Start-Up Developing First Drug to Prevent Hypoglycemia

For people with diabetes, the goal in managing the disease is to mimic the normal changes in blood sugar caused by eating, fasting, exercising and stress.

Intensive treatments lower the likelihood of severe diabetic complications that can affect cardiovascular health, kidney function and lead to blindness and a type of chronic pain known as neuropathy. They can also raise the risk of low blood sugar episodes known as hypoglycemia, which can lead to confusion and make ordinary, daily activities more difficult. In severe cases, hypoglycemia can cause brain damage or even death.

Right now, the only available treatments are used once a person is already suffering from low blood sugar. But research led by Professor Emeritus Mladen Vranic, an active member of the Department of Physiology, is making possible the first drug therapy that can prevent hypoglycemic episodes in people with insulin-dependent diabetes. Vranic explained to writer Erin Howe how his team is working to move the findings out of the lab through start-up Zucara.  

Why is finding new ways to prevent low blood sugar so important?

I have worked in the diabetes field for over 50 years. In order to prevent diabetic complications, insulin treatment is much more intense than it used to be. As a result, incidents of low blood sugar occur frequently and the impact is huge. These episodes can lead to brain damage or even death.

Insulin is often the first hormone that comes to mind when people think about diabetes, but there are other important hormones that help regulate blood sugar in diabetes. One is glucagon, which regulates glucose production (sugar) by the liver, especially when the muscle requires more energy, depending on food intake, exercise, stress and sleep. The other hormone is somatostatin, which can inhibit insulin and glucagon. My research team found that pancreatic cells, which secrete glucacon are impaired in diabetes by high somatostatin levels.

How are you translating your research into potential new therapies?

In my lab, we started a new project that uses a drug that can prevent low blood sugar incidents in different models of diabetic rats. It does this by using novel molecules to block the activity of that third hormone involved in diabetes—somatostatin — to restore the glucagon response. Our new company, Zucara Therapeutics, hopes to bring in enough support to start investigating diabetic patients, particularly those who are especially prone to low-blood sugar attacks. Using the new drug should allow insulin treatment to be intensified so that diabetes complications are fully prevented.

How did you move to transform your research into the basis for a start-up company?

With help from MaRS, U of T and The Centre for Drug Research and Development (CDRD) in Vancouver, we developed a plan on how to proceed with transforming our drug for health benefit. Professor Michael Riddell’s laboratory at York University’s School of Kinesiology and Health Science and researchers with CDRD are continuing experiments in rats to investigate whether the drug has any adverse side effects and the dynamics of the new drug. An important goal is to find out how often such a drug needs to be given to the patients.

How has your Zucara grown since it was established and what’s next for the company?

We’re advancing novel technology that shows promise to become a long-term therapeutic approach to prevent low blood sugar in people with diabetes that are insulin-treated. We’re planning to do further experiments in diabetic rats and starting investigation in diabetic patients.

What makes you passionate about this work?

Diabetes is increasing throughout the world and after cardiovascular disease and cancer, it is the main cause of premature death. We are all passionate about the possibility of a major breakthrough in treating diabetic patients. I also have a personal interest because my father died of diabetic complications.

Tell us about the people at U of T who’ve mentored or inspired you.

I was the last post-doctoral fellow of the late Professor Charles Best, who together with Professors Frederick Banting, John Mcleod and Bertram Collip, discovered insulin and saved millions of lives. Best inspired me with his passion and it was wonderful to work in his institute with a number of superb researchers.

I also met many researchers who were visitors, or worked at the Best Institute for some time. This increased my exposure to learning about the pathogenesis of diabetes, its complications, and possibilities for treatment. I was also lucky to collaborate with molecular and cell biologists and physiologists since Toronto has the largest diabetes center, worldwide.

You’ve worked with world-renowned scientists, and your own contributions to research have also garnered a lot of recognition.

I’ve been lucky to be honoured for my work in the field by being appointed Officer of the Orders of Canada and Ontario. I was also inducted as a Laureate into the Canadian Medical Hall of Fame and hold honorary degrees from the University of Toronto, University of Saskatchewan, McMaster University, Karolinska Institute and the University of Zagreb. I was very fortunate to receive the main diabetes lectureships and awards, worldwide. The most important are the American Diabetes Association’s Banting Award for research and the Renold Award for mentoring and the American Physiological Society’s Solomon Berson Award.  I am also a fellow of the Royal Society of Canada (RSC) and the Canadian Academy of Health Sciences (CAHS) and the Croatian Academy of Arts and Science.