August 2nd, 2013York University, Toronto

Minna Woo, Division of Endocrinology and Metabolism, University Health Network/Mount Sinai Hospital, TorontoDissecting the signaling pathways that control inflammation and metabolism in diabetes Myungshik Lee, Samsung Medical Center, Sungkyunkwan University, Seoul Autophagy deficiency in insulin target tissues leads to protection from obesity and insulin resistance Tony Lam, Banting & Best Diabete Centre, University of Toronto Glucagon and insulin signalling in the brain

Gary Lopaschuk, University of Alberta, Edmonton The contribution of diabetes and obesity to heart failure Minho Shong, Chungnam National University, Daejeon Mitochondrial dysfunction in metabolic diseases Zayna Khayat, International Centre for Health Innovation at the Ivey School of Business, London The end of the road in value capture from diabetes innovations: uptake by patients, practitioners and health systems

Dr Brian Rodrigues, Canadian Diabetes Association and University of British Columbia &

Dr SungWoo Park, Korean Diabetes Association and Kangbuk Samsung Hospital

Arrival and lunch buffetOpening remarks (on behalf of Canadian Diabetes Association, Korean Diabetes Association and York University)

Coffee break

Chair, SungWoo Park, Kangbuk Samsung Hospital & Sungkyunkwan University, Seoul

Chair, Gary Sweeney, York University, Toronto

Public lecture - Understanding diabetes and treatments 당뇨의 이해와 치료

CANADA-KOREA DIABETES RESEARCH INITIATIVE SYMPOSIUM캐나다-한국 당뇨병 연구 이니셔티브 심포지엄

2013 SYMPOSIUM

Head,

Division of Endocrinology and Metabolism,

University Health Network/Mount Sinai Hospital.

Associate Professor of Medicine and

Medical Biophysics, University of Toronto.

Canada Research Chair in Signal Transduction in

Diabetes Pathogenesis.

Dr. Woo received her medical degree from the University of Toronto.

She subsequently completed her subspecialty training in Endocrinology

and Metabolism and then obtained her PhD in the laboratory of

Dr. Tak Mak, from the Department of Immunology

at University of Toronto.

Her thesis topic was on intracellular signaling mechanisms that

determine life and death of different cell types.

Dr. Woo is currently the Head of the Endocrinology Division at the

UHN/MSH. Dr. Woo is a Scientist at the Toronto General Research

Institute where she leads an active research programme investigating

the molecular mechanisms of diabetes and its related diseases

including obesity, cardiovascular diseases and cancer.

Her research is supported by grants from the Canadian Institute of

Health Research and the Canadian Diabetes Association.

She is the recipient of the 2011 CDA Young Scientist Award and is

currently the Canada Research Chair in Signal transduction in

Diabetes Pathogenesis.

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Minna Woo MDFRCPC, PhD

Dissecting the signaling pathways that control inflammation and

metabolism in diabetes.

Type 2 diabetes is a global epidemic and our current state of knowledge and

treatment strategies for this disease will not overcome the increasing burden

on the healthcare demands. Insulin resistance is the underlying defect which

involves multiple tissues, and multiple cellular processes are implicated in-

cluding inflammation and oxidative stress. For the most part, compensatory

increase in insulin secretion can overcome insulin resistance at least for

maintenance of glycemic control. As such, genome wide association studies

have pointed to genes that determine function and mass of the pancreatic

beta cells as culprits. We use mouse models and take genetic approaches to

investigate fundamental genes that are involved in the cellular survival and

proliferation. Rb is one such gene, a master cell cycle regulator. The role of

Rb in islet progenitors and its effects in alpha and beta islet cells will be ex-

plored as potential novel therapeutic targets in diabetes. Also, inflammatory

signaling pathway including the JAK-STAT and regulators of reactive oxygen

species that control inflammation and metabolism as the underlying cause of

insulin resistance will be discussed.

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Dr. Lee is an expert in diverse fields such as metabolism, immu-

nology and cell death in Korea. After graduation of Seoul National

University Medical College, he finished clinical training in internal

medicine and endocrinology/metabolism, and also earned Ph.D.

from Seoul National University. After post-doctoral training at the

Scripps Research Institute in the field of immunology and molecular

biology, he has been working at the Dept. of Medicine, Samsung

Medical Center, Sungkyunkwan University School of Medicine.

During recent 5 years, he has been studying cell death-associated

inflammation, innate immunity and autophagy related to metabolism

and diabetes.

Autophagy is an evolutionarily conserved process which delivers cytoplasmic

components to lysosomes for degradation of aggregated proteins and

damaged organelles such as mitochondria. To study the role of autophagy in

insulin target tissues, we produced mice with deletion of Atg7, specifically in

skeletal muscle (Atg7Dsm mice). Atg7Dsm mice fed normal chow diet

showed reduced muscle/fat mass despite increased food intake, increased

energy expenditure, reduced tissue ATP content, and evidence of mito-

chondrial abnormalities such as morphologically swollen mitochondria, de-

creased mitochondrial oxygen consumption, reduced ATP content, impaired

COX activity together with reduced mtOxPhos gene expression.

Samsung Medical Center, Sungkyunkwan University School of Medicine

Myung-Shik LeeM.D., Ph.D.

Atg7Dsm mice fed high fat diet had markedly reduced

adiposity and improved hepatic steatosis through increasing lipid oxidation, leading to

marked improvement of insulin resistance. Metabolic studies including clamp study

demonstrated that lipolysis from adipose tissue, fatty acid oxidation, body core tem-

perature and glucose utilization were increased in Atg7Dsm mice, suggesting release

of a ‘myokine’ from autophagy-deficient skeletal muscle cells with mitochondrial

dysfunction leading to improvement of glucose-lipid profile. In search for myokine

released from autophagy-deficient muscle, we observed high induction of FGF21.

Fgf21 induction was mediated by Atf4, a master regulator of the integrated stress re-

sponse (ISR), which was in turn induced by mitochondrial dysfunction in autophagy

deficiency. Mitochondrial stressors also induced Fgf21 in an Atf4-dependent manner.

Induction of Fgf21, resistance to diet-induced obesity and amelioration of insulin

resistance were also observed in mice with autophagy deficiency in the liver, another

insulin target tissue. These findings suggest that autophagy deficiency in insulin target

tissues leads to systemic amelioration of lipid injury and insulin resistance by inducing

Fgf21, a ‘mitokine’, which is different from autophagy deficiency in insulin produc-

ing b-cells. Thus, metabolic impact of autophagy deficiency or mitochondrial dys-

function is dependent on the types of tissues affected, contrary to the current view

that autophagy deficiency or mitochondrial dysfunction would deteriorate metabolic

profile or lead to insulin resistance.

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Dr. Lam holds the J.K.McIvor (1915-1942) Endowed Chair in Diabetes

Research & the Canada Research Chair in Obesity. He is Associate Professor of

Physiology and Medicine at the University of Toronto, Associate Director of the

University of Toronto Banting and Best Diabetes Centre and Visiting Professor

of Physiology at the Shanghai Jiaotong University School of Medicine. Dr. Lam

directs a diabetes and obesity research laboratory at the Toronto General Re-

search Institute that identifies novel sensing mechanisms in the gut and the

brain that regulate hepatic glucose production, hepatic triglyceride-rich VLDL

secretion and food intake in diabetes and obesity. Dr. Lam’s findings are pub-

lished in journals such as Nature, Science, Nature Medicine and Cell Metabo-

lism.  Dr. Lam's laboratory is funded by the Canadian Institute of Health Re-

search and the Canadian Diabetes Association. Dr. Lam is the recipient of The

Endocrine Society 2013 Laureate Richard E. Weitzman Memorial Award and the

2012 Bela Issekutz Jr Memorial Lectureship at Dalhousie University.

Toronto General Research Institute, University Health Network. Departments of Physiology and

Medicine, University of Toronto. Banting and Best Diabetes Centre, University of Toronto.

Tony Lam Ph.D.

Glucagon and Insulin Signaling in The Brain

Diabetes and obesity are characterized by a disruption in glucose homeostasis due partly

to increased glucose production by the liver. A goal in diabetic therapy is to inhibit hepatic

glucose production to restore glucose homeostasis. Our laboratory has dissected insulin

and glucagon signalling mechanisms in the mediobasal hypothalamus and dorsal vagal

complex (two independent regions of the brain) that regulate hepatic glucose production

and glucose homeostasis. Insulin signals via a PI3K-independent but ERK1/2 dependent

pathway in the dorsal vagal complex to regulate hepatic glucose production, while gluca-

gon regulates glucose homeostasis via hypothalamic PKA signaling. Importantly, high fat

feeding disrupts insulin and glucagon signaling in the brain and consequently the control

of glucose production and glucose homeostasis. Studies aim to enhance insulin and

glucagon action in the brain may unveil novel anti-diabetic targets.

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Dr. Gary D. Lopaschuk is a Distinguished University Professor of Pediat-

rics at the University of Alberta, Edmonton. He is a Cardiovascular Researcher

whose research focuses on the regulation of fatty acid oxidation in the heart,

and the mechanism by which high rates of fatty acid oxidation contribute to

heart disease and heart failure. He is also examining how alterations in fatty

acid metabolism contribute to cardiovascular disease in the diabetic. At a

molecular level he has characterized a number of key enzymes important in the

regulation of cardiac fatty acid oxidation. He is also developing a number of

therapeutic strategies that involve optimizing energy metabolism in the heart

that can be used to prevent the development of heart disease, and that can

also be used to treat heart failure. His research has resulted in the publication

of over 350 original research articles, and he has been recognized by awards

such as the Canadian Cardiovascular Research Achievement Award and the

International Academy of Cardiovascular Sciences Research Achievement

Award. Dr. Lopaschuk is an Alberta Innovates Health Solution Scientist, and is

a Fellow of the Royal Society of Canada. He has served as Scientific Director

of the Mazankowski Alberta Heart Institute, and has previously served in a

number of capacities with the Heart Stroke Foundation of Canada, including as

Chair of the Scientific Review Committee and the Vice-Chair of the Research

Planning and Priorities Committee. He serves on a number of journal editorial

boards, including Circulation Research, Journal of Clinical Investigation, Ameri-

can Journal of Physiology, Cardiovascular Research, Journal of Molecular and

Scientific Director, Mazankowski Alberta Heart Institute, University of Alberta.

Distinguished University Professor, Departments of Pediatrics and Pharmacology, University of Alberta.

Alberta Heritage Foundation for Medical Research Sci-entist.

Gary D. Lopaschuk Ph.D.

Cellular Cardiology, Canadian Journal of Physiol-

ogy and Pharmacology, Heart and Metabolism, and

Cardiovascular Drugs and Therapy. He is also the President

and CEO of a biotechnology company (Metabolic Modulators

Research Ltd.), that is developing novel drugs to treat heart disease

that optimize energy metabolism in the heart.

Diabetes and obesity are risk factors for the development of heart failure (HF). However,

in patients with established HF the presence of obesity appears to be associated with a

lower risk of death compared to the non-obese patient (i.e. the obesity paradox). This

raises the question as to whether weight loss in obese individuals could worsen pre-

existing HF. We therefore investigated the effects of weight loss on cardiac function in

obese mice with HF. Obesity and HF was induced by feeding mice a high fat diet (HFD,

60% kcal from fat) and producing a transverse aortic constriction (TAC). At 6 wk post-

TAC, the obese mice were then either subjected to caloric restriction (a 40% decrease in

caloric intake) (CR-TAC) or maintained on a HFD (HFD-TAC) for a further 8 wk period.

CR-TAC mice had a decreased body weight compared to HFD-TAC mice (23.1±1.0 vs.

42.1±1.6 g, respectively, P<0.05). CR-TAC mice also showed a marked improvement in

whole body insulin sensitivity compared to HFD-TAC mice. HFD-TAC mice had impaired

systolic function compared to sham operated mice, with a reduced in vivo ejection frac-

tion (25.4 ±2.4% vs 61.9±4.0%, P<0.05, respectively), which was significantly improved

in CR-TAC mice (38±5.2%, P<0.05). Isolated working hearts from HFD-TAC mice were

insulin-resistant, showing a marked reduction in insulin-stimulated glucose oxidation and

an almost completely reliance on fatty acid oxidation as a source of energy (>95%).

CR-TAC mice showed a complete reversal of cardiac insulin resistance, and an increase

in the contribution of glucose oxidation to energy production (to 50%). We conclude

that weight loss in obese mice with HF markedly improves whole body and cardiac

insulin sensitivity, while lessening the severity of HF. These data suggest that

weight loss will not worsen HF in obese subjects with pre-existing HF.

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Dr. Shong has extensive research experience with endocrine cancer and

metabolic diseases in Korea. He has been involved in basic and translational

research in the endocrine field for more than 20 years. He holds a M.D.,

(Medicine), and a Ph.D. (Endocrinology), 1986, from Chungnam National Uni-

versity College of Medicine, Daejeon, Korea. Most recently he has been

involved in research projects on mitochondrial biology and medicine.

Mitochondrial dysfunction in metabolic diseases

Type 2 diabetes is frequently developed in the basis of insulin resistance which

is direct consequence of obesity-associated exposure of tissues to elevated

dietary nutrients, resulting the accumulation of toxic metabolic byproducts. The

organelle dysfunction involving endoplasmic reticulum (ER) and mitochondria

was investigated for the important cause of systemic glucose intolerance. The

ER dysfunction in metabolically active tissues was demonstrated as the under-

lying basis for activation of inflammatory or stress signaling pathways that are

critical in chronic insulin resistance and type 2 diabetes. Similarly, mitochondrial

dysfunction characterized with impaired oxidative phosphorylation (OxPhos) has

been proposed as an etiological mechanism of insulin resistance. However,

causative nature and initiating organ of OxPhos dysfunction for the development

of systemic insulin resistance has yet to be identified.

Dean, Chungnam National University School of Medicine.

Director, Research Center for Endocrine and Metabolic Diseases, Chungnam National University

Hospital, Daejeon, Korea

Minho ShongM.D.

To determine whether the mitochondrial dysfunction

contribute the insulin resistance and type 2 diabetes in vivo, we have analyzed metabolic

phenotypes of the mice which carrying OxPhos deficiency in both adipose tissues and islet

beta cells. Mitoribosome-associated factor (CRIF1) is a mitochondrial protein bound to

large subunit of mitochondrial ribosome and it mediates unique roles in insertion of newly

synthesized OxPhos subunits encoded by mtDNA into inner membrane. The mitochondrial

targeting sequence in amino-terminal region of MAF1 mediates the mitochondrial locali-

zation of CRIF1 in HeLa cells. The marked failure of OxPhos complex formation in

CRIF1-deficient MEFs (CRIF1-/- MEFs) results striking decrease of OxPhos complexes,

oxygen consumption rates and ultrastructural abnormalities in mitochondria. However,

CRIF1-/- MEFs derived from heterozygote mice showed normal basal OxPhos complex

formation, oxygen consumption rates and mitochondrial ultrastructures. These findings

indicate CRIF1 is essential for mitochondrial OxPhos function and its absence results in

marked mitochondrial OxPhos dysfunction.

In this symposium, the metabolic phenotypes of islet and adipose tissue specific

CRIF1-deficient mice will be discussed to support the suboptimal OxPhos deficiency is a

predisposing conditions for systemic glucose intolerance in normal and high fat diet

states.

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Dr. Zayna  Khayat is a senior leader with the International Centre for

Health Innovation, a “do tank” conceived by Industry Canada in 2009 to cata-

lyze the adoption of health innovations in health systems across Canada.  Dr.

Khayat works with private industry, health system leaders, regulators and

payers, academic researchers and students and postdocs across numerous

disciplines to build capacity for health innovation in Canada, and to build the

evidence base for what innovations have proven value creation.  Prior to joining

Ivey in 2013, Dr. Khayat was a strategy consultant in the health and life sci-

ences sector for more than 10 years, helping public and private organizations in

Canada and internationally tackle their most complex strategic and operational

challenges. In addition to her adjunct professorship at Ivey, Dr. Khayat on the

adjunct faculty in the Health Sector Strategy stream at the Rotman School of

Management at University of Toronto. She is also a senior advisor to Endeavour

Volunteer Consulting Network, and is on the advisory board of Geneyouin, a

consumer genetics startup. Zayna holds PhD in biochemistry from the University

of Toronto/Sickkids (2001), focused on the cell biology and biochemistry of

diabetes and insulin action. She resides in Toronto with her husband and 3

children.

Director of Development and Adjunct Faculty, International Centre for Health Innovation at the

Ivey School of Business, University of Western Ontario.

Adjunct Faculty, Health Sector Strategy, Rotman School of Management, University of Toronto.

Dr. Zayna A. Khayat Ph.D.

There is no shortage of proven ideas, treatments,

and solutions for how to enhance the health of the population, especially for

individuals with diabetes. And the pipeline of new ideas is ever-growing, on the back the

multitude of investments in biomedical R&D and translation of that knowledge to create

new companies, products, policies and services. However, once those solutions pass

proof-of-concept stage, and are ready to be taken up by the health system, we sorely

lack the ability to systematically leverage those solutions, adopt the leading edge inven-

tions, and commercialize products and services at a system-wide scale. The result is

ultimately an opportunity cost of capturing the full value potential that could and should

benefit the health of Canadians, the performance of the health-care system and drive

economic prosperity. Dr. Khayat will share how new models for innovation adoption are

emerging to address this major gap at the "end of the road" of value capture from health

innovation, drawing upon the unique health innovation adoption model catalyzed by the

International Centre for Health Innovation at the Ivey School of Business at Western Uni-

versity.

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YORKU N I V E R S I T EU N I V E R S I T E

UNDERSTANDING DIABETES AND TREATMENTSA Lecture For The General Public

당뇨병의 이해와 치료

당뇨병 공개강좌

Dr. Brian Rodrigues

Professor, University of British ColumbiaBoard Director & Chair of National Research Council, Canadian Diabetes Association

브리티쉬 컬럼비아 대학 교수캐나다 당뇨병학회 국립연구위원회 이사 및 위원장

박성우 성균관의과대학 교수 강북삼성병원 당뇨병센터장대한당뇨병학회 이사장역임현, 대한당뇨협회 회장

Professor University of Sungkyunkwan, Director of Kangbuk Samsung Hospital Diabetes Center,Board of Directors Korean Diabetes Association,President of Korean Association for the Patient with Diabetes

2013 SYMPOSIUM