe to inject insulin derived from a pig’s pancreas into the skin of her abdomen – multiple times a day. She has since tried so many different insulin types, tools and devices that her experience has almost mirrored the evolution of insulin therapy itself.
And today? Osborne wears a small disk-shaped sensor on her shoulder called a continuous glucose monitor. She uses a handheld device to read those numbers and she relays the information to a palm-sized computerized pump at her waist that delivers rapid-acting synthetic insulin under her skin via a tiny needle. “It’s much better than the older systems,” she says, acknowledging that even the best equipment is still a treatment, not a cure.
U of T researchers and their hospital partners recognize this as well, and are working on novel approaches to diabetes care that continue to improve lives for patients – building on something their predecessors started a century ago with the discovery of insulin. And for that, Osborne, who lives just north of Toronto, is deeply grateful. “If not for them,” she says, “I wouldn’t be here talking to you today.”
Back in 1921, Type 1 diabetes – once called juvenile diabetes – was a death sentence for the children and youth who developed it. There was no known cause, and the only treatment was a starvation diet that extended life by a few months. Into this reality came an ambitious young doctor named Frederick Banting, a farmer’s son from Alliston, Ontario. The youngest of five, he had struggled in school, flunking his first year of a general arts program at U of T’s Victoria College. Still, young Fred was serious and driven, and since the country was in dire need of doctors, he was accepted into medical school. After graduating, he served as a medical officer in England and France during the First World War. When he returned to Canada, he took a year of surgical training at Toronto’s Hospital for Sick Children. Then, unable to find a full-time staff job, he opened a small medical practice in London, Ontario. The patients were slow to arrive. Banting’s practice faltered, and he fell into debt. He picked up part-time work teaching at the University of Western Ontario (now Western University) but still could not pay his bills.
It was around this time, while preparing a lecture for medical students about the pancreas, that Banting decided to pursue a middle-of-the-night idea he’d had about curing diabetes. With no laboratory available at Western, he persuaded a reluctant John Macleod, a professor of physiology at U of T and an expert in carbohydrate metabolism, to give him lab space over the summer of 1921, along with a research assistant. The assistant turned out to be Charles Best, 22, newly graduated from U of T in biochemistry and physiology. Banting closed his medical practice and moved to Toronto. As he and Best conducted experiments under Macleod’s direction, they realized Banting’s hypothesis about curing diabetes didn’t work. They did discover, however, that injecting diabetic dogs with an extract made from the animals’ own surgically removed pancreases dramatically lowered the animals’ blood sugar levels. Aha! They knew they were on to something. They just didn’t know how to purify this extract to make it safe for human clinical trials.
Macleod invited University of Alberta biochemist James Collip, who had returned to his alma mater, U of T, for a sabbatical, to work on the purification process. Within weeks, using the pancreases of cattle from slaughterhouses, Collip figured out a way to purify the extract – now called insulin – by using a high concentration of alcohol.
Days later, the first recipient of an injection was Leonard Thompson, a 14-year-old patient at Toronto General Hospital weighing only 65 pounds and close to death. The boy responded quickly and recovered well. When the dying teenage daughter of then U.S. Secretary of State Charles Hughes rebounded to rosy-cheeked health after insulin treatment in Toronto, the international press went wild. Banting became a celebrity. He and Macleod received the Nobel Prize just one year later. Banting, upset that Best had been passed over, split the prize money with his young assistant. Macleod did the same with Collip. The team sold the patent to U of T for a dollar, and the university then licensed it royalty-free to pharmaceutical companies around the globe. By the summer of 1923, U of T’s Connaught Laboratories was producing 250,000 units of insulin a week for use in Canada and internationally. As Banting said, “Insulin belongs to the world, not to me.”
Now, after 100 years, the world needs insulin more than ever. Almost half a billion people worldwide live with Type 1 or Type 2 diabetes – a number expected to soar over the next decade due primarily to rising rates of obesity. 1 And while it’s no longer imminently fatal, the disease still kills approximately 1.6 million people every year. 2 Researchers continue to focus on ways to improve – and save – patients’ lives. “There have been, and continue to be, tremendous advances that have positively impacted the lives of people with diabetes,” says Gary Lewis, director of U of T’s Banting and Best Diabetes Centre and a senior scientist at the Toronto General Hospital Research Institute. While there is still no cure, he says U of T researchers and their hospital partners are getting closer all the time. “One kind of cure [for Type 1 diabetes] could come in the form of stem cell therapy, another in immune therapy.”
In Type 1 diabetes, an autoimmune disease usually acquired in childhood or adolescence, the immune system mistakenly kills the body’s beta cells, which produce insulin – the hormone that regulates our blood sugar levels. In Type 2 diabetes, the body either doesn’t produce enough insulin or can’t use it properly.
You might think that a transplant, of either an entire pancreas or just the islets (clusters of cells within the pancreas that include beta cells), would be an answer to curing Type 1 diabetes. But there are problems: there is always a shortage of donors; islet transplant requires two or three donors because many cells are damaged in the process; and recipients must take immune-suppressing drugs for life. These drugs carry risks of cancers and infections.
But what if we could find an unlimited source of islets that would also eliminate the need to take immune-suppressing drugs? One U of T team in the field of regenerative medicine is working on exactly that. Under Cristina Nostro, principal investigator at the McEwan Stem Cell Institute at the University Health Network, researchers start with pluripotent stem cells (informally known as cells that can “be whatever they want when they grow up”). Scientists can take these cells, and with the addition of various proteins, instruct them to behave like islet cells. The problem: if your body attacked your own islet cells (which include beta cells) before, it will attack these cells, too. A research group at the University of Washington Seattle is collaborating with Nostro on making these cells invisible to the immune system, she says. “Then we could transplant without the need of immune suppressants.”
The Washington team is taking three approaches to achieve “invisibility.” Meanwhile, Nostro’s team is working to demonstrate that these “instructed” islet cells actually function like islet cells and will not be rejected by the immune system. With patents filed and strong connections forged with Toronto General Hospital (and its ready supply of patients and surgical expertise), Nostro, also a professor in the department of physiology, is hoping to one day launch a clinical trial in Toronto. “I’m super excited,” she says. “The progress we’ve made is extraordinary.”
Another U of T team is working on tricking the immune system by manipulating T-cells, a type of white blood cell that, in Type 1 diabetes, mistakenly attacks healthy islet cells. Under Juan Carlos Zúñiga-Pflücker, a professor in U of T’s department of immunology and a senior scientist at Sunnybrook Health Sciences Centre, the team is using a specific protein to convert the misdirected T-cells into regulatory T-cells, which suppress the immune system and can prevent autoimmune disease. Zúñiga-Pflücker has co-founded a company, Notch Therapeutics, to bring this technology to market. “If you measure antibodies, which can identify children and young adults who haven’t yet developed diabetes but who are at high risk, modulating the immune system can prevent the total destruction of those cells and prolong their function,” Lewis says.
Other U of T research teams are focusing on Type 2 diabetes, which is much more common than Type 1, and much more closely linked to lifestyle. “There’s no question that if we solve the problem of obesity, we can solve most of the problem of Type 2 diabetes,” says Lewis. But obesity is a complex global epidemic that involves far more than simply choosing to eat too much or exercise too little. It’s partly genetic: Asian, Black, Hispanic/Latino and Indigenous populations have a higher risk of obesity and diabetes. It’s partly biological, with our natural human attraction to fatty and sweet tastes and our evolutionary ability to store fat. It’s partly our modern society, which necessitates sedentary, screen-based work or school. And it’s partly the social determinants of health: socioeconomic inequalities leave disadvantaged people without access to nutritious food, recreation opportunities, medical specialists or healthy outlets to manage stress. Lewis says, “In Type 2 diabetes, the social determinants of health totally swamp the genetic and biological determinants.” And they are affecting younger people. An alarming 2020 Manitoba government study found that the rate of Type 2 diabetes among children in Indigenous communities in that province is 25 times higher than that of other children. (See U of T Mississauga Opens a New Centre for Diabetes Research)
The link between stress and diet has been a particular research interest of Jacqueline Beaudry, an assistant professor in the department of nutritional sciences. She found that giving rats elevated stress hormones raised their blood sugar a little, but combining that with a high-fat diet gave them diabetes within one to two weeks. “It was very shocking,” Beaudry says. (Her PhD on the subject won the Governor General’s Academic Medal in 2014.) It is known that people who have high stress hormones tend to accumulate fat around their mid-section. But how much control do we have over our stress hormones? “We’re struggling with that all the time – especially going through a pandemic.” 3
Beaudry is now studying how various hormones affect our fat tissue, which is a major regulator of whole-body metabolism. Stress hormones target different types of fat differently; they seem to particularly target fat around our abdomen, but we don’t fully understand why. Not all fat is bad, she says. Unlike harmful white fat, brown fat is packed with energy-producing mitochondria. The presence of brown fat is also associated with lower amounts of central body fat and a lower likelihood of diabetes. “Learning more about how stress hormones target different types of fat may give us insight into how to prevent or manage the onset of chronic diseases such as obesity and Type 2 diabetes,” she says.
Bariatric surgery used to be the only effective treatment for permanent weight loss, but Lewis says it is invasive, risky and associated with long-term complications. It likely will be phased out as medical therapies for obesity improve. There are now two medications that help people lose a significant amount of weight safely. One mimics GLP-1, a gut hormone that slows digestion, lowers blood sugar, suppresses appetite, reduces weight and protects the heart. The other is a SGLT2 inhibitor, which also lowers blood sugar and protects the heart, although weight loss is often more modest.
There are also diabetes initiatives across the country. Diabetes Action Canada, under Lewis’s direction, is a national consortium of more than 100 researchers. The group teams up with people living with diabetes and their caregivers to learn how to prevent diabetes and its complications and to improve patient care in a variety of ways.
Even after 100 years, there is still no cure for diabetes. But Lewis is hopeful one is on the way. Meanwhile, treatments continue to improve dramatically. “If you develop diabetes in 2021, your life and your life expectancy are completely different than they would have been in 1921,” he says. “It’s a very exciting, very hopeful time.”
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Igniting a Century of Discovery
U of T and its partner hospitals have built a culture of innovation that has brought about major advances in health care. Here are some of the most important discoveries made by doctors and scientists affiliated with U of T in the past 100 years.
Frederick Banting and Charles Best discover insulin
The discovery of insulin spurs growth in Connaught Laboratories and public health education, leading to the creation of U of T’s School of Hygiene
Leone Farrell’s research makes possible the large-scale production of the polio vaccine
Wilfred Bigelow develops the first electronic heart pacemaker
James Till and Ernest McCulloch discover the blood-forming stem cell, which becomes the basis for regenerative medicine
Vera Peters revolutionizes the way we approach cancer treatment by showing that treating early-stage breast cancer with lumpectomy and radiation is just as effective as radical mastectomy
David Jenkins develops the Glycemic Index, which enables people to manage their blood sugar level through diet
Tak Mak helps to identify the T-cell receptor gene, a major advance in understanding the body’s immune system
Dan Drucker identifies the role of gut hormone GLP-1 in control of insulin secretion, eventually leading to new drugs to treat diabetes
Alan Hudson and Susan Mackinnon perform the first nerve transplant
John Dick identifies cancer stem cells
Derek van der Kooy uses stem cells to restore sight in blind mice
Milica Radisic becomes the first to use electrical pulses to turn stem cells into mature cardiac cells, signalling a significant advance in tissue engineering