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Research

Brief Profiles of Clinician Scientists in Division of Endocrinology

Dr. Andrew Advani

Novel therapies for the treatment and prevention of diabetic nephropathy
Diabetic nephropathy is the most common cause of kidney failure in Canada and a major risk factor for cardiovascular disease. While control of blood glucose and blood pressure, particularly with agents that block the renin angiotensin system, are welcome advances in slowing the progression of renal decline, the majority of patients continue to progress. New therapies are urgently needed. Our research is truly translational, studying the cellular processes involved in the development of the cardiovascular complications of diabetes and investigating the action of novel therapies both in vitro and in vivo. Through this, we hope to bring new treatments directly from the bench to the bedside. A number of processes are involved in the pathogenesis of diabetic complications, including oxidative stress, altered growth factor expression, aberration of the microvasculature and haemodynamic factors. Focusing, on aspects of each of these processes, our studies are heavily centred round animal models of both diabetic and non-diabetic renal disease, that closely recapitulate the human condition. With a dedicated team specializing in animal surgery, in vivo physiological assessment, molecular biology and histology, we believe we are ideally placed to reduce the time from drug discovery to clinical application.

Gillian Booth MD(Active Staff, Clinician Scientist [80% protected research time]

Major research interests: Models of care and health outcomes related to diabetes, with a focus on socioeconomic disparities in outcomes, and the impact of the built environment (neighborhood walkability and retail food environment) on the risk of diabetes and related diseases. Dr. Booth serves as advisor to the Canadian Chronic Disease Surveillance System, run by the Public Health Agency of Canada, and has played leadership roles in the development of both the 2008 and 2013 Canadian Diabetes Association Clinical Practice Guidelines, as Methodology Chair. Clinical activities: Two half-day clinics each week focusing on diabetes and pituitary disease.

Dr. Daniel Drucker (http://www.glucagon.com/druckerlabresearch.html)

Research in this lab is focused on understanding the biology of the glucagon-like peptides. Specific projects include physiological analyses of GLP-1 and GLP-2 action, understanding the biology of glucagon action, and elucidation of the functional control of both GLP-1 and GLP-2 action through studies of their respective receptors. Students and research fellows utilize a combination of techniques that involve cell culture, gene microarray and proteomic experiments, studies of signal transduction, cell proliferation and apoptosis, with a major emphasis on generation and phenotypic analysis of transgenic or knockout mice. The lab employees rodent models to delineate novel concepts of glucagon-like peptide action with a focus on potential therapeutic relevance to diabetes and intestinal disease.

Glucagon-like peptide-1. The lab maintains an active research interest in studying multiple aspects of GLP-1 action, including the GLP-1-regulated control of glucose homeostasis, and the role of GLP-1 signaling in the central nervous system. These studies employ cell lines, normal rodents, transgenic mice that over-express GLP-1 analogues, and mice with disrupted GLP-1 receptor signaling. The lab is also interested in studying the biology of exendin-4 action using studies of GLP-1 receptor -/- mice and cell and murine models. The lab uses a combination of approaches to delineate the physiological actions of GLP-1 including analyses of Glp1r-/- mice to understand the importance of GLP-1 for glucoregulation, islet growth, and apoptosis. The lab is also interested in the role of GLP-1 in the cardiovascular system and in the CNS. We are also carrying out studies to rescue GLP-1 receptor function in specific murine tissues via a transgenic approach in vivo. The importance of dipeptidyl peptidase-4 (DPP-4) for the control of incretin action is also an important focus of research investigation.

Glucagon-like peptide-2. The lab is using mouse genetics and both gain and loss of function experiments to understand the role of GLP-2 in vivo.Current projects include studies of the regulation of GLP-2 receptor expression and GLP-2 receptor signaling, and studies of both gain and loss of GLP-2 receptor signaling in vitro and in vivo. The lab employs rodent models of intestinal disease to identify potential therapeutic actions of GLP-2 in vivo. A major focus of the lab is to understand GLP-2 action via studies of GLP-2 receptor signaling in vitro, and by analysis of the downstream targets of GLP-2 in vivo.

Glucagon. The lab continues to focus on studies directed at understanding the physiology of glucagon action and wherever possible uses mouse models to complement data obtained from cell-based studies in vitro. More recent studies are focused on analysis of tissue-specific control of glucagon receptor action using genetically engineered mice, as exemplified by Gcgr-/- mice..

Dipeptidyl peptidase-4 (DPP-4). Given the importance of this key peptidase in the control of both GLP-1 and GLP-2 degradation, and its role as a key drug target for diabetes therapeutics, the laboratory is interested in the biology of DPP-4, and its importance in the control of multiple metabolic functions. Similarly, the laboratory also studies the biology of the related incretin GIP, and the PGDP oxyntomodulin.

Dr. Shereen Ezzat
We use cell and mouse models to recapitulate findings in primary human samples. Our Lab is interested in two broad areas:

1) Genetic polymorphisms:These represent frequent variations in the human genome which are statistically associated with increased disease risk. We aim to understand how these variants result in functionally distinct proteins that alter cell function.

2) Epigenetics: The assembly of DNA into a compact structure termed chromatin is essential for packaging the genome’s information into the relatively confining regions of the cell nucleus. Both common and dedicated enzymatic pathways responsible for modifying histone tail ends have now been implicated in reconfiguring chromatin structure. To this end, our lab is focusing on epigenetic mechanisms which can impose on genetic mutations. Our aim is to define the interface between extrinsic inputs such as metabolic signals which can modify the function of genetic pathways in health and disease.

Dr. I. George Fantus

The research program of Dr. George Fantus is a laboratory based program comprising basic biology and extending to translational research in human subjects. The focus of the program is Diabetes Mellitus (DM) and the research consists of the following 3 project areas:

1. Mechanisms of insulin signaling and the pathogenesis of insulin resistance.
Obesity and type 2 diabetes mellitus are characterized by insulin resistance. Investigations are performed using adipocytes (rat, mouse and human) to elucidate the insulin signaling defects caused by hyperglycemia, free fatty acids and cytokines along with studies designed to discover novel approaches and agents to increase insulin sensitivity. For example, it was discovered that the vasoactive factor, bradykinin, sensitizes adipocytes to insulin by interrupting a negative feedback inhibitory signaling pathway.

2. The pathogenesis of the complications of diabetes with a focus on diabetic nephropathy.
Hyperglycemia results in alterations in glucose metabolic pathways, cell signaling and gene expression in specific target tissues. The mechanisms by which these effects occur, and the most important of these signals which contribute to the pathological changes are being investigated. This research has identified potential targets for treatment and prevention, some of which are currently being validated in animal models.

3. Insulin resistance and cancer.
A relationship between hyperinsulinemia and cancer mortality has been suggested and elevated insulin is associated with breast cancer incidence and prognosis. Studies in cultured normal and malignant mammary epithelial cells and in insulin resistant/breast cancer mouse models are being carried out to determine the cellular and molecular mechanisms. In addition, studies with anti-diabetic insulin-sensitizing agents, e.g. metformin, are examining both nutritional interactions and therapeutic potential.

Dr. Susan R. George

The research focus in my laboratory is understanding the signal transduction mechanisms for dopamine and opioid receptors and other G protein coupled receptors in brain. We are particularly interested in the role of these receptors in neuropsychiatric disorders, such as schizophrenia, depression and drug addiction. The research is conducted at a preclinical level, using cell/neuronal culture, animal models and gene-deleted mice. A major focus of study at present is how the receptors communicate with each other and function together in coordinated signaling complexes on the cell surface to trigger particular second messenger signaling cascades such as triggered by calcium ions or cyclic AMP, how this occurs in brain and determining the functional consequences of specific receptor complex activation at the whole animal behavioral level. We are also mapping and localizing the receptor complexes in live neurons and in brain slices using state of the art methodology such as confocal FRET microscopy and others.

Dr. Richard Gilbert
Research direction - Translational research in the long-term complications of diabetes

The key objective of our laboratory is translational research, testing the potential efficacy of new therapeutic strategies in animal models, then progressing them to early phase clinical trials in patients. Major disease areas of interest are diabetic nephropathy, diabetic cardiomyopathy and diabetic retinopathy.

Techniques
In many of our studies, molecular biology, physiological, biochemistry and morphological approaches are combined.

Environment
Our laboratory employs several highly trained research technicians who enjoy the opportunity of teaching and supervising newcomers, including those with no prior experience.

Current research studies:In pursuing potential new strategies to treat and prevent the microvascular complications of diabetes, we are currently investigating:

1. Stem cell therapy. Following on from a successful early phase study of endothelial progenitor cell therapy in diabetic patients with refractory angina, we are investigating the potential efficacy of this treatment in diabetic nephropathy and associated heart failure.

2. Anti-fibrotic drug therapy. In collaboration with pharmacology and biochemistry groups, we have synthesised a range of novel, orally active, anti-fibrotic compounds for potential use in ameliorating the glomerulosclerosis and tubulointerstitial fibrosis that characterise diabetic nephropathy. These compounds are currently being tested in our animal models of diabetes complications.

3. Prognostic markers. Only one third of subjects with diabetes develop clinically significant microvascular complications, yet we treat them all similarly. Subjecting biopsy material from diabetic patients with and without nephropathy to transcriptional, proteomic and epigenetic analyses, we are investigating ways of predicting who among patients is complications-prone and who might be complications-resistant.

Dr. Gary Lewis

Dr Lewis performs whole body, integrative, physiological studies in humans and in animal models of disease. This type of research, which is also called translational research, builds on the clinician scientist’s clinical skills. Studies generally involve small numbers of subjects or animals (approximately 10 per treatment group), are short term in that they measure acute effects of interventions on the body rather than long term follow up, are intense in that they require intravenous infusions with frequent blood sampling and adjustment of infusions such as insulin and glucose. The two major lines of research interest of Dr. Lewis’ laboratory have consistently been and continue to be:

a) Determining the mechanism of intestinal and hepatic lipoprotein overproduction in insulin resistance and Type 2 diabetes. We perform studies in humans and in small animal models of insulin resistance, attempting to determine the molecular mechanisms whereby the liver and intestine overproduce lipoproteins in these conditions. We are currently examining the regulation of intestinal and hepatic lipoprotein particle production by hormones and inflammatory factors in humans, particularly as they pertain to the insulin resistant condition.

b) Determining the mechanism of high density lipoprotein (HDL) lowering in hypertriglyceridemic states such as insulin resistance and Type 2 diabetes. An additional major thrust of my laboratory has been to determine the mechanisms responsible for HDL lowering in hypertriglyceridemic states. Our current focus is on the mechanism whereby HDL triglyceride enrichment and interaction with hepatic lipase affects HDL clearance from the circulation.

Other lines of research interest are:

c) The effect of free fatty acids on pancreatic beta cell secretory function. In a series of in vivo experiments in humans and rats we have demonstrated ‘lipotoxicity’ from elevated plasma free fatty acids on pancreatic beta cell function. We are currently examining the role of oxidant stress, ER stress and inflammation in mediating the deleterious effects of lipids on beta cell function. These studies involve hyperglycemic and euglycemic clamps.

d) In vivo studies in genetically altered mice investigating the mechanisms of insulin resistance, impairment of pancreatic beta cell function and mechanism of action of pharmacological agents:

i. The role of c-reactive protein (CRP) in modulating insulin action and secretion. CRP is a marker of inflammation and its plasma level is elevated in insulin resistant states and Type 2 diabetes. CRP has recently been shown in vitro to impair insulin action. Using hCRP-transgenic mice and antisense technology we are investigating whether CRP plays a causative role in the development of insulin resistance and/or pancreatic beta cell impairment.

ii. CB1 receptor agonism and antagonism-differentiation of CNS fromf peripheral tissue-mediated beneficial metabolic effects. The CB1 receptor antagonist ramonabant has recently been approved in some countries for the treatment of obesity and has been shown to have a number of beneficial metabolic effects in humans. It is currently not known whether the beneficial effects of CB1 receptor antagonists are mediated via a direct CNS effect or via effects on CB1 receptors in liver and other peripheral tissues. We are examining this issue using CB1 receptor knockout mice, CB1 agonists and antagonists and liver-specific CB1 null and reconstituted mice, the latter kindly provided to us by collaborators at the NIH

iii. In collaboration with the regenerative medicine scientists atf U of T we are testing the function of insulin-producing stem cells in mice

Bruce Perkins, MD
(Clinician Investigator, Division of Endocrinology, Department of Medicine, University of Toronto).

Dr. Perkins research initiatives focus on using epidemiological techniques to explore the natural history of diabetes complications and novel strategies for their prevention. His major clinical research areas include: 1. Exploring the pattern of renal function decline and its determinants early in the course of nephropathy in type 1 diabetes. 2. Characterizing the natural history of diabetic polyneuropathy and defining the best methods for clinical assessment. 3. Diabetes technologies, including the process of care for intensive insulin therapy

Dr. Minna Woo (http://medbio.utoronto.ca/faculty/woo.html)

Our lab uses of genetic mouse models and takes a whole-body approach to delineate molecular mechanisms in specific tissues in the development of type 1 and type 2 diabetes. Two major areas of research are as follows:

1. Genetic determinants of pancreatic beta cell survival and cell death.
Not surprisingly, many of the molecules involved in islet survival/death are also known to play a role in tumourigenesis. Therefore the challenge in our lab is better understand the fine regulation that is required for the islets to have enhanced survival and function without promoting tumour formation. We use pancreas-specific gene knockout mice to study the role of many of the fundamental genes that are involved in cell cycle and apoptosis regulation in determining beta cell mass and function that control glucose homeostasis.

2. Neuronal effects insulin signaling in regulation of peripheral insulin sensitivity.
In the course of our study, we have also discovered that insulin gene is not only expressed in the pancreas but also in the brain! These newly discovered neurons appear to have a profound effect in determining peripheral insulin sensitivity and diabetes susceptibility. Using our novel mouse model, we are investigating the potent effects of these neurons controlling adipogenesis and cardiac metabolism.
Brief Biosketch of each Clinical and Clinical Epidemiological researcher:

Dr. Sophie Jamal

Dr. Jamal specializes in the treatment of metabolic bone diseases including osteoporosis. She has a PhD in Clinical Epidemiology and is co-director of the Toronto Centre for the Canadian Multicentre Osteoporosis Study. She is a member of Scientific Advisory Council for Osteoporosis Canada and a member of the editorial boards of Osteoporosis International and the Journal of Bone and Mineral Research. She conducts clinical research in 2 mains areas: the effects of organic nitrates on postmenopausal osteoporosis and studying the etiology and treatment of fractures among patients with impaired kidney function. She has received grants from the Kidney Foundation and the CIHR to conduct her research. In addition, Dr Jamal teaches a seminar course on how to conduct randomized trials in the Department of Health Policy Management and Evaluation, supervises PhD and Masters students, and serves as a research supervisor for summer student projects.

Dr. Lorraine Lipscombe

Dr. Lipscombe’s research focuses on diabetes epidemiology and health services, with a particular focus on diabetes in women. Specific areas of interest include:

  1. The association between diabetes and breast cancer
    There is growing evidence of a link between diabetes and certain forms of cancer. Using Ontario health care databases, we are exploring the risk of future diabetes among breast cancer survivors and the impact of breast cancer therapies. We are also examining the impact of diabetes and diabetes therapies on breast cancer prognosis in this population.
  2. Barriers to diabetes prevention in women with gestational diabetes
    Women with gestational diabetes have a higher risk of type 2 diabetes, however no formal prevention programs exist for this population. Our research is aimed at exploring the impact of timing since pregnancy on readiness for lifestyle change, and barriers to lifestyle change that may be unique to young mothers. We are establishing a cohort of Toronto women with gestational diabetes who will be surveyed during pregnancy and during their first and second postpartum years, and then followed longitudinally for risk of diabetes. Our data will help guide the development of a diabetes prevention program for women with gestational diabetes.
  3. Adverse drug effects in elderly patients with diabetes
    Our team at the Institute for Clinical Evaluative Sciences is exploring the long-term safety of medications in elderly patients with chronic disease. My research focuses on the safety of drugs in patients with diabetes, such as thiazolidinediones and antipsychotic agents.

Dr. Ravi Retnakaran
The Early Natural History of Type 2 Diabetes and Cardiovascular Disease in Women

One approach to studying the early natural history of a disease is to study the changes that take place over time in a high-risk population prior to the development of the condition of interest. In this context, my research focuses on the early pathophysiology of type 2 diabetes (T2DM) and cardiovascular disease (CVD) studied through long-term longitudinal evaluation of subjects at varying degrees of risk for the future development of these disorders. A central component of this program is a large prospective observational cohort study involving >600 women recruited in pregnancy and followed longitudinally for several years postpartum. In this ongoing study, participants undergo detailed cardio-metabolic characterization at recruitment in pregnancy and at 3-and 12-months postpartum. At 12-months postpartum, they are recruited into a 10-year prospective observational cohort study, involving detailed characterization of glucose homeostasis, beta-cell function, insulin sensitivity, cardio-metabolic risk factors (both traditional and non-traditional) and vascular function at regular intervals, including 2-years postpartum and then every 2 years thereafter. The concept underlying this program is that the gluco-regulatory response to the metabolic challenge posed by pregnancy provides unique physiologic insight into a woman’s future risk of metabolic and vascular disease. Indeed, in a series of recent papers, we have demonstrated that a woman’s glucose tolerance status in pregnancy provides a window to her future risk of both T2DM and CVD, ranging from high risk (i.e. in women with gestational diabetes (GDM)) to intermediate risk (i.e. in women with mild abnormalities of glucose tolerance in pregnancy) to low risk (i.e. in those women that maintain perfectly normal antepartum glucose homeostasis). This program also involves a series of sub-studies, including those assessing (i) endothelial function, (ii) the impact of diet, (iii) the hormonal composition/effects of breastmilk and (iv) effects on early metabolic and anthropometric development in the offspring.

Dr. Anna Sawka

My research is primarily focused on thyroid cancer, including epidemiology, outcomes, radioactive iodine treatment, quality of life, and complications of treatment. Other areas of interest include thyroid diseases and endocrine neoplasia. I am involved in the following types of research: knowledge synthesis (systematic reviews), knowledge translation, decision aids, observational studies, surveys, quality of life research, qualitative research, and economic analyses.

Dr. Baiju Shah

is a health services researcher at the Institute for Clinical Evaluative Sciences (ICES). His research interest is on measuring, understanding and improving the quality of diabetes care for patients in Ontario. He has three main areas of focus: 1) Diabetes care for ethnic, immigrant and aboriginal populations. 2) Care for and long-term consequences of gestational diabetes. 3) Different models or systems for delivering diabetes care. His research uses the large administrative databases at ICES, as well as other data sources such as chart abstraction. He is also conducting studies (including RCTs) of interventions to close the gaps in quality of care.

Dr. Bernard Zinman

The primary research interests of our program relate to the prevention of the long term complications of diabetes, identifying early biomarkers of diabetes and related metabolic abnormalities, the development and evaluation of new therapies for both type 1 and type 2 diabetes, diabetes in Aboriginal Canadians and the prevention of diabetes in high risk populations. The studies all involve human subject clinical investigation and include epidemiologic observation cohorts as well as clinical trial intervention studies . The research program is centred in the Leadership Sinai Centre for Diabetes research unit which includes facilities for research subject interaction and is supported by research nurses, research assistants, administrative staff and statisticians. Some of the more significant studies undertaken in this unit are the Diabetes Control and Complication Trial [DCCT], the Diabetes REduction Assessment with ramipril and rosiglitazone Medication [DREAM] trial , the Renin Angiotensin System Study [RASS] and the CANadian Outcome Evaluation [CANOE] Trial.

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