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Pathophysiology - Currently Funded

Dr. Camille Attané (Postdoctoral Fellowship Award funded 2012-2015)

Centre de Research-CHUM (Montréal, QC)

Supervisor: Dr. Marc Prentki

Title: Role of glycerolipid/free Fatty Acid cycling in beta-cell fuel excess detoxification

In type 2 diabetes, high blood glucose and high blood fats can be toxic to the beta cells (insulin-producing cells) of the pancreas. In order to cope with too much fat and glucose, cells detoxify themselves, but how this happens is not clear. Dr. Camille Attané plans to find out the importance of the cycle of fat production and breakdown and the release and use of glycerol (produced when the body uses stored fats for energy) in beta cell protection. Understanding how beta cells detoxify excess fat and glucose may lead to the discovery of new ways to treat type 2 diabetes.

 

Ms. Pei-Shan Cai (Doctoral Student Research Award funded 2011-2013)

Ontario Cancer Institute (Toronto, ON)

Supervisor: Dr. Minna Woo

Title: Investigating the role of Rb and Rb-family of proteins in cell cycle regulation of pancreatic β-cells

Beta cells were once thought to be non-dividing cells; however, it is now known that these cells indeed maintain the ability to divide. Ms. Cai is hoping to define the role of two proteins – retinoblastoma (Rb) and p107 protein – that control cell growth and death in pancreatic beta cells. This research will lead to a better understanding of beta cell growth which could lead to new therapeutic strategies for the prevention and treatment of diabetes.

 

Dr. Angelo Calderone (Operating Grant funded 2011-2014)

Montreal Heart Institute (Montréal, QC)

Title: The impact of diabetes on the biological role of cardiac neural stem cells during scar healing

Clinical studies have revealed that people with diabetes have a higher mortality rate following a heart attack. This could be due to inadequate scar healing following myocardial infarction. The inadequate healing of the damaged diabetic heart may be related, in part, to an impaired biological response by cardiac resident neural stem cells. Dr. Calderone is examining the impact of diabetes on the cardiac resident neural stem cell function during scar healing in the ischemically damaged heart. This research will provide important insight into impaired wound healing and may provide new treatments for people living with diabetes.

 

Dr. Willeke De Haan (Postdoctoral Fellowship Award funded 2011-2014)

University of British Columbia (Vancouver, BC)

Supervisor: Dr. Michael R. Hayden

Title: Mechanisms underlying protective effects of ABCA1 and HDL in beta cell survival

Low levels of the good HDL cholesterol is a risk factor for the development of diabetes. HDL has been shown to reduce beta cell death via an unknown mechanism. HDL also interacts with ABCA1 (essential for beta cell function). Dr. De Haan is not only examining the impact of changes in HDL and ABCA1 on beta cell survival, but also the mechanism by which HDL and ABCA1 affect beta cells as well as the impact of changes in plasma HDL levels on the development of diabetes. This research could contribute to the development of new strategies to prevent and treat diabetes using HDL and ABCA1 as targets.

 

Dr. Daniel J. Drucker (Operating Grant funded 2011-2014)

Mount Sinai Hospital (Toronto, ON)

Title: GPR119 and the control of glucose homeostasis

Activation of a receptor, called GPR119, stimulates the production of insulin, leading to improved regulation of blood glucose levels in the body. Dr. Drucker is examining the role of this receptor and how it functions in mice with abnormal blood glucose levels and insulin resistance. This research will help improve the current understanding of how GPR119 works within the body and determine whether or not it could be a useful target for new therapies for type 2 diabetes.

 

Dr. Jason R. B. Dyck (Operating Grant funded 2011-2013)

University of Alberta (Edmonton, AB)

Title: Abnormal Fatty Acid Metabolism and the Development of Insulin Resistance

Dr. Dyck is studying a novel pathway that may be contributing to the development of insulin resistance in the middle-aged population. This research could help to identify a treatment for insulin resistance associated with aging and diet-induced obesity, which may also be used for treatment of the majority of Canadians (>;40 years) who are at risk for developing type 2 diabetes.

 

Dr. Jennifer Estall (Operating Grant funded 2012-2015)

Institute de Recherches Cliniques de Montréal (Montréal, QC)

Title: Beta-cell mitochondrial function and the pathogenesis of diabetes

In the pancreas, beta cells produce insulin (the hormone that lowers blood glucose). Research has shown that people with type 2 diabetes have low levels of a protein called PGC‐1 in their beta cells. This protein allows a cell to produce more energy. If the PGC‐1 levels are low in beta cells, they may not be able to respond to changing energy demands in the body. Dr. Jennifer Estall and her team are investigating how changes in the levels of PGC‐1 affect beta cell function and if low levels of PGC‐1 contribute to the development of diabetes. With this knowledge, researchers may be able to design better treatments for diabetes or may be able to find new ways to predict a person's risk of developing diabetes.

 

Mr. Zhi Chao Feng (Doctoral Student Research Award funded 2012-2015)

The University of Western Ontario (London, ON)

Supervisor: Dr. Rennian Wang

Title: Determination of the Mechanisms by which the c-Kit Tyrosine Kinase Receptor Regulates Pancreatic Beta Cell Proliferation, Function and Survival.

Beta cells in the pancreas make and release insulin, the blood glucose lowering hormone. Type 2 diabetes can develop when too many beta cells die, causing not enough insulin to be released. Recently, Dr. Rennian Wang's team found that a protein (called the c-Kit receptor) that sits on the wall of cells, helps maintain enough beta cell survival and insulin release. When this protein doesn't work properly, beta cells die or stop functioning, and this leads to the onset of type 2 diabetes. Mr. Zhi Chao Feng is examining the role of c-Kit to find out how it helps beta cells to function and survive, allowing it to protect against diet-induced diabetes. These studies will help created a better understanding of how and why diabetes develops.

 

Dr. Matheiu Ferron (Postdoctoral Fellowship Award funded 2011-2013)

Columbia University (New York, NY, United States of America)

Supervisor: Dr. Gerard Karsenty

Title: Regulation of glucose metabolism by bone resorption

Ostocalcin, a hormone secreted by osteoblasts (cells responsible for bone formation), stimulates insulin secretion by the pancreas and insulin sensitivity in peripheral organs. Dr. Ferron is trying to determine the role played by osteoclasts in the control of osteocalcin activity and, therefore, in insulin secretion. This research could result in a new treatment for people with type 2 diabetes.

 

Mr. Kevin P. Foley (Doctoral Student Research Award funded 2011-2013)

The Hospital for Sick Children (Toronto, ON)

Supervisor: Dr. Amira Klip

Title: How does Glucose Transporter 4 (GLUT4) get sorted into the insulin-sensitive compartment?

Skeletal muscle is the major storage depot for glucose, which enters muscle cells through a glucose transporter (GLUT4) at the cell surface. Following a meal, insulin levels increase, triggering GLUT4 to move from insulin- responsive, GLUT4 storage vesicles (GSV) to the surface for glucose uptake. This process fails in prediabetes leading to type 2 diabetes. Mr. Foley is investigating how GLUT4 sorts into GSV in muscle cells, how sorting is regulated by 'molecular switches', how insulin manipulates this sorting network, and how conditions emulating prediabetes may cause defective GLUT4 sorting. This research has the potential to generate strategies to combat prediabetes and its progression to type 2 diabetes.

 

Dr. Herbert Y. Gaisano (Operating Grant funded 2010-2013)

University of Toronto (Toronto, ON)

Title: Mechanism and rescue of islet alpha cell dysregulated glucagon secretion in type 1 diabetes

In the pancreas, alpha cells release glucagon (which causes blood sugar to go up) and beta cells release insulin (which causes blood sugar to go down). In type 1 diabetes, glucagon release does not work properly, which can cause life-threatening low blood sugar after insulin injections. No treatment has been developed to regulate glucagon secretion. Dr. Herbert Y. Gaisano is examining pancreatic alpha-cells to determine why glucagon is not released properly in type 1 diabetes to determine if there are ways to fix this process.

 

Dr. Sara R. Hamilton (Postdoctoral Fellowship Award funded 2010-2013)

University Health Network (Toronto, ON)

Supervisor: Dr. Pamela S. Ohashi

Title: Role of the hyaluronan receptor, rhamm in T cell function and autoimmune responses

In type 1 diabetes, the immune system attacks insulin-producing cells (islet cells). Dr. Sara Hamilton is looking at a protein, called Rhamm, that acts to turn on and off immune cells called T cells. Dr. Hamilton will find out if Rhamm is part of the process that leads to type 1 diabetes in an effort to find out more about how and why type 1 diabetes develops, and if there are ways to stop it from developing.

 

Dr. Nathalie Labrecque (Operating Grant funded 2012-2015)

Maisonneuve-Rosemont Research Centre (Montréal, QC)

Title: Delineating the role of memory T cells in type 1 diabetes

Beta cells produce insulin, the hormone that lowers blood glucose. Immune cells, called T cells, normally attack infectious agents (bacteria and viruses), but in type 1 diabetes some T cells begin to attack the body's own beta cells. Dr. Nathalie Labrecque and her team will investigate the roles of a specific subset of T cells (memory T cells) in the development of type 1 diabetes, and if the T cell attacks on beta cells could be stopped using various drugs. Dr. Labrecque hopes that these drugs could be designed to stop only the attack on beta cells, while leaving the ability to fight infection unharmed. If successful, this could help develop effective treatments for type 1 diabetes.

 

Dr. Tony K. T. Lam (Operating Grant funded 2010-2013)

University Health Network (Toronto, ON)

Title: Glucagon action in the control of glucose homeostasis

Normally, blood sugar is regulated by two hormones: glucagon, which makes blood sugar increase; and insulin, which makes blood sugar decrease. Recent studies have shown that, in normal rats, insulin acting in the brain causes reduced sugar production in the liver – a "brain-liver axis" of control. This axis does not work properly in rats with diabetes. Dr. Tony K.T. Lam is investigating if a similar "brain-liver axis" exists for the hormone glucagon. If this axis exists, Dr. Lam will investigate how it acts normally and in diabetes.

 

Dr. Gary F. Lewis (Operating Grant funded 2011-2014)

University Health Network (Toronto, ON)

Title: Mechanism of fatty acid-induced impairment of glucose-stimulated insulin secretion

In a series of four studies, Dr. Lewis will study how high fat levels in the blood, called free fatty acids, damage the pancreas. In the first, he will determine whether a medicine called Buphenyl is able to protect against the damaging effects of fat. In the second, he will investigate whether an anti-inflammatory antibody, called XOMA 052, protects the pancreas against fatty acids. In the third, he will examine how insulin itself affects the pancreas' susceptibility to fatty acids. And, in the fourth, he will study the genetic influences that underlie this susceptibility. These studies will help us to understand what causes the pancreatic dysfunction that is typical of type 2 diabetes, and may identify potential new treatments that will counteract it.

 

Dr. Gareth E. Lim (Postdoctoral Fellowship Award funded 2012-2015)

University of British Columbia (Vancouver, BC)

Supervisor: Dr. James D. Johnson

Title: Role of the 14-3-3 proteins in glucose homeostasis and metabolism

Recent evidence shows that a family of proteins (originally discovered in the brain), called 14-3-3 proteins, might regulate insulin signaling. If this is so, these proteins might provide a new target for increasing insulin action in insulin resistance (a risk factor for diabetes) and in diabetes. Dr. Gareth Lim will test if the 14-3-3 proteins are essential in the regulation of blood glucose and metabolism, in order to further examine how insulin controls blood glucose levels.

 

Dr. Dan S. Luciani (Operating Grant funded 2012-2015)

Child & Family Research Institute (Vancouver, BC)

Title: Roles of Bax and Bak apoptosis proteins in beta-cell endoplasmic reticulum stress and diabetes

Too little exercise, poor diet and obesity can raise the blood levels of glucose and fats and cause insulin resistance, leading to type 2 diabetes. At first, the pancreas can adapt to insulin resistance by telling more beta cells (insulin-producing cells) to grow and by telling the beta cells to produce more insulin. However, if the demand on the beta cells gets too severe, they become stressed: they fail and eventually die. How beta cells fail and die when they are stressed is not yet understood. Dr. Dan Luciani and his team are exploring if and how two proteins, called Bax and Bak, protect or harm beta cells during the stress that leads to diabetes. Dr. Luciani and his team believe their research will lead to new information that can be used to find new ways to keep beta cells alive and functioning and would prevent type 2 diabetes from developing.

 

Dr. Patrick E. MacDonald (Operating Grant funded 2011-2014)

University of Alberta (Edmonton, AB)

Title: Distinct roles of PI3 kinase isoforms in glucose and incretin-stimulated insulin secretion from human islets

Reduced insulin release from beta cells represents a major factor contributing to the development of diabetes. Dr. MacDonald is studying the role of PI3 kinase family members in insulin release at the cellular level in human beta cells. Understanding how insulin release is controlled will help to identify the processes that fail in type 2 diabetes and may lead to new treatments.

 

Dr. André Marette (Operating Grant funded 2011-2014)

Laval University (Ste-Foy, QC)

Title: Exploring the mechanisms of action and anti-diabetic potential of novel omega-3 derived bioactive lipids

It is well known that long chain omega-3 (ω-3) polyunsaturated fatty acids (PUFA) consumption reduces the risk for type 2 diabetes. It was recently discovered that ω-3 PUFA are substrates for a new family of bioactive lipids known as resolvins, protectins and maresins. Dr. Marette is studying the influence of these lipids on glucose and lipid metabolism. This research could lead to the discovery of previously unrecognized therapeutic targets for insulin resistance and type 2 diabetes.

 

Ms. Renjitha Pillai (Doctoral Student Research Award funded 2011-2014)

University of Waterloo (Kitchener, ON)

Supervisors: Dr. Jamie W. Joseph and Dr. Brandan J. McConkey

Title: Mechanistic role of ARNT/HIF beta in glucose-stimulated insulin secretion.

Abnormalities or impairment in glucose stimulated insulin secretion (GSIS) is one of the earliest detectable defects of type 2 diabetes. Ms. Pillai is investigating the role of a certain gene (ARNT/HIF-1B) in the regulation of GSIS. This research will expand our current knowledge on the mechanisms that regulate insulin secretion from pancreatic beta cells. It will also provide valuable information on the role of ARNT/HIF1B in regulating GSIS, which could be potentially used for developing new therapies for the treatment of type 2 diabetes.

 

Dr. Constantin Polychronakos (Operating Grant funded 2011-2014)

The Montreal Children's Hospital (Montréal, QC)

Title: The insulin-specific T-cell repertoire in type 1 diabetes

In people with type 1 diabetes, insulin is the target of attack by immune system T-cells that destroy insulin- producing beta cells. Dr. Polychronakos is not only trying to identify the rare T-cells that carry a TCR (antibody-like molecule) that targets insulin, and to determine the specific structure of those TCRs, but to develop antibodies that specifically target the TCR of these T-cells. Such antibodies could potentially be used for new treatments to target and destroy the cells responsible for type 1 diabetes.

 

Dr. Alexey V. Pshezhetsky (Operating Grant funded 2010-2013)

Center de recherche CHU Sainte-Justine (Montréal, QC)

Title: Lysosomal sialidase Neu1: novel role in insulin signalling

Dr. Alexey V. Pshezhetsky is examining how the absorption of glucose is controlled by insulin, and how this process is impaired in mice that are fed a high-fat diet. Dr. Pshezhetsky hopes to further identify how energy is metabolized and how glucose is taken into cells in order to find ways to predict the development of diabetes.

 

Dr. Ravi R. Retnakaran (Operating Grant funded 2011-2014)

Mount Sinai Hospital (Toronto, ON)

Title: Vitamin D and the Early Pathophysiology of Type 2 Diabetes in Women with a History of Gestational Diabetes

Women who have had gestational diabetes (GDM) are at increased risk of ultimately developing type 2 diabetes, particularly in the first few years following their pregnancy. Recently, it has emerged that low levels of vitamin D in the blood may be associated with diabetes. Dr. Retnakaran is examining the role of vitamin D in determining whether a woman gets GDM in pregnancy and whether she later develops type 2 diabetes in the years after delivery. If low vitamin D is found to be related to GDM and type 2 diabetes in young women, then it may be possible to prevent these conditions by raising vitamin D levels.

 

Dr. Robert A. Screaton (Operating Grant funded 2011-2014)

Children's Hospital  of Eastern Ontario (Ottawa, ON)

Title: The Role of Sik2 in Beta Cell Biology

Beta cell failure in diabetes is still not well understood. The goal of Dr. Screaton's research is to study the role of Sik2, which is believed to stop beta cell proliferation and insulin secretion, by observing the effects of removing Sik2 from beta cells in mice. If we can better understand how proteins like Sik2 work in beta cells, we can find better ways of preventing type 2 diabetes.

 

Dr. Yi Sun (Postdoctoral Fellowship Award funded 2011-2013)

The Hospital for Sick Children (Toronto, ON)

Supervisor: Dr. Amira Klip

Title: Regulation of GLUT4 vesicle mobilization and tethering through molecular motors and linker proteins.

Muscle insulin resistance precedes type 2 diabetes, yet not much is known about what happens at the molecular level. In cultivated muscle cells, insulin resistance can be recreated to impair the arrival at the cell surface of vesicles carrying glucose transporter4 (GLUT4). Dr. Sun is investigating how insulin signaling cells work within the body, and how they regulate certain proteins (Rab13 and Rab8A) in order to allow GLUT4 vesicles to reach their target membrane. This research will map the final steps of GLUT4 mobilization to increase glucose uptake into muscle cells, and could possibly identify new defects that lead to insulin resistance.

 

Dr. Marta Szabat (Postdoctoral Fellowship Award funded 2012-2015)

University of British Columbia (Vancouver, BC)

Supervisor: Dr. James D. Johnson

Title: Mechanisms of beta-cell lipotoxicity in type 2 diabetes

Beta cells in the pancreas make and release insulin, the blood glucose lowering hormone. Type 2 diabetes can develop when too many beta cells die or stop functioning properly, causing not enough insulin to be released. High amounts of fat in the blood lead to beta cell death and dysfunction, but researchers do not know why this happens. Dr. Marta Szabat plans to use new technology to look at the genes and proteins in beta cells to find out how fats can damage beta cells. This study will improve researchers' understanding of the causes of beta cell death and dysfunction and how this leads to diabetes. Dr. Szabat hopes that her research will help in the search for ways to prevent, manage, and ultimately cure diabetes.

 

Dr. Robert G. Tsushima (Operating Grant funded 2011-2014)

York University (Toronto, ON)

Title: Role of Endogenous Cholesterol in Beta-Cell Stimulus-Secretion Coupling

Obesity is a risk factor for developing type 2 diabetes and high blood cholesterol is found in obese people. Statins are widely prescribed drugs used to treat patients with high cholesterol, including diabetic patients. Statins work by lowering cholesterol levels in the body. Recent clinical studies have shown statins may increase the risk of developing diabetes in patients. However, how lowering cholesterol can affect the beta cells in the pancreas is not well known. Dr. Tsushima is studying the effects of low cholesterol on beta cells and insulin release. This research may clarify the mechanism how lowering cholesterol by statin treatment may lead to the development of diabetes.

 

Dr. Dennis E. Vance (Operating Grant funded 2011-2014)

University of Alberta (Edmonton, AB)

Title: Phosphatidylcholine metabolism and insulin resistance

Phosphatidylcholine (PC) is an essential component of cells. The liver manufactures PC by the choline pathway or by the PEMT pathway. Previous studies have shown that there is a direct link between the PEMT pathway and type 2 diabetes. When wild type mice are fed a high fat diet, they gain weight and develop type 2 diabetes, however, mice that lack PEMT do not develop type 2 diabetes or obesity. Dr. Vance is investigating how the mice that lack PEMT are protected from type 2 diabetes and if the complications of type 1 diabetes are attenuated. This research could lead to the development of an inhibitor of PEMT as a novel treatment for type 1 and type 2 diabetes.

 

Dr. Rennian Wang (Operating Grant funded 2011-2014)

The University of Western Ontario (London, ON)

Title: Aldehyde dehydrogenase 1 (ALDH1) activity in the developing human fetal pancreas.

One of the major problems in people with diabetes is the loss of insulin-producing cells in the pancreas. Recently, studies using adult mouse pancreas demonstrated that ALDH1 is a marker of pancreatic progenitors. ALDH1+ cells were able to give rise to new insulin-producing cells. However, our understanding of the precise roles of ALDH1 in developing human pancreas is limited. Dr. Wang is trying to determine whether ALDH1+ cells in developing human pancreas represent insulin-producing precursors and the functional role of ALDH1 in regulating insulin+ cell formation. This research could help in the development of more successful strategies for generating insulin- producing cells for treatment of diabetes.

 

Dr. Michael B. Wheeler (Operating Grant funded 2012-2015)

University of Toronto (Toronto, ON)

Title: Identification of novel biomarkers in the development of type 2 diabetes

Type 2 diabetes develops when the body does not make enough insulin (the hormone that lowers blood glucose), or does not properly use the insulin that is made. Dr. Michael Wheeler wants to know how insulin deficiency happens: whether it is because beta cells (insulin‐producing cells) start dying, or because they stop working properly. Dr. Wheeler believes that beta cells stop working as the first cause of type 2 diabetes. He and his team will study people with prediabetes and at high risk for developing diabetes, and will examine proteins and molecules in their beta cells and blood to try to determine what happens to beta cells during the progression from prediabetes to diabetes. These studies will help define how type 2 diabetes develops. Dr. Wheeler hopes that these studies will allow him to develop future tests to predict who is at a high risk for developing prediabetes and diabetes.

 

Dr. Daniel A. Winer (Operating Grant funded 2012-2015; Clinician Scientist Award funded 2012-2017)

University Health Network (Toronto, ON)

Title (Operating Grant): B Lymphocyte Dysregulation in the Metabolic Syndrome

Title (Clinician Scientist Award): Mechanisms of B Lymphocyte Dysregulation in Insulin Resistance

Inflammation in the fat that surrounds internal organs (called visceral adipose tissue, or VAT) is known to be a major cause of insulin resistance, a risk factor for developing type 2 diabetes. Previously, Dr. Daniel Winer found that certain immune cells contribute to obesity‐related inflammation and insulin resistance. Dr. Winer and his team are now analyzing two subtypes of immune cells and immune system molecules called antibodies to determine how the immune system contributes to insulin resistance. They will then determine if they can block these processes in a way that could reverse inflammation. This research could lead to new ways to diagnose and treat insulin resistance, obesity‐related inflammation, and type 2 diabetes.

 

Ms. Lama Yamani (Doctoral Student Research Award funded 2011-2014)

McGill University (Montréal, QC)

Supervisor: Dr. Louise Larose

Title: The role of Nck1 and PERK interaction in pancreatic β-cell function

Ms. Yamani is investigating the significance of the interaction between the Nck and PERK proteins in the body's ability to produce and respond to insulin. This research will shed light on mechanisms that control insulin production and biological actions related to glucose control. This will enable us to learn more about the causes leading to the development of diabetes and open up avenues to design new therapeutic approaches to prevent and/ or cure diabetes.

 

Dr. Peter Zahradka (Operating Grant funded 2012-2015)

University of Manitoba (Winnipeg, MB)

Title: Beneficial metabolic and vascular effects of adiponectin require its proteolytic conversion to the globular form

Type 2 diabetes develops when the body does not make enough insulin (the hormone that lowers blood glucose), or does not properly use the insulin that is made. A hormone that is produced by fat cells, called adiponectin, has been shown to influence how the body handles high blood glucose. Adiponectin also protects the arteries against a common complication of diabetes, called atherosclerosis (hardening of the arteries). Dr. Peter Zahradka and his team aim to find out how adiponectin regulates blood glucose levels and the health of blood vessels. Normally, adiponectin can be found in two forms. Dr. Zahradka will investigate which form has benefits in the body. He hopes his research will show ways to create better treatments to improve blood sugar control and reduce artery disease in people with diabetes.

 

Previously Funded