Our Research Members

Lipid and Lipoprotein Disorders in Insulin Resistant States, Metabolic Syndrome and Type 2 Diabetes; Incretin Regulation of Intestinal Lipid and Lipoprotein Metabolism. Current areas of interest and active research in our laboratory include: Mechanistic studies of the link between diabetes and the increased risk of cardiovascular disease; Mechanisms of metabolic dyslipidemia in insulin resistant states; Regulation of Intestinal Lipid and Lipoprotein Metabolism by Gut Peptides; GLP-1 and GLP-2 signaling in the intesteine; Molecular biology of atherogenic lipoproteins and apolipoprotein B and involvement in the development of atherosclerosis; Mechanistic links between childhood obesity, insulin resistance, and the risk of development of premature atherosclerosis; mechanisms of action of hypolipidemic drugs at the cellular and molecular level.

Despite current treatments, people with diabetes continue to be affected by the long-term consequences of the disease. These long-term consequences are called complications and they include eye disease, kidney disease, nerve disease and heart disease. Kidney disease due to diabetes is the most common cause of kidney failure requiring treatment with dialysis or kidney transplantation and people with kidney disease are much more likely to also suffer from heart disease. Our research program is focused on the discovery and development of new treatments for kidney disease and heart failure, especially kidney disease or heart failure caused by diabetes; and on improving the lives of people living with Type 1 diabetes today. To help us achieve these goals we have three research strands:
1) Understanding the roles that epigenetic processes play in kidney disease and heart failure. 2) Repurposing existing therapies and exploration of the glucose-independent effects of diabetes treatments. 3) Learning about the experiences of young adults living with Type 1 diabetes.

Dr. Mahavir Agarwal is a psychiatrist by training who joined the University of Toronto Faculty in the spring of 2019. He is staff psychiatrist and Clinician-Scientist at the Centre for Addiction and Mental Health (CAMH) where he runs the Mental Health and Metabolism Clinic and the Clozapine Clinic in the Schizophrenia Division. His research interests lie in understanding the pathophysiology of metabolic and cognitive disturbances observed in schizophrenia, especially the severely elevated risk of obesity and type 2 diabetes observed in this population and the cognitive worsening that results from poor metabolic health. He is focusing on the role of insulin resistance in the brain in determining cognition and metabolic risk. To this end, he employs a multi-disciplinary approach to studying metabolic and cognitive outcomes using multi-modality neuroimaging, measures of cognitive functioning, and glucose metabolism (i.e. euglycemic pancreatic clamps and the oral glucose tolerance test).

Dr Johane Allard is a Gastroenterologist and a Professor of Medicine, cross-appointed to the Department of Nutritional Sciences, the Institute of Medical Sciences and the School of Graduated Studies of the University of Toronto. She is a Senior Scientist at the Toronto General Research Institute. Her research interest is nutrition related to obesity, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), malnutrition and nutrition support. She conducted previous studies on dietary intakes, gene expression, fatty acid composition, micronutrients and oxidative stress. More recently, she focused on NAFLD. 

Her group was the first to describe altered intestinal microbiota in patients with biopsy proven NASH compared to healthy controls. Following up on these findings, Dr. Allard with the bariatric surgery team at the University Health Network was awarded a CIHR operating grant examining the “Role of intestinal microbiota in NAFLD pre and post bariatric surgery.” Initial analysis showed that those with NASH had higher liver enzymes, insulin resistance, and presence of diabetes compared to those with a normal liver. Additionally, with bariatric surgery, there was a significant improvement in liver histology, biochemical, and clinical parameters but about 19% of patients had persisting NAFLD despite similar weight loss. These patients had less improvement in waist circumference and glycemic control. Studies on the intestinal microbiota and metabolites are pending.

Dr Allard is also the principal investigator of a CIHR team grant with Dr Gaisano as co-PI. She is heading a group of clinical/translational researchers and basic scientists, aiming at “Exploiting the therapeutic effects of the fecal microbiome in bariatric care”. The goals of the team grant are:

1. To track the changes in the intestinal microbiome in morbidly obese patients undergoing bariatric surgery and determine the relationship with improvement in insulin resistance, diabetes, and weight loss.
2. To test the effect of fecal microbiota transplant of lean donors into morbidly obese patients on insulin resistance, body weight and NAFLD.
3. To determine if fecal microbiota transplant from morbidly obese patients post-bariatric surgery can improve the in vivo parameters of insulin resistance, glucose-induced insulin synthesis, and obesity/weight loss in germ-free mice. The objective is to determine the specific candidate microbial species or genes in the mice that account for these beneficial effects.

Our laboratory performs both animal and human (all age groups) experiments. The main focus of research in my lab includes food intake regulation and glycemia; carbohydrates, sweeteners, appetite and health; proteins, amino acids and food intake; dietary control of peptide hormone and neurotransmitter metabolism; and food composition, dietary status and chronic disease. My laboratory is committed to elucidating the dietary determinants and mechanisms of glycemic control and food intake. Recent study topics include: (1) investigating the effect of milk products and novel milk products on metabolic control (glycemia and gut hormones), satiety and food intake, (2) the effect of pulses and pulse ingredients on glycemic response, subjective appetite, food intake and gut hormones, and (3) investigating the effects of high vitamin intake during pregnancy on neurotransmitter gene expression and their relationship with fat mass and insulin resistance in the Wistar rat offspring at birth, at weaning and beyond.

My research is focused on understanding how morphogen signalling pathways control developmental processes, including the differentiation of human pluripotent stem cells into diverse tissues.  Stem cell-based therapies for a variety of disorders are being explored including the use of beta cells as a cell replacement therapy for diabetics.  Protocols to produce pancreatic beta cells from human pluripotent stem cells have been established, but these beta cells are fetal-like and immature, requiring long term (months) in vivo implantation to acquire a more adult phenotype. Several studies indicate that the vascular niche is critical in this maturation process. We recently developed a proprietary microfluidic device that enables the in vitro production of perfusable vasculature.   We are currently exploring whether and how introduction of islet specific vasculature can enhance the efficient production of stem cell derived beta cells and promote their survival, function and maturation.

My research focuses on pancreatic function and insulin sensitivity in malnutrition.

I created an animal model of malnutrition and we are studying the acute and long-term effect of malnutrition on pancreatic function and insulin action. We also have performed and are currently doing clinic studies in low resource countries.

My program of research develops and evaluates community-based prevention programming for South Asian adults and adolescents living in Canada at risk for diabetes using mixed-methods designs from a socio-ecological perspective. A current project I am leading is the South Asian Adolescent Diabetes Awareness Program (SAADAP) funded by the Child and Youth Diabetes Strategy Fund by the Lawson Foundation. I am also a present fellow at the Institute of Clinical Evaluative Sciences (ICES) examining variation in the prevalence of diabetes across immigrants from the South Asian Diaspora in Ontario.

1) Regulation of tissue uptake and metabolism/signaling properties of fatty acids, especially within the brain.2) Genetic and dietary regulation of plasma fatty acid concentrations.

My research program examines how individuals balance energy homeostasis in conditions of excess dietary fat and elevated hormones and how abnormalities in these processes can lead to obesity and chronic disease development such as Type 2 Diabetes. More specifically, my research focuses on the immense functional role of stress (glucocorticoids), gut and pancreatic hormones in adipose tissue metabolism, and other peripheral tissues. I utilize cell culture and whole animal models to tease apart the molecular and cellular regulators of energy expenditure to better understand how they govern body weight, and glucose homeostasis.

Obesity is a major global health concern and is a major risk factor for other disorders, including diabetes, hypertension, and heart disease. A complex neuronal system has evolved to maintain energy homeostasis, and also glucose homeostasis. Leptin, ghrelin, glucose, glucagon-like peptides, and insulin are known peripheral signals that act to regulate feeding and energy balance by modulating the expression of neuropeptides in the brain, specifically the hypothalamus. The afferent hormones leptin and insulin have common physiological responses and intracellular signaling mechanisms, but insulin resistance and leptin resistance are major metabolic problems, sometimes leading to type 2 diabetes. We have a strong track record of neuroendocrine research, focussing on molecular and cellular biology using hypothalamic neuronal cell models. Our research program includes studies of the regulation and signalling mechanisms in many of the neuropeptide-expressing neurons involved in energy homeostasis, and the molecular/cellular events leading to leptin/insulin resistance. Importantly, there is also a direct relationship between nutritional status and reproduction, another long-term interest of my laboratory, therefore my research program is poised to utilize all the information gained from our work to provide insight into the complex nature of integrated neuroendocrine control of basic physiology.

The main focus of research in my lab is on atherosclerosis and specifically on interactions between cells and extracellular matrix during vascular remodeling. We are investigating mechanisms of vessel wall thickening and remodeling using experimental models of arterial injury in mouse, rat and rabbit, studying the role of extracellular matrix, cell-surface integrin receptors, the novel discoidin-domain receptors and MMPs in mediating SMC responses. In collaboration with Dr. Adria Giacca, we are studying the effect of high glucose and insulin on SMC growth and matrix remodeling in atherosclerosis.

I am a transplant hepatologist and clinician-scientist using a systems biology approach to studying metabolic complications post-liver transplant. Post-transplant Diabetes Mellitus (PTDM) has been shown to significantly compromise long-term transplant patient survival in around 25% of patients. However, its pathogenesis is poorly understood with need of further investigation to implement precisely designed preventive and therapeutic strategies. My research program uses a combination of Systems Biology and Machine learning approaches to layers of data from patient samples, using in vitro and in vivo models for validation. Using this unique approach, we hope to understand and develop more precise strategies to optimize the prevention and management of PTDM in our liver transplant recipients, thereby improving their long-term survival.

My research focuses on health outcomes and quality of care related to diabetes. Specific interests include: 1) how neighbourhood characteristics (e.g. community design, the food environment) contribute to the prevalence of obesity and diabetes; 2) gender, socioeconomic, and regional differences in diabetes outcomes; 3) health care strategies to improve the quality of diabetes care and 4) the application of geographic analytic tools to health care planning. Much of this work is done using linkage of large secondary databases including provincial administrative health care data, population-based surveys and census, retail and other environmental data sources. Students and research fellows use epidemiological and health services research methods to study diabetes and its outcomes at a population-level.

The major interests of the Brubaker laboratory relate to the synthesis, secretion and biological activities of gut hormones and, in particular, the intestinal glucagon-like peptides, GLP-1 and GLP-2. These hormones play important roles in the regulation insulin and glucagon secretion, beta cell proliferation, intestinal growth and function, and food intake. GLP-1 mimetics are currently in use for the treatment of patients with Type 2 diabetes, while a long-acting GLP-2 analog has recently been approved for the treatment of patients with intestinal insufficiency due to short bowel. Some of the areas that are currently under investigation in the lab include:

1. Regulation of GLP-1 and GLP-2 synthesis and secretion by the intestine, with particular focus on dietary nutrients and intracellular signalling pathways; and
2. Mechanisms of action of GLP-1 and GLP-2 to stimulate beta cell and intestinal growth, respectively, with a major emphasis on the roles of novel intra- and extracellular mediators of these effects, as well as possible carcinogenic effects.

Students and fellows utilize a wide-variety of approaches to investigate the physiology and pathophysiology of the glucagon-like peptides, including normal and genetically-modified animals, cell culture and imaging approaches, in combination with tissue and cellular analyses at the mRNA and protein level

Dr. Cafazzo leads the development of technologies as a way to keep people out of hospital by allowing for self-care at home for those with chronic conditions such as diabetes, asthma, end-stage renal disease and congestive heart failure.

These strategies are aimed at helping people before their conditions become acute and medical intervention is required. The emphasis here is improving patient self-efficacy.

One such solution is bant. Designed for adolescents with Type I diabities, bant simplifies diabetes management by connecting to a glucometer via Bluetooth. It also connects teens in a secure community of peers and helps them self-manage by rewarding positive behaviour every time they use their glucometer.

Main interests are mechanisms of neural synchrony and entrainment (epilepsy), hypoglycemic seizures, and neurodegenerative processes.
A) We have several projects on cellular mechanisms and local system dynamics of epilepsy, particularly the biophysics of the transition to seizure, and the role of electrotonic coupling via gap junctions. Molecular biological and cellular electrophysiological techniques are being used to measure the upregulation of gap junctions in several in vitro and in vivo seizure models.
B) Hypoglycemic seizures are a major problem in juveniles with diabetes. We are studying the pathophysiology of hypoglycaemic seizures in juvenile animals both in vitro and in vivo, noting that the most severe seizures seem to be associated with mainly subcortical seizure-like EEG activity, which could also be related to the ‘dead in bed’ or sudden unexplained death sometimes noted with juvenile hypoglycemic events. Also we are examining the pathophysiology of neuronal injury which is enhanced by glucose reperfusion. Glucose reperfusion is also associated with a significant upregulation of gap junctional expression, the significance of which remains to be elucidated. However is is known that provision of nutrients to neurons requires intact astrocytic gap junctional communication.

Current research interests in type 1 diabetes mellitus include the physiology of renal hyperfiltration in diabetic nephropathy, cardiorenal interactions and endothelial function, the effect of pharmaceutical agents on the urinary proteome, and functional gene polymorphisms in humans.

Research in my lab focuses on the relationship between diet, gut microbiota and health. We have been focusing on the establishment of the intestinal barrier and the role played by the gut microbiota in its regulation, at the transcriptional and post-transcriptional gene expression level. Building on recent findings linking gut microbiota, intestinal barrier and the metabolic syndrome, we are now expanding our research to understand how the establishment of the gut microbiota in early life may be linked to developing this condition in later life.

Dr. Connelly is a clinician scientist and staff physician at St Michael’s Hospital where his clinical responsibilities involve echocardiography and cardiac MRI. His basic science laboratory is involved in exploring mechanisms of diabetic complications, principally diastolic heart failure and developing novel therapeutic strategies to treat this. Dr. Connelly also collaborates closely with the Sunnybrook Health Sciences Centre in elucidating the role of real time cardiac metabolism in the pathogenesis of post MI remodeling, and developing novel MR techniques to enable non-invasive tissue characterization.