Profiles of BBDC Members Primarily Involved In Diabetes Research

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Sievenpiper, John - MD, PhD, FRCPC

University of Toronto Appointment(s): Associate Professor, Department of Nutritional Sciences, Faculty of Medicine

Other Appointment(s): Consultant Physician, Division of Endocrinology and Metabolism, St. Michael's Hospital
Scientist, Li Ka Shing Knowledge Institute, St. Michael's Hospital
Knowledge Synthesis Lead, Toronto 3D Knowledge Synthesis and Clinical Trials Unit, St. Michael's Hospital

Contact Information:
St. Michael's Hospital, Toronto 3D Knowledge Synthesis & Clinical Trials Unit
6137-61 Queen Street East
Toronto, ON   M5C 2T2

Phone: (416) 867-7475
Fax: (416) 867-7495

Diabetes Related Research Activities:

My research program continues to strive to identify and investigate important diet and disease questions in the area of cardiometabolic risk and diabetes.  We use knowledge synthesis techniques (systematic reviews and meta-analyses) and randomized controlled trials to address the need for high quality data to inform clinical practice guidelines and public health policy, as well as guide the design of future trials.  Clinical practice guidelines and public health policy are moving away from the more traditional macronutrient-centric dietary approaches (“low-fat”, “low-carb”, “high protein”) to more food and dietary pattern based approaches.  I have helped to initiate and steer this change in the 2013 guidelines of the Canadian Diabetes Association (CDA) and the upcoming 2015 guidelines of the European Association for the study of diabetes (EASD). My research program has attempted to keep up with this modernization, as reflected in the main ongoing food and dietary pattern based foci of my research program: sugars (fructose, sucrose, high fructose corn syrup), dietary pulses (beans, peas, chickpeas, lentils), tree nuts, and portfolio and low glycemic index dietary patterns.

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Singh, Krishna - PhD

University of Toronto Appointment(s): Assistant Professor, Department of Surgery

Other Appointment(s): Scientist, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto

Contact Information:
St. Michael's Hospital
30 Bond Street
Toronto, ON   M5B 1W8

Phone: (416) 925-8493

Diabetes Related Research Activities:

Background: Germ-line mutations in the tumor suppressor gene BRCA2 (breast cancer 2, early onset) predispose carriers mostly to breast cancer, and BRCA2 mutation carriers also face a 2-fold increase in the risk of developing diabetes. Hyperglycemia, the hallmark of diabetes, is a major risk factor for endothelial dysfunction leading to vascular complications. The relationship linking role of BRCA2 in the development of diabetes and endothelial dysfunction remains mainly unexplored.

Methods: To elucidate the role of BRCA2 in diabetes and endothelial apoptosis/dysfunction in vitro, we silenced BRCA2 in human umbilical vein endothelial cells (ECs) and evaluated the markers of EC function and apoptosis following hyperglycemia.

Results: We first confirmed the basal expression of BRCA2 in ECs at transcript and protein levels by qPCR and immunoblotting, respectively. Interestingly, hyperglycemia significantly induced BRCA2 expression after 48 hours of treatment. We then silenced BRCA2 in ECs and confirmed successful silencing at transcript and protein levels. Hyperglycemia significantly increased the reactive oxygen species (ROS) production in the BRCA2-deficient ECs in comparison to control ECs. Increased ROS production was associated with exacerbated DNA-damage in BRCA2-silenced ECs as evidenced by increased expression and activation of DNA double-stranded breaks (DSBs) marker H2A.X and reduced RAD51-foci formation, an essential regulator of DSB repair. Increased DSBs were associated with significantly increased activation of p53. Elevated levels of DNA-damage and activated-p53 were further associated with significantly increased hyperglycemia-induced apoptosis in BRCA2-silenced ECs as measured by immunoblotting for cleaved-caspase-3, Bax and by TUNEL-staining. Key indices of endothelial function, including tube formation and NO production, were significantly reduced following hyperglycemia-treatment in BRCA2-deficient ECs.

Conclusion: Our data for the first time, show an entirely novel role of BRCA2 as a regulator of endothelium in the setting of hyperglycemia, and provide important clues regarding the potential susceptibility of BRCA2 mutation carriers to hyperglycemia-induced cardiovascular complications.

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Sochett, Etienne - MB, ChB, FRCPC

University of Toronto Appointment(s): Associate Professor, Department of Paediatrics, University of Toronto

Other Appointment(s): Co-Director, Bone Health Centre, The Hospital for Sick Children.
Paediatric Endocrinologist, Department of Paediatrics, Division of Endocrinology, The Hospital for Sick Children.
Project Investigator, Research Institute, The Hospital for Sick Children.  

Contact Information:
The Hospital for Sick Children
555 University Avenue, Room 5114
Toronto, ON   M5G 1X8

Phone: (416) 813-6218
Fax: (416) 813-6304

Diabetes Related Research Activities:

Cardio Renal Dysfunction in Type 1 Diabetes:

Over the last 15 years, the direction of my renal research activities has been in understanding the early pathophysiology of diabetic nephropathy in adolescents with type 1 diabetes.  This area is widely acknowledged as being central to the prevention of diabetic nephropathy.  My efforts have involved the development and use of methodologies for measurement of urinary growth factors, ambulatory blood pressure monitoring and renal hemodynamic testing.  Study directions in this patient population have included; (a) the natural history of expression and progression of microalbuminuria (CV ref; 13, 21, 22) (Grant; PSI; 122,000) (Fellow: Lawson, M); (b) determinants of microalbuminuria expression i. Puberty; ii. Urinary Growth Factors (growth hormone, IGF-1 and TGG-beta); iii. Kidney size; iv. Dietary protein intake (14, 19, 24, 27) (PSI; 137,000) (Cummings, B). (c) the natural history of hypertension expression using Ambulatory Blood Pressure Monitoring (17) (d) The interaction between hypertension and microalbuminuria expression (Jefferies, C). (e) The relationship between diurnal blood pressure changes and glomerular hemodynamic alterations (34, CIHR 108, 773 – and Div Funds 34,000; Curtis, J). My role in this program includes, the underlying conceptual basis, supervision of the day to day administration and responsibility for the academic outcomes.

Over the last 8 years, I have developed a collaborative relationship with 3 adult nephrologists at the Toronto General Hospital, Dr. Judith Miller, Dr. James Scholey and Dr. David Cherney.  The focus of these more recent studies is the control and modulation of glomerular hemodynamic function in adolescents and young adults with uncomplicated type 1 diabetes.  Two studies have been completed and published (Renin Angiotensin Inhibition (CIHR) and Renal Hemodynamic function and COX2 Inhibition (JDRF) and Renal Hemodynamic Function). A third Nitric Oxide (CIHR) and Renal Hemodynamic function has just been completed and the results are being written up.  Funding is being applied for 2 further studies; specifically; Vitamin D and Rental Hemodynamic Function and Growth Hormone Inhibition and Renal Hemodynamic Function.  Our current team comprises of Dr. David Cherney (Clinician Scientist, Division of Nephrology, Dept. of Medicine), Dr. James Scholey (Clinician Scientist, Division of Nephrology, Dept. of Medicine), Dr. T. Bradley, a Paediatric Cardiologist, Ria Dekker (Research Assistant) and Yesmino Elia (Research Manager).  The principle achievements include (i) papers in Diabetes, Kidney International and Journal of the American Society of Nephrology and more recently in Diabetes Care (ii) providing evidence that the hyperfiltration state in diabetes is mediated by factors other than the rennin angiotensin system (iii) completion of the COX2 and NO grants and (iv) the addition of Dr. J. Scholey to the group of investigators.

I am also participating as a member of the HSC team in a multinational ‘Adolescent Type 1 diabetes Cardio-Renal Protection Study (AdDIT)’. Dr. D. Dunger (Cambridge, England) is the overall Principal Investigator and Dr. D. Daneman, the HSC PI.  I was responsible for the Screening Phase (Protocol: Screening for Microalbuminuria in Type 1 diabetes) in which 500 adolescents with Type 1 diabetes were screened on two separate occasions with three early morning urines in 2008.  I am currently responsible for the Observational Phase which commenced September 2011 and runs until 2016.  I also initiated, with our Co-Authors at Toronto General Hospital, an Ancillary Study to the Observational Arm of AdDIT in which markers of renal inflammation will be measured in the urine in a sub-cohort of the Observational Arm over a duration of the study.  This will allow us to address several questions regarding urinary proteomics and the development of renal and cardiovascular disease in adolescents with Type 1 diabetes.

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Sokolowski, Marla - PhD

University of Toronto Appointment(s): Professor, Department of Ecology and Evolutionary Biology, Faculty of Arts and Science

Other Appointment(s): Co-director of the Child and Brain Development Programme, Canadian Institute for Advanced Research

Contact Information:
Earth Sciences, Room 2070
25 Wilcocks St.
Toronto, ON   M5S 3B2

Phone: (647) 330-6398

Diabetes Related Research Activities:

The Drosophila melanogaster corpora cardiaca (CC) is functionally homologous to the mammalian pancreatic alpha cells and anterior pituitary gland.  The CC is the site of biosynthesis and secretion of the fly glucagon homolog, adipokinetic hormone (AKH).  The foraging gene (for) in D. melanogaster encodes a cGMP-dependent protein kinase (PKG) and is evolutionarily conserved across taxa.  for has a well-established role in the regulation of feeding behavior and metabolism.  We have identified a CC-specific role for for in the regulation of adult feeding behavior, lipid metabolism, and starvation stress response.  Our research uncovers a novel role for foraging and PKG in the CC, and begin to elucidate a putative mechanism whereby juvenile experience can influence adult metabolism and health outcomes. 

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Steiner, George - MD, BA, FRCPC, FCAHS

University of Toronto Appointment(s): Professor Emeritus, Departments of Medicine and of Physiology

Contact Information:
Toronto General Hospital
200 Elizabeth Street, Room 12EN213
Toronto, ON   M5G 2C4

Phone: (416) 340-4133
Fax: (416) 340-3314

Diabetes Related Research Activities:

Diabetes, lipoproteins and atherosclerosis.

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