Our Research Members

We study how insulin and exercise stimulate glucose entry into muscle and how this fails in insulin resistance and type 2 diabetes. We explore intracellular signals, movement of vesicles containing glucose transporter 4 (GLUT4) and strategies to render muscle cells insulin-resistant. We generated platforms of muscle cells in culture and transgenic mice expressing tagged GLUT4 in muscle, to test GLUT4 movement in vivo. We found that signals downstream of PI3-kinase bifurcate into activation of Akt leading to Rab8A and Rab13 activation, and Rac1 activation that controls actin filament remodelling. Orr collaborator Erik Richter (University of Copenhagen) found that mice lacking Rac1 in muscle become insulin-resistant. Mechanistically, we find that, in cells rendered insulin resistant by exposure to saturated fatty acids, GLUT4 translocation becomes defective along with alterations in Rac1 signalling to actin rather than in the Akt pathway. These studies will aid in identifying specific steps affected in muscle that curtail stimulation of glucose uptake by insulin in obesity.

Saturated fatty acids also render monocytes invasive and macrophages pro-inflammatory, producing cytokines that make muscle cells insulin-resistant. In vivo, high fat feeding of mice  causes direct activation of the NOD innate immunity recognition receptors in macrophages and that contributes to whole-body insulin resistance. We documented a particular infiltration of inflammatory macrophages and neutrophils in muscles of high fat-fed mice and of obese, insulin-resistant humans, and we find that an early feature of obesity is production of infiltrating monocytes in the bone marrow. These collective findings contribute to our understanding of the link between inflammation and insulin resistance. 

Finally, more recently we have investigated how glucose and insulin cross microvascular endothelial cells of capillaries, in an effort to understand the molecular underpinnings of their delivery to tissues. Defects in this step in obesity will have impact on insulin action on glucose uptake in muscle and fat cells in vivo.

My research program has three projects directly related to diabetes:

1) Angiotensin II is a peptide produced in the kidney that leads to progression of diabetic kidney disease. We have identified a group of proteins regulated by angiotensin II in kidney cells and demonstrated that these proteins were involved in kidney fibrosis. We have also demonstrated that measurements of these proteins in urine correlate with kidney fibrosis. We are now studying the mechanisms of regulation of these angiotensin II-activity proteins. Agents that inhibit these proteins may represent new potential treatments of diabetic and other kidney diseases.

2) The mechanisms leading to development of early diabetic nephropathy are still poorly understood. By studying the urinary peptidome of patients with juvenile diabetes mellitus type I and no known diabetic complications, we have identified several peptides of protein uromodulin. We are now investigating the potential function of these peptides and proteases that cleave them from uromodulin, in order to enhance our understanding of the early events leading to kidney injury in type I diabetes.

3) Male sex has been associated with increased risk of progression of kidney disease. We have recently discovered that male sex hormones affect metabolic enzymes in kidney cells and may result in maladaptive metabolic changes in the kidney. These effects were demonstrated in two different animal models of diabetes, where male animals had increased expression of these enzymes and increased kidney hypertrophy and oxidative stress. We are now investigating how sex hormones affect metabolism in kidney cells and whether we can modify the maladaptive effects of testosterone through manipulation of metabolism.

My clinical research focuses on:

1. The impact of obesity on metabolic dysfunction
2. The pathophysiology and risk factors for the development of type 2 diabetes mellitus (T2DM)
3. Risk factors for cardiovascular disease in individuals with metabolic abnormalities
4. Strategies for the treatment of T2DM. 

I am particularly interested in understanding the pathophysiology of T2DM in individuals with various degrees of obesity and differential patterns of body fat distribution.

Mary L’Abbé, C.M, PhD, is an expert in public health nutrition, nutrition policy, and food and nutrition regulations. Her research program on Food and Nutrition Policy for Population Health examines the nutritional quality of the food supply, food intake patterns at the national population level, and consumer research on food choices in association with risk of obesity and other chronic diseases, including diabetes. For example, some of her CIHR and other funded research activities include:

•  Assessing levels and types of sugars, including added sugars in the Canadian food supply
•  Diabetes education intervention and research investigating supports and barriers to diabetes care among multiethnic communities in Toronto (in collaboration with the Diabetes Education Centers at the North York General hospital and Mackenzie Health)
• Investigating national population-level dietary patterns associated with obesity, metabolic syndrome, diabetes and cardiovascular disease
• Examination of the application of different nutrient profiling methods to define “healthy foods” and their application in polices to support diet related NCD reduction
• Building tools to support improved consumer choice of healthier foods or to support nutrition interventions in primary care/disease prevention, e.g. Big Life Salt Calculator has been developed (http://www.projectbiglife.ca/sodium/) – A sugar app, One Sweet App, was developed and launched in 2015 and is currently being updated.
• Research on consumer attitudes and understanding and use of nutrition labelling and claims on food packages, front-of-pack labelling, and effects of different criteria in their development and application (note that L’Abbe’s consumer surveys include questions about health/disease status in order to link food choice/attitudes to particular diseases including diabetes) 

We have just recently received funding from the Sanofi-Pasteur – University of Toronto – Université Paris-Descartes International Collaborative Research Pilot and Feasibility Program on “Comparison of two Front of Pack food rating systems for identifying foods consistent with Canada’s Food Guide and Guidelines for diabetes prevention and management”

Nutrient sensing in the Gut and the Brain, Diabetes, Obesity, Glucose and Lipid metabolism.

The Lee lab has a primary interest in the regulation and perturbation during disease of the microvascular endothelial barrier. Using cell biology techniques and primary microvascular human endothelium and supplemented by animal models, we investigate the regulation of insulin transport out of the circulation.

Dr. Leiter has several research interests including clinical trials on the prevention of atherosclerosis, especially in diabetes, and the dietary and pharmacologic treatment of diabetes mellitus, hyperlipidemia, hypertension, and obesity. He was an investigator in many of the landmark diabetes trials including the DCCT, ACCORD, and ADVANCE and is on the Executive/Steering Committees of many ongoing outcome trials in both the diabetes and lipid areas.

The Lewis lab has had a long interest in the mechanisms of various aspects of diabetic dyslipidemia, including postprandial lipemia, HDL lowering and hypertriglyceridemia, as well as the metabolic effects of free fatty acids on insulin action and secretion. Dr. Lewis and Adeli made the important observation that the intestine overproduces lipoproteins in insulin resistant states, elucidating a number of regulatory mechanisms of intestinal lipid mobilization and lipoprotein secretion. In his current funded work Dr. Lewis is determining, in integrative physiological studies in humans and animal models, the mechanisms of intestinal lipid mobilization and lipoprotein secretion. In addition, Dr. Lewis is the Principal Investigator of Diabetes Action Canada, one of the chronic disease networks funded through the Strategy for Patient-Oriented Research (SPOR) Initiative, and undertakes translational research with active patient engagement.

Dr. Lipscombe’s research program is aimed at improving the care and outcomes of persons living with diabetes with a particular focus on women, and targeting special female populations at higher risk for diabetes who would benefit from more focused diabetes prevention strategies. Her specific priority areas of interest include the association between breast cancer and diabetes, pregnancy planning in women with diabetes, post-partum diabetes risk and prevention in women with gestational diabetes, and drug safety in seniors with diabetes.

Dr. Lovshin directs the Diabetes Complications Research Laboratory (DCRL), a new clinical investigation unit in the division of Endocrinology & Metabolism at the Sunnybrook Health Sciences Centre. Dr. Lovshin’s research interests are focused on understanding the mechanisms of diabetes complications, with a specific focus on improving vascular health and reducing vascular complications and events associated with metabolic diseases including Type 1 and Type 2, and Obesity. Through clinical investigative techniques which span epidemiology to translational mechanistic clinical studies, Dr. Lovshin is interested in determining how changes in the cardio-renal axis contribute to heart and kidney complications in diabetes. Dr. Lovshin is also interested in changes in the diabetic retina and central nervous system and in determining how these pathophysiological changes contribute to complications in the eye and brain.

Obesity is the strongest risk factor for type 2 diabetes but many people with diabetes are not obese. Dr. Luk’s research focuses on identifying the signaling pathways linking obesity and diabetes, and determining the role of adipose tissue in metabolic syndrome.

My lab is interested in the impact of stress biology on T1D and T2D. We are dedicated to discovering how stress can (dys)regulate the physiological functions of key endocrine tissues– primarily skeletal muscle and pancreatic islets/beta cells– during diabetes. We define “stress” as: 1) hyperglycemia, or nutrient overexposure (a negative perturbation); 2) aerobic exercise (a positive perturbation); or 3) the combination of both. More specifically: we investigate the molecular, metabolic and bioenergetic mechanisms by which stressors can regulate cell, tissue and whole-body glucose homeostasis in T1D and T2D.

Some big picture questions we are asking:
– How does cell metabolism shift to resolve acute stress? What happens to these pathways when stress becomes chronic?
– Organisms with hyperglycemia, T1D and T2D have low aerobic fitness. Which tissues/cell types, circulating factors, or other molecular mechanisms underlie the low fitness phenotype?
– Do beta cells and skeletal muscle communicate during stress?

We use a mix of in vivo physiological phenotyping, in vitro molecular biology, imaging/histology, metabolomics and bioenergetics platforms in our projects. The ultimate goal is to understand the complex stress-induced mechanisms that underpin diabetes, especially at early onset, in order to help prevent disease.

As a pediatric endocrinologist who cares for children with diabetes, obesity and other chronic medical conditions on a daily basis, I am concerned about the prospects for their future health. This has driven me to seek answers to some of the meaningful questions that are going to benefit their health and this has prompted me to pursue a clinical research program. My research interests include the study of conditions associated with type 1 diabetes, such as celiac disease and the evaluation of early atherosclerotic risk factors in young patients with endocrine conditions who are at high risk of cardiovascular disease including both type 1 and type 2 diabetes, insulin resistance and obesity. I have conducted clinical studies to identify patients at risk and study the impact of this process on the health of these children.

These studies are also evaluating interrelated risk factors for atherosclerosis in these high risk populations and the effectiveness of lifestyle, diet and drug therapy treatment strategies. Specifically we evaluated dietary intake in patients with type 1 diabetes as well as standardized activity assessments which showed high rates of dietary fat intake and inactivity, which worsened during adolescence. As part of my research, I adapted an innovative method to study endothelial function as a marker of early atherosclerosis which we able to evaluate as a reversible indicator of disease with the potential to assess the effectiveness of different treatment strategies on reducing early atherosclerotic changes.

Longer term, the findings of this research will be used to develop guidelines for clinical practice, prevention and treatment strategies. It is hoped that the effective translation of this research into clinical practice will help to manage cardiovascular disease risk in children with the ultimate goal of cardiovascular disease prevention.

Polymer materials are powerful tools to modulate the delivery of therapeutics. Our team works on developing dynamic polymer systems that interface with our body’s biology in order to improve biopharmaceutical delivery. We apply our biointerfacing polymer materials to enhance precision medicine with the goal of increasing treatment efficacy and improving patient outcomes. We use our materials to address key challenges in biopharmaceutical delivery for diabetes therapeutics.

My research focuses on evaluating dietary and lifestyle risk factors for obesity, type 2 diabetes (T2D) and cardiovascular diseases across the life-course and in local and global populations. As a trained chronic disease epidemiologist, I use a combination of population-based approaches and lifestyle modification trials to address research questions related to the prevention of T2D, with the goal of informing public policies and dietary recommendations to promote health. I recently joined the Department of Nutritional Sciences at the University of Toronto as an Assistant Professor and hold a Tier 2 Canada Research Chair in Nutrition and Chronic Disease Prevention. I have a strong track record of publications on diet quality with an emphasis on sugary beverages and cardiometabolic health including meta-analyses and primary research studies in large cohorts. These contributions have played a vital role in guiding policies to limit intake of free sugars in Canada, the US and globally. My continued research in low- and- middle income countries has focused on reducing risk of T2D by improving the quality of carbohydrate staple foods in the diet and has now expanded to also explore food insecurity. Among my more recent research activities, I am exploring ethnic differences in cardiometabolic risk among Canadian children to help inform clinical practice guidelines and am exploring the extent to which cardiometabolic health and environmental sustainability are compatible goals when defining optimal diets at different life stages using provincial and national data. I am currently a co-Investigator on a CIHR-funded trial to improve beverage quality in children in Quebec and a National Institutes of Health-funded trial to replace sugar sweetened beverages with noncaloric beverages on obesity and cardiometabolic risk factors in adults.

I currently lead the Li Ka Shing Centre for Healthcare Analytics Research and Training (LKS-CHART) of St. Michael’s Hospital. The LKS-CHART is composed of a team of data scientists with expertise in biostatistics, computer science (with a focus on machine learning, deep learning, and natural language processing), and operations research engineering (with a focus on simulation modeling and optimization). Our team works closely with clinicians and hospital management to solve ‘real world’ problems with advanced analytics. For example, the LKS-CHART team has recently developed a machine learning algorithm that constantly monitors inpatients with diabetes to predict hypoglycemic events in advance so clinicians can proactively manage patients more effectively. 

We are interested in the endoplasmic reticulum stress/unfolded protein response (UPR) and integrated stress response (ISR) signals as drivers of macrophage (MF) phenotype and tissue destruction in autoimmune diabetes (T1D).

MF infiltration in the islets is a well-established mechanistic driver of insulitis and b cell death in T1D. Functionally, infiltrating MF in pancreatic lesions exhibit an inflammatory phenotype with NADPH-driven superoxide and ROS production and TNF-a and IL-1b secretion (in a STAT1-dependent mechanism). Via production of these effector molecules, MF act in a synergistic fashion with infiltrating dendritic cells and T cells to drive islet cell dysfunction and death. Conversely, modulating MF phenotype has a dominant impact on the course of disease in experimental models of spontaneous and induced T1D, reducing the onset and severity of insulitis. Given this, manipulation of MF function becomes an attractive therapeutic target in T1D to control autoimmune pathology and as a tool to promote transplant tolerance.

Cellular stress signals play a key role in myeloid inflammatory potential. UPR stress can drive JNK and STAT1 activation, promote TNFa secretion, and inflammasome maturation/IL-1b production in MF and DC. Likewise the ISR plays a dominant role in controlling MF phenotype and inflammatory potential. For example, our lab demonstrated the ISR kinase GCN2 regulates IL-6 and IL-12 production promoting endotoxemic mortality. However, stress signals can also suppress inflammation as reactive oxygen species driven ER stress promotes myeloid-dependent immune suppression in tumors. Further, we have found GCN2 suppresses inflammatory T cell proliferation and systemic autoimmunity. Importantly modification of stress signaling by pharmacologic approaches has a potent impact on outcomes in inflammation, transplantation, autoimmunity and cancer. These striking findings show stress signaling is a cell and context-dependent modifier of immune function providing novel druggable targets; however, it is paramount to clearly delineate the role (either pro- or anti-inflammatory) of stress signaling modules in the pathologic process.

In our research project we are examining the role of metabolism and stress signaling in inflammatory pathology in T1D using mouse models of disease. Moreover we are examining the follow-on prediction that manipulation of MF phenotype via antagonists or agonists of UPR stress and/or the ISR will modulate the phenotype of MF; thereby reducing autoimmune pathophysiology and/or promoting islet transplant acceptance.

Individuals with mood disorders are differentially affected by abnormalities in glucose handling, hyperglycemia, and diabetes mellitus. Evidence indicates that both mood disorders and diabetes are highly associated with neurocognitive impairment as well as changes in brain volume and structure. Points of pathophysiological commonality have been implicated between mood disorders and diabetes and include alterations in metabolic effector systems, immunoinflammatory dysregulation, oxidative stress, and incretin systems. We have coined the moniker “Metabolic Syndrome Type II” to characterize these points of commonality. The Mood Disorder Psychopharmacology Unit (MDPU) is engaged in a plethora of both descriptive and interventional studies that aim to identify the effect of abnormal glucose homeostasis, insulin resistance, and incretin dysregulation on brain structure and function. The MDPU welcomes multidiscipline centre of excellence and research characterizing the psychiatry and endocrinology interface.