Insulin 100: U of T researchers work on novel drug therapies for diabetes, other illnesses

In the 100 years since Frederick Banting and Charles Best discovered insulin as a treatment for diabetes, the process of drug discovery has changed radically – from lab equipment to techniques and technology.

But pharmaceutical scientists’ drive to develop life-saving drugs remains as strong as ever.

“Insulin is a phenomenal example of how important drug discoveries can change the lives of people all over the world,” says Lisa Dolovich, dean of the University of Toronto’s Leslie Dan Faculty of Pharmacy.

“We’re really proud to be working on therapeutic discovery and new diagnostics that we hope will also have significant impacts on people’s health and quality of life.”

Whether focused on diabetes or other conditions, researchers at Leslie Dan are part of a culture of innovation and discovery inspired by Banting and Best that benefits from the faculty’s breadth of expertise and research approaches.

“It provides new opportunities and new ways of thinking to infuse our different labs because people can learn from one another,” says Dolovich. “And, of course, we benefit from having students who have been educated in different areas, all coming together in pharmaceutical sciences.”

Here are five researchers at the Leslie Dan Faculty of Pharmacy who are pushing the boundaries when it comes to drug treatments for diabetes and other diseases:

Understanding mechanism of drug-induced diabetes may lead to new treatments

One of the first stages of drug discovery is understanding cellular pathways and what goes wrong in different conditions in order to find ways to counteract these effects.

“Part of my research is trying to discover new drug targets and then collaborating with chemists to make small molecules that we hope might eventually be turned into therapeutics,” says Carolyn Cummins, an associate professor at the Leslie Dan Faculty of Pharmacy. “This drug discovery research is central to the pharmaceutical sciences.”

Cummins studies how glucocorticoids – stress hormones that are often prescribed as anti-inflammatory drugs – cause drug-induced diabetes. These drugs activate a receptor in the liver that stimulates the body to produce glucose, and, if they are taken chronically, predispose patients to conditions such as obesity and diabetes.

Her work focuses on the nuclear receptors involved in the glucocorticoid signalling pathways. A better understanding of how these signalling pathways work and what happens when they are overstimulated may suggest new drug targets and a way to dose the anti-inflammatories to avoid this side effect.

Although her work is at the early stages of drug discovery, she says her research is still informed and broadened by considering the patient perspective.

“As pharmaceutical scientists, we have the capacity to learn about the patient perspective because we have access to front-line clinicians and pharmacists,” she says.

Clinical collaborations key to moving research forward

Interacting and collaborating with clinicians is a key element of Shana Kelley’s research, enhancing her ability to make new breakthroughs and allowing her to see first-hand the challenges related to curing disease. 

“If you go to see a collaborator at a hospital, you cannot miss seeing the people who are there to receive care,” says Kelley, a University Professor. “We have a very collaborative clinical community in Toronto, and it is such a huge resource for people like me, but it also keeps the patients top of mind.”

Kelley and her team develop technologies that use molecular biology and nanotechnology to detect and diagnose disease – and look for drug targets in large volumes of sample – and they frequently collaborate with clinicians to access patient samples. Much of their work has focused on systems that scan large populations of cells to look for specific genetic sequences or mutations, which can be used for early detection of diseases such as cancer.

Kelley’s team isn’t focused on a single disease. They apply their expertise to solve problems that apply to different types of conditions.

“Pharmaceutical science is a broad field, and it’s very inclusive,” says Kelley. “In our faculty, we feel really strongly about solving critically important problems, and so it has a culture that lends itself to discovering new things and developing new technologies.”

The focus on applying discoveries to solve problems is a particular strength of the Leslie Dan Faculty of Pharmacy, according to Dolovich.

“We see beyond the boundaries of one medical area or one condition and look at these problems from the drug perspective or from the device perspective,” she says. “We can build on discoveries that have happened within the context of one medical condition [so it can be] considered for others.”  

Drug delivery technologies for improving patient health

Professor Shirley Wu and her team develop new drug delivery technologies to ensure drugs reach their intended targets in the body.

The research is multidisciplinary and can be applied to many different diseases, so collaborations with experts in these diseases is essential.

“A lot of work can’t be done with just one lab,” says Wu. “We have the technology to improve drug delivery, but we need other people’s expertise to understand the biology and assess what we develop.”

Wu’s team has led work relating to a number of conditions, including cancer, diabetes and Alzheimer’s disease.

To improve insulin therapy in diabetes, her team has studied intelligent insulin delivery over the last two decades. Recently, they developed a “smart” microneedle patch to help people with diabetes manage hypoglycemia, a potentially dangerous complication of insulin therapy. The patch senses low blood sugar levels and, in response, automatically releases the hormone glucagon, which raises blood sugar levels. The non-invasive and painless device is currently in preclinical development.

Wu says that her team approaches research with the intent to make a difference for patients.

“We want to improve patient care, their health and their lives,” says Wu. “After we published the first paper on the microneedle patch, we received multiple emails from patients and relatives asking when and where we were going to run clinical trials. This is an in-demand treatment, which motivates us to work harder and faster toward clinical use.”

Advanced biologics may help treat complications of diabetes

When insulin was discovered 100 years ago, it was the world’s first biologic treatment that used a protein to treat disease. A century later, researchers at U of T are also developing advanced biologics to help treat conditions such as diabetic retinopathy, an eye condition that can cause vision loss and blindness that affects about a third of people with diabetes.

An impermeable physiological barrier in blood vessels around the eye – the blood-retina barrier – protects the eye from molecules circulating the body through the blood. But in diabetes, high blood sugar levels cause the barrier to “leak,” damaging the retina and causing blindness.

“Right now, there are limited drugs to treat diabetic retinopathy and they don’t work for everyone, so there’s an urgent need to develop other medications that could benefit patients,” says Stéphane Angers, professor and associate dean of research. “We’re developing a biologic that uses a completely different mechanism than the existing treatment, and our preclinical research shows that this biologic is very powerful for promoting barrier function.”

Angers and his team developed an antibody that regulates a signalling pathway involved in blood-retina barrier function in order to strengthen the barrier. To help bring this biologic treatment to the clinic, he has launched a start-up company to complete the preclinical work, and he hopes that the drug will be ready to start clinical trials within a couple of years.

“Our Toronto-led effort to develop a biologic for people with diabetic retinopathy follows the legacy of Banting and Best,” says Angers. “Being in a drug discovery ecosystem, we’re ideally positioned at the [Leslie Dan Faculty of Pharmacy] to develop new drugs and translate our research into drug therapies.”

Clinical experience informs drug discovery process

Just as researchers aim to move discoveries into the clinic, clinician-scientists also bring their front-line perspectives back to drug discovery.

“Because we have health professionals and students learning and working alongside those who are focused on scientific discovery, we can cross the bridge from drug discovery to health care,” says Dolovich. “It allows us to think about how new drug discoveries are going to impact patients and their care and the professionals who deliver that care. All that information feeds back into the drug discovery process.”

Marisa Battistella is a pharmacist and clinician-scientist specializing in chronic kidney disease (CKD). “People with diabetes are at higher risk for other conditions, including CKD, and often take many different types of medication, which may result in drug interactions,” she says.

Battistella’s research focuses on pharmacy practice, including using genomics to guide drug selection and optimizing patient medications, which may also include de-prescribing.

She says having clinical and basic scientists working together helps to spur innovation in drug discovery.

“Clinician-scientists and basic scientists are all trying to improve patient care – that’s our ultimate goal. Having these collaborations is really important and they can inform each other in ways to improve research and patient care,” she says. “I have the relationships at the hospital to roll out discoveries made in the lab, but we can also explain to researchers at the faculty how we translate research or clinical studies into practice.”

Battistella is also active in education, not only as a course instructor and co-ordinator, but also serving as a preceptor and mentor. “Students often ask really good questions or they dig deeper into a particular disease or medication,” she says. “Their questioning minds help inform my thinking and help me to think deeply and consider ideas or research questions we could pursue.”

With nearly four million Canadians living with diabetes and this number projected to grow over the coming years, U of T students studying both pharmacy and pharmaceutical sciences will play active roles in improving diabetes care in the future, says Dolovich.

“We’re proud that we graduate pharmaceutical scientists and pharmacists who will be in a position to help people with diabetes, whether it’s in community pharmacy, in hospital, or research settings,” she says. “We do our best to prepare our students to take up the challenge and contribute as integral members of the health-care team.”