Researchers at the Toronto General Hospital Research Institute ([no-lexicon]TGHRI[/no-lexicon]) have shown that the diabetes medication empagliflozin can eliminate the need for insulin pump users to track their carbohydrate intake.
People with type 1 diabetes do not produce insulin, a hormone required to control the amount of sugar in the blood. In addition to diet and exercise, many people with type 1 diabetes require lifelong insulin therapy to control their blood sugar levels.
Modern insulin pumps can monitor blood sugar levels and automatically adjust insulin delivery based on their users’ changing needs. These pumps, called “hybrid closed loop” systems, automatically deliver small amounts of insulin throughout the day, but depend on the user to determine how much insulin to give at mealtimes. The amount of mealtime insulin that a person needs depends on the amount of carbohydrates that they consume, so it is important for insulin pump users to keep track of the carbohydrate content of their meals. Unfortunately, this process is very difficult and time-consuming.
“An easier approach to administering mealtime insulin would be to simply signal that you are about to eat a meal by pressing a button on your pump, without having to carefully count the carbohydrate content of a meal. This approach is called ‘meal announcement’,” explains Dr. Bruce Perkins, a Senior Scientist at TGHRI and the senior author of the study. “Meal announcement is simple, but the insulin doses are less precise than when you count the grams of carbohydrate in your meal.”
To address these complexities, Dr. Perkin led a study to see whether the diabetes drug empagliflozin could reduce or eliminate the need to count carbohydrates. The study enrolled thirty adults who use insulin pumps. Over two months, each participant engaged in several insulin delivery strategies, including meal announcement and carbohydrate counting, with and without empagliflozin.
When participants combined the simple meal announcement and empagliflozin, their blood sugar was as well controlled as when they counted carbohydrates. When participants counted carbohydrates, the addition of empagliflozin further improved blood sugar control, substantially increasing the time spent in the target blood sugar range.
“If insulin pump users take empagliflozin, they can replace carbohydrate counting with a simple meal announcement strategy. The empagliflozin seems to make the automated insulin system work better over the course of meals. This switch can save people time and effort, without compromising blood sugar levels,” says Dr. Perkins. “Managing blood sugar levels in type 1 diabetes can be very challenging, but the strategy that we have identified has the potential to make it a little easier.”
Dr. Perkins’ team is currently studying the impact of empagliflozin in a much longer study.
This work was supported by Diabetes Canada, the Lunenfeld Tanenbaum Research Institute at Sinai Health Systems, McGill University, the Toronto General Hospital Research Institute and the UHN Foundation. A Haidar holds a Tier 2 Canada Research Chair in Diabetes Mellitus at McGill University.
Haidar A, Yale JF, Lovblom LE, Cardinez N, Orszag A, Falappa CM, Gouchie-Provencher N, Tsoukas MA, El Fathi A, Rene J, Eldelekli D, Lanctôt SO, Scarr D, Perkins BA. Reducing the need for carbohydrate counting in type 1 diabetes using closed-loop automated insulin delivery (artificial pancreas) and empagliflozin: A randomized, controlled, non-inferiority, crossover pilot trial. Diabetes Obes Metab. 2021 Feb 2. doi: 10.1111/dom.14335.
The Joint Genomics Program between UHN’s Princess Margaret Cancer Centre and the Ontario Institute of Cancer Research (OICR) will benefit from the recent accreditation of an OICR genomics facility. OICR Genomics recently passed the highest standards for clinical research set by the College of American Pathologists (CAP).
The facility is one of the few labs in the world to gain CAP accreditation for identifying mutations (i.e., changes in the genetic code) and comprehensive testing of all forms of genetic changes in whole genomes. “What sets our program apart is the amount of information that our genetic test produces. Our clinical case assay can provide whole genome sequences for normal and tumour samples from the same patient—as well as detailed data on which genes are active in the tumour,” says Dr. Carolyn Ptak, Program Manager and Quality Assurance Lead of OICR Genomics.
“By providing a complete view of the genes that are present in cancers and when these genes are turned on or off, the program will deliver profound insights on new treatments and how to tailor these to individual patients,” says Dr. Trevor Pugh, Senior Scientist at Princess Margaret Cancer Centre, and Senior Investigator and Director of Genomics at OICR.
The joint program was established to alleviate administrative hurdles and ease the transfer of samples and data between UHN and OICR for common research projects. The collaboration brings together researchers involved in basic, translational and clinical research under a single coordinated vision: to facilitate the use genomic knowledge to guide clinical management of cancer patients. The program is advancing this aim through the following actions:
An example of the research being supported by the Joint Genomics Program is a clinical trial led by Drs. Jennifer Knox and Steven Gallinger. The trial, named PASS-01, is assessing two approved treatments for metastatic pancreatic cancer, which has one of the lowest survival rates of all cancer types. The program is providing clinical grade and detailed genomic data (i.e., sequences of the whole genome and active genes). This data will provide deep insight into the disease biology and determine whether the effectiveness of treatments can be linked to genetic features.
The accredited facility is also intended to support studies from the Marathon of Hope of Cancer Centres Network, of which Princess Margaret Cancer Center is a major partner.
“This is a landmark achievement—one that reflects this team’s strong dedication to conducting clinical genomics research of the highest quality in terms of data collection and analyses,” says Brad Wouters, EVP of Science and Research at UHN. “It is a great way to kick off our expanded joint genomics program.”
T Pugh holds a Tier 2 Canada Research Chair in Translational Genomics and is supported by an OICR Senior Investigator Award.
Dr. Susan Marzolini, Scientist at KITE Research Institute, led a study to determine how cardiac rehabilitation programs in Canada were affected by the first wave of the COVID-19 pandemic.
The research team surveyed 144 cardiac rehabilitation programs in Canada during the height of the first wave. They found that about 40% of the programs had shuttered.
For patients with cardiovascular disease, cardiac rehabilitation programs provide exercise training, guidance on nutrition, as well as psychological counselling. They are effective at reducing hospital readmissions and death from cardiovascular disease.
“Given how vitally important these programs are to helping those recovering from cardiovascular disease, we wanted to explore the factors that affected the safe delivery of these programs,” explains Dr. Marzolini.
The pan-Canadian survey asked the managers of cardiac rehabilitation programs about the effect of the first wave on program closure, their delivery method, the admission of patients into the program, and conditions that made program delivery easier or harder.
The team found that the primary reasons for closing the programs were redeployment of staff and the necessity of restricting access to buildings in close proximity to hospitals or long-term care facilities.
Of the programs that remained open, many exercise and education services transitioned from group and face-to-face sessions to individual sessions by phone. The admission of patients also had to be limited to those with lower medical risk, because program providers felt that they could not safely deliver rehabilitation programs at a distance to high-risk patients, such as those with cognitive impairment. Almost half of the program managers also reported patients’ difficulties in accessing and using technology as major barriers to the delivery of the rehabilitation programs.
“New policies are needed to guide the safe operation of cardiac rehabilitation programs during the pandemic,” says Dr. Marzolini. “Alternative strategies for lower-risk patients such as group-based rehabilitation sessions by phone would free up resources so that high-risk and vulnerable patients can receive the tailored support that they need. Low-technology strategies such as sending resources by mail would also enable these programs to support those without access to technology.”
This work was supported by the Toronto Rehab Foundation.
Marzolini S, Ghisi GLM, Hébert AA, Ahden S, Oh P. Cardiac Rehabilitation in Canada During COVID-19. CJC Open. 2021 Feb. doi: 10.1016/j.cjco.2020.09.021.
A new study from The Institute for Education Research (TIER) has revealed that medical school orientation can be a source of lasting tension and uncertainty for students, particularly those of diverse backgrounds.
Students entering medical school are quickly introduced to many of the social and professional aspects of the medical profession. Orientation is meant to be an informative period that welcomes students and sets the stage for a positive medical school experience. Unfortunately, if inclusion is not a priority in its design, orientation can cause students stress and uncertainty as they begin to develop their professional identity.
To understand the source of this stress and uncertainty, a research team led by Dr. Marcus Law, an Education Investigator at TIER, explored student experiences during medical school orientation.
The research team interviewed 16 students from five Canadian medical schools. From these interviews, several issues emerged that were related to students’ personal identity and feelings toward their medical school orientation.
Students described being indirectly introduced to the identity of the dominant medical professional (e.g., white, heterosexual, high socioeconomic status and a science-based education background). Students felt tensions when they were introduced to this identity, particularly if it differed from their own. These tensions were especially distressing and long-lasting for students from underrepresented groups.
According to Dr. Law, “Students from underrepresented groups were welcomed into medical school, but once they arrived, they felt pressures to hide their unique qualities and backgrounds in order to match what they thought a doctor looks like.”
Students also described sensing a gap between their school’s investment in diversity and the way that it approached inclusion. Some students felt that their faculty voiced the importance of including students of all backgrounds, but their words were not backed by actions.
This study indicates that medical schools can achieve diversity, but still fall short when it comes to ensuring that everyone feels like they belong.
“We encourage medical schools to take a second look at their orientation programs to ensure that they are inclusive of students with diverse backgrounds and experiences, particularly those from marginalized groups,” says Dr. Law. “Increasing diversity is not enough. Schools need to safeguard inclusion from the moment that students walk through the doors.”
This work was supported by The Institute for Education Research and the UHN Foundation.
van Buuren A, Yaseen W, Veinot P, Mylopoulos M, Law M. Later is too late: Exploring student experiences of diversity and inclusion in medical school orientation. Med Teach. 2021 Feb 2:1-15. doi: 10.1080/0142159X.2021.1874326.
As the weather gets warmer and the days longer, it is a great time to bike to UHN. Biking is sustainable, provides much needed exercise and allows you to avoid overcrowded public transit.
UHN is home to extensive bicycle infrastructure that continues to expand in response to growing demand during the pandemic. While UHN builds the capacity for more bicycle parking, new policies are being implemented to ensure that users can access spots when they arrive to work.
Bicycle Parking Dos and Don’ts
Given the high demand for this resource, it is important that it is shared equitably among all staff. Long-term storage of your bike is not permitted because it hinders the ability of UHN to accommodate all cyclists in our research community. To guard against this, periodic patrols will identify and tag bicycles that appear to be abandoned or stored on-site for an extended period of time. Owners of these bicycles will have two weeks grace before they are removed and donated to community organizations. New signage will be installed shortly to remind users of this policy.
Bike Share Toronto UHN Discount
If you are interested in cycling to work but don’t have access to a bicycle, Bike Share Toronto offers 24/7 access to 5,000 bikes and 465 stations across the city. Bike Share Toronto is kindly offering UHN employees a $40 discount off annual memberships. See here for details on how to easily request your discount code.
Expanded Biking Infrastructure in Toronto
The City of Toronto is also increasing cycling infrastructure by installing over 25 km of a planned 40 km of new protected bike lanes. Some of the most recent bike lane additions are on University Avenue, Bloor Street, Dundas Street and Danforth Avenue. See here for updated information on bike lanes near you.
Join the UHN Bicycle User Group
If you are choosing to bike to work this summer, be sure to take safety precautions such as completing regular bike maintenance, using lights and wearing a helmet at all times. For up-to-date cycling information, join the UHN Bicycle User Group by contacting UHNcycling@uhn.ca.
A recent study led by researchers at UHN and SickKids has revealed a potential treatment for glioblastoma, which is the most aggressive and most common brain cancer in adults.
The research team identified a drug-like chemical compound that slows the growth of glioblastoma stem cells—these cells contribute to initiating or 'seeding' the cancer and its ability to resist treatment. The study was co-led by Dr. Cheryl Arrowsmith, Senior Scientist at Princess Margaret Cancer Centre and Chief Scientist at The Structural Genomics Consortium (SGC), Dr. Peter Dirks, neurosurgeon at SickKids and Dr. Panagiotis Prinos, senior research associate at the SGC and the University of Toronto.
Cancer stem cells, first discovered at UHN in the 1990s, are now recognized to be responsible for the growth and recurrence of many cancers.
“Glioblastoma presents further challenges to treatment because the tumours comprise diverse types of cells. As well, not many drugs can reach the brain because of a physiological 'filter' known as the blood-brain barrier,” says Dr. Arrowsmith.
Elevated levels of a protein called PRMT5 have recently been linked with the severity of brain tumours. PRMT5 belongs to a class of proteins called epigenetic regulators, which have been the focus of intense drug discovery efforts in recent years, including 50 novel drug-like candidates developed by the SGC in a program led by Dr. Arrowsmith.
Recognizing the potential for a treatment strategy, the research team tested 39 epigenetic drug-like candidates on glioblastoma stem cells isolated from 26 patients. Two of these molecules were found to be highly promising. Further testing revealed that they were effective at reducing PRMT5 in glioblastoma stem cells and prevented those cells from growing. One of the molecules, LLY-283, was able to efficiently cross the blood-brain barrier and prevent tumour growth in experimental models.
“These results show that targeting PRMT5 may be an effective therapeutic strategy for patients,” says Dr. Arrowsmith. “We now have a better understanding of how these potential drug candidates halt glioblastoma stem cells from growing and multiplying.”
Currently, no effective chemotherapies exist for children with glioblastoma. The team’s work with pediatric glioblastoma stem cells suggests that targeting PRMT5 may also be an effective strategy for treating glioblastoma in children.
This work was supported by Stand Up To Cancer Canada, Genome Canada, Canadian Institutes of Health Research, Ontario Institute for Cancer Research, The Structural Genomics Consortium and The Princess Margaret Cancer Foundation. T Pugh holds a Tier 2 Canada Research Chair in Translational Genomics. M Tyers holds a Tier 1 Canada Research Chair in Systems and Synthetic Biology. B Haibe-Kains holds a Tier 2 Canada Research Chair in Computational Pharmacogenomics.
Sachamitr P, Ho JC, Ciamponi FE, Ba-Alawi W, Coutinho FJ, Guilhamon P, Kushida MM, Cavalli FMG, Lee L, Rastegar N, Vu V, Sánchez-Osuna M, Coulombe-Huntington J, Kanshin E, Whetstone H, Durand M, Thibault P, Hart K, Mangos M, Veyhl J, Chen W, Tran N, Duong BC, Aman AM, Che X, Lan X, Whitley O, Zaslaver O, Barsyte-Lovejoy D, Richards LM, Restall I, Caudy A, Röst HL, Bonday ZQ, Bernstein M, Das S, Cusimano MD, Spears J, Bader GD, Pugh TJ, Tyers M, Lupien M, Haibe-Kains B, Artee Luchman H, Weiss S, Massirer KB, Prinos P, Arrowsmith CH, Dirks PB. PRMT5 inhibition disrupts splicing and stemness in glioblastoma. Nat Commun. 2021 Feb 12. doi: 10.1038/s41467-021-21204-5.
Deep brain stimulation (DBS) is being explored as a treatment for individuals with Alzheimer disease. Researchers have previously shown that stimulation applied to the fornix—a memory-related structure located deep in the brain—can cause vivid flashbacks of old memories and events in some, but not all, individuals with Alzheimer disease. The occurrence of flashbacks suggests that the stimulation is activating brain circuits involved in memory recall.
“It is a mystery why only certain individuals experience these flashbacks—especially considering that the fornix is stimulated in everyone who undergoes the procedure,” says Krembil Senior Scientist Dr. Andres Lozano, who led a recent study that has shed new light on how DBS causes flashbacks.
DBS involves the use of surgically implanted electrodes to stimulate specific regions of the brain. DBS has been successfully used to reduce the symptoms of certain neurological conditions, including tremors in Parkinson disease. In this study of DBS for Alzheimer disease, DBS electrodes are implanted to stimulate the fornix.
Although the fornix is the main target in this type of DBS, other brain structures are likely activated at the same time due to the placement of the electrodes. Lozano’s team suspected that this effect, which would vary between patients, may be the key to why only certain patients experience flashbacks.
The researchers examined scans from 39 individuals with mild Alzheimer disease who previously participated in a clinical trial of fornix DBS to reduce memory impairment. Using computer modeling of the connections between different brain regions, the team identified three structures involved in flashbacks. They found that flashbacks were associated with stimulation of the fornix, the anterior commissure (a collection of nerve fibres that connects the two halves of the brain), and the bed nucleus of the stria terminalis (a part of the brain’s emotion and memory circuits).
Patients were more likely to experience flashbacks when electrodes were placed in such a way that they stimulated these three regions. This finding provides further evidence that these deep brain structures make up an important memory-related circuit.
“Our findings reveal the areas of the brain where electrical stimulation produces DBS-induced memory recall, in approximately half the patients,” says Dr. Lozano. “By demonstrating the importance of stimulating different, yet connected brain regions with DBS, these results improve our understanding of the brain circuits involved in memory. This information will help us to refine the DBS procedure so it has the greatest therapeutic impact for people with Alzheimer disease, and perhaps other forms of dementia.”
This work was supported by the Canadian Institutes of Health Research, the German Research Foundation and the Toronto General & Western Hospital Foundation. A Lozano is the RR Tasker Chair in Functional Neurosurgery.
Germann J, Elias GJB, Boutet A, Narang K, Neudorfer C, Horn A, Loh A, Deeb W, Salvato B, Almeida L, Foote KD, Rosenberg PB, Tang-Wai DF, Wolk DA, Burke AD, Salloway S, Sabbagh MN, Chakravarty MM, Smith GS, Lyketsos CG, Okun MS, Lozano AM. Brain structures and networks responsible for stimulation-induced memory flashbacks during forniceal deep brain stimulation for Alzheimer's disease. Alzheimers Dement. 2021 Jan 21. doi: 10.1002/alz.12238.
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