Diabetes

Dalla Lana School of Public Health

Artificial Intelligence

Sunnybrook Health Sciences

Women's College Hospital

A team of researchers at the University of Toronto and its partner hospitals are working on a way to deploy artificial intelligence to predict diabetes risks in patients.

Jay Shaw, a scientist at Women’s College Research Institute and an assistant professor in the department of physical therapy in U of T’s Temerty Faculty of Medicine, co-leads a team that was recently awarded more than $900,000 in funding over three years from CIFAR (Canadian Institute for Advanced Research) to develop a novel framework for the responsible deployment of machine learning models to predict diabetes risk in Ontario’s Peel region, one of the largest and most diverse communities in Canada.

The project, co-directed by epidemiologist Laura Rosella, a professor at the Dalla Lana School of Public Health, has developed models that use routinely collected data in the health system to help predict diabetes onset up to five years before a diagnosis.

“Our team developed and validated models that can predict diabetes incidence and complications in advance,” Shaw says. “These models have already been validated, meaning that their performance for accomplishing their goals of predicting diabetes onset and complications has already been established, allowing us to focus on how best to implement these models so that they are used effectively and responsibly.”

Shaw, Rosella, and their team will use these models to build a dashboard that can be used by health system decision-makers to plan health system interventions that address diabetes-related prevention needs and bridge gaps in health equity by identifying high-risk populations.

Peel region was selected as a site to deploy the models because it’s an area where the burden of diabetes is high, with a 2015 diabetes incidence rate of 1,192 per 100,000 – an increase of 182 per cent since 1996, according the region’s 2019 health status report. Peel also has a diverse population where 51 per cent of residents are immigrants and 62 per cent identify as a visible minority.

It is estimated that by 2030, nearly 14 million Canadians will have either diabetes or pre-diabetes. This is expected to cost health systems nearly $5 billion. The complexity of the disease progression and diagnostics, along with increasing health disparities based on socioeconomic factors, has led to worse rates and outcomes for marginalized populations.

The researchers hope the framework they develop will help decision-makers better understand how they can responsibly use resources to improve prevention and diagnosis of the disease and, in turn, improve health outcomes.

Class of diabetes drugs cuts dementia risk in older adults, research shows

lanthierj — Wed, 14 Dec 2022 17:52:21 +0000

Class of diabetes drugs cuts dementia risk in older adults, research shows

lanthierj Wed, 12/14/2022 - 12:52

Cutline

(photo by Yiu Yu Hoi/Getty Images)

Erin Howe

Topic

Breaking Research

Graduate Students

Dalla Lana School of Public Health

A class of medication for Type 2 diabetes may help older people with the condition reduce their risk of dementia.

The findings are contained in a new study by Walter Swardfager, an assistant professor of pharmacology and toxicology at the Temerty Faculty of Medicine and a scientist in the Sandra Black Centre for Brain Resilience and Recovery at Sunnybrook Research Institute, and graduate student Che-Yuan (Joey) Wu.

Their research shows sodium-glucose cotransporter-2 (SGLT2) inhibitors are associated with a 20 per cent lower dementia risk when compared to another kind of medication known as dipeptidyl peptidase-4 inhibitors (DPP4).

Often, the first medication prescribed to people with Type 2 diabetes is metformin. When metformin alone doesn’t have the desired effect, additional therapies such as SGLT2 and DPP4 inhibitors, may be added or substituted. For many patients, physicians will choose between these two classes of drugs.

SGLT2 inhibitor medications, which include dapagliflozin and empagliflozin, are commonly prescribed. These drugs lower blood sugar by causing the kidneys to remove sugar from the body through urine. DPP4 inhibitor medications – which include linagliptin, saxagliptin and sitagliptin – work by blocking the action of an enzyme that destroys an insulin-producing hormone.

“The beautiful thing is that some diabetes medications, including the SGLT2 inhibitors, might manipulate the pathophysiology at an early stage before dementia develops,” says Swardfager. “We hope this strategy could prevent dementia for a group of people who are most vulnerable.”

From left: Walter Swardfager and Che-Yuan (Joey) Wu (photo by Erin Howe)

The study, published in the journal Diabetes Care, looked at more than 106,000 people aged 66 years and older. To make their observations, the researchers examined Ontario health records for people who were newly prescribed one of either kind of medication and who hadn’t previously experienced dementia. Then, they compared incidences of dementia between the two groups over a period of nearly three years.

They identified incident cases of dementia by hospitalization with a dementia-related diagnosis, three physician claims for dementia within a specified time frame, or by the prescription of a medication used to slow cognitive decline.

Though scientists don’t fully understand why, diabetes is known to increase a person’s risk of dementia, including vascular dementia and Alzheimer’s disease, by as much as two times.

The most common types of dementia involve deposits of abnormally folded proteins, as well as metabolic and vascular changes, in the brain.

Diabetes is known to damage blood vessels throughout the body, especially the small vessels, says Swardfager. The condition may also impair the brain’s smallest vessels.

“Under the current clinical guidelines, physicians have limited options to slow cognitive changes or lower the risk of dementia in people with diabetes,” says Wu. “Now, we have a potential candidate to help intervene in this process.”

The team next hopes to explore a newer class of diabetes drug called glucagon-like peptide-1 receptor agonists. Those drugs also have shown some promise for having brain benefits.

Wu and Swardfager hope to determine whether the benefits of particular drugs might be greater for certain individuals, and how this might contribute to personalized therapy or co-therapy with other medications to slow down dementia.

Swardfager is also excited by the potential for further studies that could help unlock some of dementia’s most complex mysteries.

“If we can give medications for diabetes early enough to protect the brain, it might have a real impact on an individual's trajectory,” says Swardfager. “Knowing which drugs show benefit may also offer new insights into how dementia begins and progresses in living people.”

This research was supported by funding from the Canadian Institute of Health Research, the Natural Sciences and Engineering Research Council of Canada, the Alzheimer’s Association, Brain Canada, the Weston Brain Institute, Alzheimer’s UK, the Michael J. Fox Foundation and the Canada Research Chairs Program.

Public health researchers use telemedicine to manage diabetes and hypertension in rural Pakistan

geoff.vendeville — Wed, 02 Mar 2022 15:56:15 +0000

Public health researchers use telemedicine to manage diabetes and hypertension in rural Pakistan

geoff.vendeville Wed, 03/02/2022 - 10:56

Cutline

A Rural Health Center clinic in Khalaspur. ��οresearchers in public health are using telemedicine to manage chronic conditions like diabetes and hypertension (photo courtesy of RHC)

Heidi Singer

Topic

Breaking Research

Researchers at the University of Toronto's Dalla Lana School of Public Health (DLSPH) are working to implement telemedicine for managing diabetes and hypertension in rural Pakistan – care that is urgently needed to replace traditional services disrupted by the COVID-19 pandemic.

Amid the chaos and calamity of COVID-19, the potential for telemedicine is finally being realized in health care and health systems around the world. The DLSPH team is hoping to learn whether specialists in Pakistani cities can use it to support health providers on the ground, not just to re-establish care but to provide even better treatments than they offered pre-COVID-19.

Xiaolin Wei

“Pandemics will teach us how to adopt new technologies to remote care,” says Xiaolin Wei, an associate professor at DLSPH, epidemiologist and global health policy scientist leading the study. “Remote management will be the future of health care – especially for primary care which has a low capacity in low- and middle-income countries (LMICs). There is a great potential for chronic, serious diseases like diabetes and hypertension as they are the rising burden of disease in LMICs.”

In many parts of Pakistan, care for chronic diseases has fallen apart, Wei says. The country suffers high rates of diabetes and hypertension, and once patients begin to improve, they sometimes discontinue treatment because it's too expensive.

As a result, Wei hopes to improve not just care but patient education. The team is using new technologies such as ECHO training platform to allow senior physicians based in Karachi to train and mentor nurses and other health providers in rural parts of the Punjab, and to see patients directly via video. Patients will also have access to a mobile app to monitor their blood pressure, blood sugar and medications.

The project is co-led by Dr. Amir Khan, the head of Pakistan’s Association of Social Development and an award winner in leading health policy changes.

“The development of telemedicine in LMICs and the progress we have made has been exponential,” says Hammad Durrani, the project manager and a PhD student at the Institute of Health Policy, Management and Evaluation (IHPME). “What we have achieved in the past two years of COVID-19 in terms of digital health diffusion and adoption is equivalent to the development of the past 20 years globally. Patients and providers are more willing and governments have fast-tracked the regulatory paperwork.”

Hammad Durrani

The disruption offers a chance to “reinvent virtual and hybrid virtual/in-person care models, with a goal of improved health-care access, outcomes, and affordability,” he says.

For the current project, the ��οresearch team will focus on the most vulnerable patients first, and will also offer remote COVID-19 education and treatment. They believe their learnings will help to combat the same diseases among South Asian and other populations in Ontario, in regions such as Peel.

“Globally, we have seen that due to COVID-19, care for other diseases such as heart diseases, diabetes and cancers has been delayed,” says Durrani. “This stands true for Canada also, where we see patients [who] are struggling to get access to care for conditions like mental health and heart disease. At the moment, telemedicine is not part of our usual treatment delivery options, especially for specialist care. Our model is definitely something to think about even for a developed country like Canada to improve access to quality health care.”

Patients today appear more open to telehealth, and more interested in health overall, says Wei. He argues that the disruption of the pandemic has opened new opportunities to deliver medicine differently.

“I can see health literacy has been raised up, even in remote areas of developing countries,” Wei says. “The pandemic has raised people’s interest in their own health. That could open opportunities for us to measure disease and improve outcomes even in places where it has been difficult.”

The research is supported by a grant from the Canadian Institutes of Health Research.

Insulin 100: Parks Canada unveils commemorative bronze plaque at U of T

rahul.kalvapalle — Fri, 12 Nov 2021 20:15:21 +0000

Insulin 100: Parks Canada unveils commemorative bronze plaque at U of T

rahul.kalvapalle Fri, 11/12/2021 - 15:15

Cutline

Christine Allen, U of T’s associate vice-president and vice-provost, strategic initiatives, and Christine Loth-Brown, vice-president, Indigenous Affairs and Cultural Heritage, Parks Canada, unveil the plaque (Photo by Johnny Guatto)

Topic

Myhal Centre for Engineering Innovation & Entrepreneurship

Toronto General Hospital

One hundred years ago this month, scientists at the University of Toronto and its partner hospitals carried out the first studies that demonstrated the ability of insulin to lower blood sugar levels in animals and prevent their death from diabetes.

Three months later, insulin was successfully administered to a person with type 1 diabetes at Toronto General Hospital. His life would become the first of millions around the world to be saved by insulin – one of the landmark medical discoveries of the 20^th century.

On Friday, the historical significance of the discovery was marked by the unveiling of a commemorative bronze plaque at a ceremony hosted by Parks Canada and the Historic Sites and Monuments Board of Canada (HSMBC) at the Myhal Centre for Engineering Innovation & Entrepreneurship on U of T’s St. George campus.

The event was attended by government dignitaries including Sonia Sidhu, member of parliament for Brampton South. The final location of the plaque, which is inscribed by bilingual text, will be determined at a later date.

“The story of insulin is a brilliant example of the power of collaboration – in this case, how a university, its hospital partners and a pharmaceutical company could work together and change the world,” said Christine Allen, U of T’s associate vice-president and vice-provost, strategic initiatives.

“On this illustrious foundation, ��οand its hospital and industry partners built a culture of discovery, innovation and collaboration that has transformed health care and continues to have a ripple effect worldwide.

From left: Patricia Brubaker, Richard Alway, Sonia Sidhu, Christine Allen, Christine Loth-Brown and Lynn Wilson (photo by Johnny Guatto)

The ceremony marked the culmination of Insulin 100, a year-long campaign to mark the centenary of insulin’s discovery and celebrate a legacy of health innovation that continues to be advanced by ��οand its partner hospitals, research institutes and industry partners.

“The Parks Canada plaque not only serves as a fitting reminder of the critical research discoveries made here at ��ο– it will also inspire future trainees and researchers whose work will be pivotal in the health research discoveries made over the next hundred years,” Allen said.

Patricia Brubaker, a professor in the departments of physiology and medicine at the Temerty Faculty of Medicine and member of the faculty’s Banting & Best Diabetes Centre, described the key areas of diabetes research being investigated by ��οfaculty and students today.

“Our interests cover the spectrum of diabetes research, including not only type 1 diabetes, but also type 2 diabetes, which is now reaching epidemic levels, affecting one in six Canadians, as well as gestational diabetes or diabetes during pregnancy,” said Brubaker, who has been conducting diabetes research for four decades.

“We are studying the causes of diabetes through research into obesity, a major risk factor for type 2 diabetes; we are interrogating new approaches to the treatment of diabetes, including stem cell replacement therapy and new pharmacologic treatments; and our researchers are exploring the fundamental mechanisms that underlie the normal regulation of glucose and fat metabolism and how this is disrupted in diabetes, leading to long-term complications such as kidney and cardiovascular disease.”

Brubaker also reflected on the impact of insulin and diabetes research on her own life. As a person living with type 1 diabetes, she noted she is “one of legions who would not be alive today without the discovery of insulin.”

In addition to saving countless lives, the discovery of insulin helped establish U of T, its partner hospitals and Toronto more generally as a vanguard of diabetes research and treatment.

In April, some of the latest developments in the field were discussed at the Insulin100 conference, a two-day virtual symposium that drew over 6,000 attendees from around the world.

Also in April, U of T’s Banting & Best Diabetes Centre and Diabetes Action Canada hosted “100 Years of Insulin – Celebrating its Impact on our Lives,” a public celebration and forum featuring an array of topics of interest to people living with diabetes.

It was at this public celebration that Canada Post unveiled a special stamp to commemorate the discovery of insulin. The stamp, which depicts a vial of insulin resting on an excerpt from Banting’s unpublished memoirs, was unveiled from the Banting House National Historic Site of Canada in London, Ont. – in the very room where Banting first got the idea that eventually led to the discovery of insulin. Brubaker and Scott Heximer, chair of the department of physiology at the Temerty Faculty of Medicine and a principal investigator at the Ted Rogers Centre for Heart Research, worked with Canada Post and Banting House to ensure the stamp’s historical accuracy and help source archival material.

The stamp would be the first of several commemorations to mark the place of insulin in the cultural tapestry of Canada’s heritage.

In May, Historica Canada released a Heritage Minutes segment paying tribute to the discovery. The segment depicts the plight of 13-year-old diabetes patient Leonard Thompson, and the efforts of Banting and Best to formulate and refine the insulin treatment that ultimately saves Thompson’s life. Again, experts from ��ο– including science and medicine librarian Alexandra Carter, archivist Natalya Rattan and medical historian Christopher Rutty – were consulted on the project to ensure historical accuracy.

In July, the Royal Canadian Mint issued its own commemoration in the form of a two-dollar coin depicting a monomer (a building block of the insulin molecule), insulin cells, blood cells, glucose and the scientific instruments used in early formulations of insulin.

The importance of insulin was recognized almost immediately after its initial discovery. In 1923, the Nobel Prize in Physiology or Medicine was awarded to Frederick Banting and James McLeod, who isolated insulin in U of T’s department of physiology. The prize was shared with physiology and biochemistry student Charles Best and biochemist James Collip.

��οresearchers continue to be recognized for their stellar work in advancing diabetes research.

Brubaker was honoured last year with a Lifetime Achievement Award from Diabetes Canada, a recognition of her longstanding contribution to diabetes research and the Canadian diabetes community. And, earlier this year, Daniel Drucker, professor of medicine in the Temerty Faculty of Medicine and a senior investigator at the Lunenfeld-Tanenbaum Research Institute at Sinai Health, was awarded a Canada Gairdner International Award for research on glucagon-like peptides that has helped revolutionize treatments for type 2 diabetes – an honour he shared with collaborators at Harvard University and the University of Copenhagen.

'A Swiss Army knife': Daniel Drucker bets the gut hormone GLP-1 can be used to treat far more than diabetes

Christopher.Sorensen — Wed, 03 Nov 2021 14:28:07 +0000

'A Swiss Army knife': Daniel Drucker bets the gut hormone GLP-1 can be used to treat far more than diabetes

Christopher.Sorensen Wed, 11/03/2021 - 10:28

Cutline

A pioneer of gut hormone research that led to therapies for type 2 diabetes, obesity and short bowel syndrome, Daniel Drucker is investigating whether the same hormones can help treat everything from heart disease to Alzheimer's (photo by Johnny Guatto)

Brianne Tulk

Topic

Mount Sinai Hospital

Research & Innovation. Faculty of Arts & Science

Daniel Drucker is unraveling a medical mystery.

Drucker, a professor in the department of medicine at the University of Toronto’s Temerty Faculty of Medicine and a senior scientist at the Lunenfeld-Tanenbaum Research Institute at Sinai Health, has pioneered research on gut hormones that has led to life-changing therapies for people with type 2 diabetes, obesity and short bowel syndrome.

Now, Drucker’s lab is studying how these same hormones work in the context of other conditions throughout the body, which could result in treatments for an even wider variety of diseases.

Drucker, an inductee to the Canadian Medical Hall of Fame and winner of the Canada Gairdner International Award, is most well-known for his contributions to the discovery of glucagon-like peptides (GLP-1 and GLP-2), gut hormones that help control insulin and balance blood sugar levels, and for the development of related therapies for diabetes, obesity and intestinal failure.

Yet, beyond conventional metabolism, drugs based on GLP-1 can also reduce plaque formation in arteries, or atherosclerosis, and control inflammation in several organs. Plaque and inflammation are linked to heart attack, stroke and other cardiovascular diseases – some of the leading causes of death in people with type 2 diabetes and obesity.

The drugs also show promise for treating liver disease and Alzheimer’s disease.

In a study recently published in JCI Insight, Drucker’s research team investigated the role that specific GLP-1 receptors play to make GLP-1 drugs effective against cardiovascular and liver disease in the aorta and liver of mice.

In the first half of the study, Drucker’s team saw that the GLP-1 drug reduced plaque in the arteries, but the presence or lack of the GLP-1 receptor in blood vessel and immune cells in the aorta did not play a role.

“We’ve ruled out the importance of receptors in these cell types, but we still don’t fully understand how GLP-1 reduces atherosclerosis," says Drucker.

This negative result was valuable, but the second story the paper told was more novel.

The mice developed fatty liver disease, liver fibrosis and liver inflammation through the same high-fat diet that triggered plaque development in their arteries. The researchers saw that the mice with GLP-1 receptors in specific cells in their livers responded well to the GLP-1 drugs, whereas the “knockout” mice without the GLP-1 receptor in these cells did not – despite both groups losing weight as an effect of the GLP-1 drug.

This outcome suggests that even though weight loss has conventionally been important for GLP-1 action to reduce fat and inflammation in the liver, it may not be the whole story. In, fact GLP-1 may reduce liver inflammation through mechanisms independent of weight loss.

“This paper is the first to show that even though weight loss is the same in both groups of animals that we studied, the animals that were missing the GLP-1 receptor in the immune cells in the liver did not have the same therapeutic benefit,” Drucker says. “It's really the first paper to show that there's another element to the story of how GLP-1 works in the liver.”

GLP-1 drugs are already in phase three trials to treat liver diseases such as non-alcoholic steatohepatitis, a more aggressive form of fatty liver disease. So, it was not surprising for the researchers to see that mice treated with GLP-1 drugs saw reduced liver inflammation.

But Drucker said it was exciting to identify GLP-1 receptors in specific immune cells in the liver, which may be necessary to get the full therapeutic effects of GLP-1 drugs to treat fatty liver and liver inflammation. This finding could lead to more targeted and effective treatment options.

Overall, the study is another piece in the puzzle of how GLP-1 works in different areas of the body. But researchers still need a better understanding of how GLP-1 drugs produce their multiple therapeutic benefits in treating diseases.

“If I could figure out how GLP-1 reduces heart attacks and strokes, and I knew where that magic was happening, maybe we could make even better, more targeted GLP-1 therapies to produce more effective medicines,” Drucker says.

Drucker credits his background as a clinician scientist for bringing the perspective of patients and their unmet medical needs into his research. Although he hasn’t been directly involved in patient care for 12 years, he calls his training as a physician and a clinician scientist the “secret sauce” to his research.

“What clinician scientists are really good at is asking the important questions that are directly relevant to human disease,” he says. “I’ve always tried to ask questions that are not just interesting for the sake of basic science, which is important by itself, but also questions that might inform how disease pathophysiology and drugs work clinically.”

He says that what makes the GLP-1 story so exciting is that physicians are able to treat diabetes and obesity by conventionally lowering blood sugar or bodyweight, but also by attacking cardiovascular risk, the number-one cause of death these patients face.

“Until recently, there haven't been therapies that go beyond lowering blood sugar or reducing bodyweight to actually show there's a reduction in death,” Drucker says. “GLP-1 therapies are changing the natural history of these diseases.”

Improved disease outcomes may soon extend to other conditions. Emerging data suggest that GLP-1 drugs have an anti-inflammatory effect to treat a wide variety of diseases, and the next frontier could be Alzheimer’s disease now that GLP-1 drugs targeting the condition recently entered phase three trials.

Drucker says that if GLP-1 drugs work to treat Alzheimer’s, it would likely reflect a combination of neuroprotection, improved brain metabolism and reduction of inflammation associated with the condition, which could also improve cognition and slow the course of disease.

“Whether it’s in the pancreas, blood vessels, the liver, or the brain, increased inflammation is a driving component of the pathology of all kinds of different diseases,” he says. “I believe that one reason GLP-1 is the Swiss Army knife of metabolism – that it can do so many different things in so many different organs – is its ability to reduce inflammation.”

Exactly how that happens, however, is still shrouded in mystery, Drucker says.

“There’s a huge amount of uncertainty as to how GLP-1 controls inflammation in different organs in the body, and that’s a major focus for our lab right now.”

Cloaking technology: Helping therapeutic cells evade your immune system

lanthierj — Fri, 08 Oct 2021 10:57:51 +0000

Cloaking technology: Helping therapeutic cells evade your immune system

lanthierj Fri, 10/08/2021 - 06:57

Cutline

Andras Nagy (Photo provided by Sinai Health Foundation)

Paul Fraumeni

Topic

Breaking Research

Institute of Biomedical Engineering

Institutional Strategic Initiatives

Toronto General Hospital

Medicine by Design

Mount Sinai Hospital

University Health Network

Stem Cells

Stem cell pioneer Andras Nagy has a way of describing the work of your immune system: “It’s surveillance inside our body.”

That surveillance does us good when harmful bacteria or viruses enter our body. The immune system releases fighter cells to kill the invaders.

But regenerative medicine therapies often involve transplanting tissues or cells into a person. When new heart or pancreatic cells are transplanted, for example, the immune system will see these good things as enemies and reject them. Drug treatment can be used to suppress this immune response, but it can leave the person open to serious infection.

Nagy, a professor in the department of obstetrics and gynaecology at the University of Toronto's Temerty Faculty of Medicine and a senior investigator at Sinai Health System’s Lunenfeld-Tanenbaum Research Institute, and his research team have been experimenting with a process called “cloaking,” which he believes could be used to hide therapeutic cells from the immune surveillance system and allow them to do their good work.

Though this research will one day be applicable to all cell therapies, Nagy’s team is currently testing the cloaking technology with insulin-secreting pancreatic cells that are made from stem cells and could be a powerful cell therapy for type 1 diabetes.

Stem cells are cells that can be reprogrammed and turned into an unlimited source of any type of human cell needed for treatment. Nagy notes that the first years of stem cell research were at the basic science level, as scientists worked to understand the nature of stem cells. He says about 10 years ago, there was a notable shift to what he calls “translational” research. His work is part of this wave of applied science; in fact, in 2015 he co-founded a biotech company, panCELLa Inc., to make his cell technologies widely available.

“Regenerative medicine is at a point now where we can translate our research into therapies that can help all humankind,” he says.

The Canada Research Chair in Stem Cells and Regeneration, Nagy says that researchers have long known that transplanted cells and tissues can be attacked by the immune system.

“We wondered if there was a way to hide or ‘cloak’ these good cells, so the immune response wouldn’t destroy them,” says Nagy. “But before we could move into that we had to deal with a significant hurdle – the safety of the implanted cells.”

Nagy points out that when these new cells are created, there is a chance they could mutate and become cancerous. The more cells needed for a therapy, the more cell divisions that take place, meaning a higher chance of mutation and cancer.

In earlier research, partially funded by a previous Medicine by Design team projects award, Nagy published a paper in Nature that described a “fail safe” cell technology that he and his team devised that can increase the safety of a cell graft and has a formula to quantify the risk of mutation so that people can make an informed decision on whether such a risk is acceptable to them.

The fail-safe system is a switch that eliminates potentially dangerous cells during cell therapy. The switch is introduced into stem cells, which are then turned into the therapeutic cells. The switch is turned on by a drug that can be added to the cell graft or applied directly into the body after transplant.

Nagy says the killer switch is fail safe because it is composed of two genes, one required for division and one that can trigger cell suicide, stitched together. If a mutated gene begins dividing, the drug is there to activate the kill switch and kill the cell. And if the cell loses the switch, it also loses the ability to multiply.

With the important first step of creating the fail safe switch done, Nagy turned to the cloaking, work that is supported by his team’s current Medicine by Design team projects award.

Nagy’s team is one of 12 sharing nearly $21 million in funding from Medicine by Design over three years. Funded by a $114-million grant from the Canada First Research Excellence Fund, Medicine by Design is an institutional strategic research initiative that is working at the convergence of engineering, medicine and science to catalyze transformative discoveries in regenerative medicine and accelerate them toward clinical impact.

“Medicine by Design has been really important in supporting scientists in bringing the possibilities of regenerative medicine to patients. I’m grateful to Medicine by Design for funding the high-risk and high impact projects that many other funding agencies often say are just too ambitious.”

The cloaking technology involves turning off certain genetic switches in the cells created from stem cells to avoid detection by the immune system. This work was supported by findings from a devastating cancer found in Tasmanian devils, the marsupial native to the Australian state of Tasmania.

Between 1996 and 2015, 95 per cent of the Tasmanian devil population was wiped out as a result of contagious facial cancer cells transmitted when the devils bit each other. Nagy’s research found that the cancer had a way of cloaking itself from the devils’ immune system, which backed up his theory that cells could be hidden from the immune system.

Nagy identified eight genes that are central to immunity. He reasoned that just as the Tasmanian devils’ facial cancer could avoid detection by turning off the right genetic switches, his stem cell-derived cells could similarly become cloaked. Scientists in Nagy lab have been testing the cloaking in mice with encouraging results.

Sara Vasconcelos

Working with Nagy are Maria Cristina Nostro, senior scientist at the University Health Network’s (UHN) McEwen Stem Cell Institute and associate professor, department of physiology at U of T; and Sara Vasconcelos, scientist at the UHN’s Toronto General Hospital Research Institute and associate professor at U of T’s Institute of Biomedical Engineering.

The Nostro lab’s focus is to generate insulin-secreting pancreatic cells from stem cells. These cells could one day have the potential to treat patients with type 1 diabetes. Nostro works closely with Vasconcelos, whose lab focuses on helping to keep the transplanted cells alive once they enter the body. Cells need oxygen and other nutrients, which are delivered through the blood vessels.

Together, the team is testing ways to integrate Nagy’s technologies into Nostro’s functional pancreatic cells. Vasconcelos’s aim is for these therapies to survive in the body.

“When you just transplant the cells, they don’t have blood vessels, so they’ll die, independent of whether the immune system kills them or not. If they die, we’ll never know if it was the immune system or lack of oxygen,” Vasconcelos says. The Vasconcelos lab team repurposes small vessels, which exist in fat. They then use the vessels as units to increase blood flow and allow the cells to engraft and survive after they have been transplanted.

Nagy says the combination of the fail safe and cloaking technologies will make for a powerful therapy. “On the one hand, we can now introduce good cells into recipient’s body that can be hidden from the immune response and do the work they were intended to do. And that means doctors won’t have to use immunosuppression drugs. Finally, if one of the newly created cells is cancerous to the patient, our safe-cell technology can kill it or at least give us information on risk that we can communicate to the patient.”

When stem cell-derived therapies are created for individual patients, Nagy says, it is expensive, costing hundreds of thousands of dollars per patient. Nagy envisions turning his cells that combine fail safe and immune cloaking technologies into “off-the-shelf” products that can be used by anyone and are inexpensive.

Nagy has been building a notable research career in regenerative medicine since he came to Canada from Hungary in 1989, initially joining the lab of renowned researcher and University Professor Janet Rossant at the Samuel Lunenfeld Research Institute (now the Lunenfeld-Tannenbaum Research Institute) at Mount Sinai Hospital.

With a focus on skin cells, U of T's Michael Sefton seeks 'huge step forward' in diabetes treatment

Christopher.Sorensen — Wed, 25 Aug 2021 16:29:55 +0000

With a focus on skin cells, U of T's Michael Sefton seeks 'huge step forward' in diabetes treatment

Christopher.Sorensen Wed, 08/25/2021 - 12:29

Cutline

Michael Sefton, a ��οtissue engineer and executive director of Medicine by Design, is investigating whether dendritic skin cells can aid in the successful transplantation of insulin-producing islet cells in diabetes patients (photo by Neil Ta)

Paul Fraumeni

Topic

Institute of Biomedical Engineering

Princess Margaret Cancer Centre

Donnelly Centre for Cellular & Biomolecular Research

Chemical Engineering

Faculty of Applied Science & Engineering

Medicine by Design

University Health Network

Can dendritic cells found in the skin be an important piece of the puzzle of enabling stem cell transplants for diabetes?

Michael Sefton, a renowned University of Toronto tissue engineer, is confident enough about the possibility that – with support from the type 1 diabetes non-profit JDRF – he is about to launch a major new chapter in his research.

The work will build on a finding from a research team at the University of Alberta in 2000 that proved islet cells (also called islets of Langerhans), which produce insulin and are found in the pancreas, could be transplanted from a donor into the livers of people living with type 1 diabetes. The patients who were treated saw their diabetes disappear for long periods of time and no longer needed to inject insulin. The procedure came to be known as the Edmonton Protocol.

“It was a huge finding from that group,” says Sefton, who is executive director of Medicine by Design and University Professor in the department of chemical engineering and applied chemistry and the Institute of Biomedical Engineering in the Faculty of Applied Science & Engineering. “But the problem was the liver. It was a hostile environment to those new cells and mounted an immune response that killed many of them and the patients’ diabetes returned eventually.”

Nevertheless, it got Sefton thinking: What if there was a better place to implant the cells?

He thought of the skin. Research had proven that the skin – or just under it – is an area less likely to be hostile to transplanted cells such as pancreatic cells. Not only that, but implanting cells under the skin is less invasive than doing so in the liver. The cells could be retrieved more easily, which might make the therapy safer for the patient

But the method raised another problem. The skin has too few blood vessels to enable the implanted cells to survive and enable the body to manage blood sugar. Could scientists find a way to create blood vessels?

In 2016, JDRF awarded Sefton more than $1 million to explore the possibility. To create the blood vessels, the Sefton team used a material that contained methacrylic acid (MAA).

“Once we insert a polymer gel with MAA under the skin, the MAA interacts with the living system in the body (mice are currently being used) and it creates the blood vessels,” Sefton says. “We’re just beginning to understand how MAA works. And this enables the implanted pancreatic cells to deliver insulin throughout the body to do its work in controlling blood sugar and, thus, stopping the diabetic condition.”

Another major hurdle was obtaining enough pancreatic cells for transplant. Sefton, whose lab is located at the Donnelly Centre for Cellular and Biomolecular Research, says about a million pancreatic islets (each islet contains about a thousand cells) were needed for each patient treated through the Edmonton Protocol model. Acquiring the islets often required two donors.

But now, Sefton says, scientists such as Maria Cristina Nostro – a senior scientist at McEwen Stem Cell Institute, University Health Network, who is also a Medicine by Design-funded researcher and an associate professor of physiology at the Temerty Faculty of Medicine – can create insulin-producing cells from stem cells, which provides an unlimited supply.

With these big problems solved, the team still has another one to deal with – the immune response that the body mounts when the new pancreatic cells are transplanted.

The body’s natural response is to reject, say, a new heart or kidney. It’s the body going after what it perceives to be an invader, in the same way the immune system attacks harmful bacteria or viruses that have entered the body.

While, as Sefton says, the skin tends to respond differently than the liver, there will still be a response enacted that will try to reject the transplanted pancreatic islets once implanted.

This is where Sefton believes the dendritic cells can play an important role.

Discovered by German pathologist Paul Langerhans (the same scientist who also discovered the pancreatic islets named for him) in 1869, dendritic cells are powerful immune cells found in the skin.

“They will, of course, mount an immune response once we implant the pancreatic islets,” Sefton says. “But we believe that the MAA has properties that will work on the skin’s dendritic cells to be tolerant of the pancreatic cells. We don’t want to suppress the immune system because that is dangerous for the patient.

“We want to fool it into accepting the new pancreatic cells as if they are part of the patient’s body. And if we can do that, we’ll have taken a huge step forward.”

Sefton and his team will use the new JDRF grant over the next two years to continue to explore this hunch.

Adventurous health science research isn’t new to Sefton, who has built a record for innovation in biomedical research that has earned him global respect.

He was named a University Professor in 2003, the highest honour ��οbestows on its faculty. In 2017, he was honoured with the Order of Canada for his leadership in biomedical engineering. Before joining Medicine by Design, he was director of U of T’s Institute of Biomedical Engineering and boasts many scientific achievements as a scientist, including being among the first to combine living cells with polymers and effectively launching the field now called tissue engineering.

Today, as the executive director of the Medicine by Design strategic research initiative, Sefton speaks with both pride and excitement about the work of scientists tackling difficult health challenges using regenerative medicine, a branch of health research and treatment that has exploded globally since stem cells were discovered by ��οscientists James Till and Ernest McCulloch at Toronto’s Princess Margaret Hospital – now Princess Margaret Cancer Centre – in 1961.

“The hallmark of our approach is the convergence of scientists from a multitude of disciplines across the University of Toronto and our nine partner research hospitals,” he says. “We’ve got biologists, biochemistry experts, physicists, engineers and specialists in all aspects of medicine working together and sharing ideas. Our goal is to think way beyond the obvious and to act boldly in finding ways to improve treatment and maybe even cure major diseases.”

Medicine by Design was founded in 2015 with a $114 million from the Canada First Research Excellence Fund. The projects in Medicine by Design’s portfolio focus on using stem cells as living therapies, harnessing the body’s capacity for repair, disabling the triggers of disease and creating technologies to advance regenerative medicine.

Within that slate of exploration, Medicine by Design research teams are making progress on treating a multitude of diseases such as restoring vision lost to age-related macular degeneration, using stem cells to treat diseased livers in patients who have no hope of a liver transplant, stopping dangerous and hard-to-diagnose abdominal aortic aneurysms before they do their damage and creating methods to help the brain repair itself after stroke.

“We place a huge emphasis on new ideas and research that is risky,” says Sefton. “That’s the way you have to think when you want to really change things. I want people to hear about our work and think that what we are trying to achieve is impossible. l believe firmly that when it comes to disease, we don’t have to just accept what nature gives us with, say, cancer or stroke or diabetes. We can do better than nature.”

He also emphasizes that advances in technology are essential components of enabling breakthroughs. He points to the importance of tools like CRISPR, a powerful gene editing technology that won the Nobel Prize for Emmanuelle Charpentier and Jennifer Doudna in 2020 for creating opportunities that were unthinkable even 30 years ago.

“That’s why I say that 30 years from now, regenerative medicine will be at the centre of how we treat disease,” says Sefton. “It will be standard practice and it will be giving us a level of health we would have never thought possible.

“We may well be able to even eliminate many diseases.”

Low-glycemic diet reduces cardiometabolic risks for people with diabetes: ��οstudy

Christopher.Sorensen — Thu, 12 Aug 2021 16:54:53 +0000

Low-glycemic diet reduces cardiometabolic risks for people with diabetes: ��οstudy

Christopher.Sorensen Thu, 08/12/2021 - 12:54

Cutline

(Photo by Sharon Pittaway via Unsplash)

Topic

Alumni

Nutritional Sciences

A low-glycemic diet results in small but important improvements in cardiometabolic risk factors, including blood sugar levels and body weight, for people with diabetes, according to a University of Toronto study analyzing multiple clinical trials.

The improvements were evident over and above existing drug or insulin therapy, suggesting that a low-glycemic diet might be especially useful as an add-on treatment to help people with diabetes achieve therapeutic targets.

The glycemic index (GI) rates how quickly different foods affect blood sugar levels. White breads and highly processed foods have a high glycemic load, while whole foods, vegetables and fruits tend to rate lower.

John Sievenpiper

“Diet and lifestyle modifications are foundational for managing diabetes, but for patients who require insulin or other medications, dietary patterns with a low GI are likely to improve blood glucose control as well as cholesterol levels, body weight and markers of inflammation,” said John Sievenpiper, an associate professor in the departments of nutritional sciences and medicine at U of T’s Temerty Faculty of Medicine and the study’s principal investigator.

The study, published in the journal The BMJ, included more than 1,600 participants with type 1 or 2 diabetes from over two dozen randomized, controlled trials that looked at the effect of low-GI diets in diabetes. Participants were mostly middle-aged, overweight or obese with moderately controlled type 2 diabetes treated with drugs or insulin.

The researchers saw reductions in risk factors such as fasting glucose, low-density lipoprotein (LDL) cholesterol, triglycerides, body weight, systolic blood pressure and C-reactive protein (a chemical associated with inflammation), but not blood insulin levels, high-density lipoprotein (HDL) cholesterol or waist circumference.

“We predict that these reductions would translate to an important reduction of risk for major cardiovascular events, the leading cause of death in people with diabetes,” said Sievenpiper, who is also a staff physician and scientist at St. Michael’s Hospital, Unity Health Toronto. “So there is clearly an opportunity for patients to benefit by shifting to low-GI dietary patterns.”

The glycemic index was developed by ��οProfessor David Jenkins and colleagues in the 1980s. He and other researchers have shown that low-GI foods, which include fruits and vegetables, as well as many pulses and whole grains, can help keep blood sugar levels steady and reduce the risk of heart disease in people with diabetes.

Clinical guidelines for diabetes treatment across the world recommend a low-GI diet, although the last guideline from the European Association for the Study of Diabetes is more than 15 years old and researchers have conducted many trials since then.

Laura Chiavaroli

The researchers, including first author and post-doctoral fellow Laura Chiavaroli, found that the certainty of evidence was high for reduction in blood sugar levels and moderate for most other outcomes.

They point out limitations that may have affected their results, including imprecision in the evidence for the effect of low glycemic index dietary patterns on LDL cholesterol and waist circumference, and the small number of available trial comparisons for blood pressure and inflammatory markers.

Yet, they write that, overall, the evidence supports existing recommendations for the use of low-GI dietary patterns in the management of diabetes.

The study was funded by the Diabetes and Nutrition Study Group of the European Association for the Study of Diabetes, the Canadian Institutes of Health Research, Canada Foundation for Innovation and the Ministry of Research and Innovation’s Ontario Research Fund.

The study is the largest and most comprehensive synthesis to date, and will help inform an update to the European Association for the Study of Diabetes’s guideline.

Researchers use AI to predict risk of developing type 2 diabetes

Christopher.Sorensen — Thu, 22 Jul 2021 13:23:07 +0000

Researchers use AI to predict risk of developing type 2 diabetes

Christopher.Sorensen Thu, 07/22/2021 - 09:23

Cutline

��οresearchers Laura Rosella and Vinyas Harish found that a machine learning model was about 80 per cent accurate in determining who will develop type 2 diabetes (photos courtesy of Rosella and Harish)

Gabrielle Giroday

Topic

Dalla Lana School of Public Health

Artificial Intelligence