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2007 Diabetes Research Highlights

Carlen, Peter L.

Departments of Medicine (Neurology), Physiology and IBBME

The main aim of these experiments is to prevent or more successfully treat the potentially devastating consequences of hypoglycemic seizures, a common problem of type 1 diabetes. The mechanisms of hypoglycemic seizures and brain damage remain unclear. Our lab has developed novel in vitro models of hypoglycemic seizures using intact blocks of brain tissue, which have not been previously described. Using electrophysiological recording techniques and applying pharmacological agents, we are testing the following hypotheses:

The hippocampus, a structure deep in the brain related to learning and memory, is more susceptible than the cerebral cortex to hypoglycemic seizures and subsequent brain damage.
The seizures per se generated by the hypoglycemic state, greatly enhance the hypoglycemic-induced brain damage, due to the hypermetabolic state created by the seizures. Seizures cause the rapid depletion of cellular fuels, leading to metabolic collapse of brain cells. This damage is ameliorated by preventing these seizures or by replenishing oxidative fuels. Furthermore, brain regions prone to seizure activity will have a higher susceptibility to hypoglycemic damage.

These experiments are giving us greater insights into the fundamental mechanisms of hypoglycemic seizures and hypoglycemic brain damage. Abdelmalik PA, Shannon P, Yiu A, Liang P, Adamchik Y, Weisspapir M, Samoilova M, Burnham WM, Carlen PL. Hypoglycemic seizures during transient hypoglycemia exacerbate hippocampal dysfunction. Neurobiol Dis. 2007 Jun;26(3):646-60. Epub 2007 Mar 14.

Abdelmalik PA, Liang P, Weisspapir M, Samoilova M, Burnham WM, Carlen PL. Factors which abolish hypoglycemic seizures do not increase cerebral glycogen content in vitro. Neurobiol Dis. 2008 Feb;29(2):201-9. Epub 2007 Aug 29.

We are now investigating both the cellular and brain anatomical location of onset of hypoglycemic seizures, recording from cells in brain slices, and with depth electrodes from rats and mice undergoing hypoglycemia. To date two intriguing hypotheses have developed from this work: 1) the primary cellular component of hypoglycemic seizures in hippocampal brain slices appears not to be from neurons, but from glia, 2) the brainstem and not the cortex appears to be the primary anatomical brain site generating hypoglycemic seizures.

Colton, Patricia

Department of Psychiatry

Our group's psychosocial research focuses on the relationship between type I diabetes and eating disorders. Eating disorders are more common in pre-teen and teenage girls with type 1 diabetes than in their non-diabetic peers.

Eating disorders in individuals with type 1 diabetes are often persistent, can seriously worsen blood sugar control, and increase the risk of both hospitalization and diabetes-related medical complications. Little is known about the mechanisms of risk for eating problems in this high-risk population, and how each condition may influence the course of the other over time. We are therefore carrying out a longitudinal study of eating disturbances, psychosocial functioning and medical status in a cohort of girls with type 1 diabetes. This study is entering its 8th year, and our participants are now in their late teen years. This study is revealing that eating problems are common through the teen years, and that these problems are very likely to persist and worsen over time. We aim to better understand the clinical course of these problems, and to identify early individual and family risk factors and protective factors for eating problems, in order to better tailor prevention and intervention efforts for this high-risk group.

Cummins, Carolyn

Faculty of Pharmacy

Several members of the nuclear hormone receptor superfamily have been implicated in protecting against diseases associated with the metabolic syndrome. For example, from data obtained using animal models, it appears the liver X receptors (LXR and LXR) are protective against atherosclerosis, dyslipidemia, and diabetes and activation of the farnesoid X receptor (FXR) is protective against cholesterol gallstone disease. The current focus of the Cummins lab is on the study of these nuclear hormone receptors and their roles in regulating glucose metabolism. Recently, we have shown that LXR is involved in the regulation of cholesterol conversion to glucocorticoids in the adrenal gland and are investigating the influence of this finding on glucose metabolism and the onset of type 2 diabetes. Cummins CL, Volle DH, Zhang Y, McDonald JG, Sion B, Lefrançois-Martinez AM, Caira F, Veyssière G, Mangelsdorf DJ, Lobaccaro JM. Liver X receptors regulate adrenal cholesterol balance.J Clin Invest. 2006 Jul;116(7):1902-12.

Drucker, Daniel J.

Department of Medicine

The Drucker lab is carrying out studies focused on understanding the biology of the glucagon-like peptides and the translational relevance of glucagon, GLP-1, GLP-2 and oxyntomodulin for the treatment of disorders of energy homeostasis. The lab utilizes murine models engineered to exhibit selective or generalized loss of incretin receptor signaling to understand the importance of incretin action. Analysis of the phenotype of Gipr-/-, Glp1r-/- and Gipr-/-:Glp1r-/- mice demonstrate that the importance of GLP-1 and GIP for beta cell function is offset by the actions of these hormones in peripheral tissues such as the central nervous system and adipose tissue, as outlined in Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure J Clin Invest. 2007 Jan;117(1):143-52. Incretin receptor knockout mice have also been useful for understanding the mechanism of action of DPP-4 inhibitors, agents that inhibit the action of dipeptidyl peptidase-4, a key enzyme regulating the inactivation of incretin hormones. Continuous administration of the DPP-4 inhibitor vildagliptin lowered blood glucose in WT mice but completely failed to regulate beta cell function or glucose homeostasis in double incretin receptor knockout (DIRKO) mice Incretin receptors for glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide are essential for the sustained metabolic actions of vildagliptin in mice Diabetes. 2007 Dec;56(12):3006-13.

Fantus, I. George

Department of Medicine

Our laboratory is involved in three areas of research related to diabetes; the first being how high levels of glucose (sugar) cause the chronic complications of diabetes, such as kidney failure and blindness, and the second, investigating why people with type 2 diabetes do not respond normally to insulin, (called insulin resistance), and how this might be improved, and the third, how and why insulin resistance is related to cancer, in particular breast cancer.

Our research into complications has been focused on nephropathy (kidney disease) and the potential role of a pathway by which excess glucose entering a cell is metabolized. In this pathway, called the hexosamine biosynthesis pathway (HBP), a glucose-derived molecule is added onto proteins which alter their structure and function, a process called O-glycosylation. In renal glomerular mesangial cells this process caused increased expression of genes and synthesis of proteins which are implicated in the development of diabetic nephropathy (1). Inhibiting this pathway by genetic or pharmacological methods could have the potential to eventually prevent and/or treat this most serious complication.

Our recent studies in insulin resistance were stimulated by the clinical observation that treatment of people with high blood pressure (HBP) and type 2 diabetes with ACE (angiotensin converting enzyme) inhibitors, a common medication used to treat HBP, sometimes resulted in lowering of blood glucose. This drug results not only in a decrease in angiotensin, a hormone which raises BP, but also in elevation of bradykinin, a peptide hormone that lowers BP. We demonstrated that bradykinin enhances insulin signaling and glucose uptake directly in fat cells, that is, independent of its effects on blood vessels and blood pressure. The mechanism involves NO (nitricoxide) signaling which inhibits the enzyme JNK (Jun kinase) which, when activated, causes insulin resistance.

The development and prognosis of breast cancer appears to be increased by insulin and insulin receptors are expressed on malignant mammary epithelial cells (3). The mechanism of insulin's actions is not clear but activation of enzymes mediating growth signals, namely PI3-kinase and Akt/PKB and mTOR (mammalian target of rapamycin) may be involved. Metformin, a drug used in type 2 diabetes sensitizes cells to insulin, in part by activating AMPK (AMP activated protein kinase) and inhibiting mTOR. This occurs in tumor cells in culture (4, 5) and current studies are investigating the actions of insulin and metformin in mouse models of breast cancer.

Gaisano, Herbert

Departments of Medicine and Physiology

The Gaisano laboratory has been investigating the mechanisms by which SNARE and associated exocytotic proteins regulate insulin secretion. The central working hypothesis is that SNARE proteins (Syntaxin, SNAP-25) act to link together the distal components of insulin secretion, including not only exocytosis of the insulin granule, but also K+ (KATP and Kv2.1) and Ca2+ channels, priming and mobilization of insulin granule pools, into the fine sequence of events leading to secretion. Towards these areas, we reported the following recent contributions:

We demonstrated the role of priming proteins [Munc13-1, RIM2 and GEF2] and their complex interactions in mediating the different exocytotic events in islet beta cells, including compound and sequential insulin granule exocytosis, and exocytosis potentiated by GLP-1. (E Kwan et al., Diabetes 56:2579, 2007 PMID: 17639022). (Pancreas 25:e45, 2007 PMID: 17895835). (Diabetes, Obesity and Metabolism 9:99, 2007 PMID: 17919184).
We have furthered contributed to elucidating the role of syntaxin 1A in influencing KATP channel opener drug actions on islet b-cell KATP channels (B. Ng et al, Diabetes 56:2124, 2007 PMID: 17496234); and functional domains within SNAP-25 that distinctly functional regulate beta cell Kv2.1 channel (Pancreas 35:10, 2008 PMID:18192874). Our pioneering contributions to this field were published in a review (Y Leung and E Kwan et al, Endocrine Reviews 28:653, 2007 PMID: 17878408).

Going forward, our lab has now established new methods to: 1) examine islet cells (particularly glucagon-secreting alpha cells) in situ within intact islets using pancreatic slices (like brain slices) and by patch clamp electrophysiology; and 2) single insulin granule exocytotic kinetics using TIRF-microscopy.

Gilbert, Richard E.

Department of Medicine

Our research group focuses on the development of new potential therapies for the prevention and treatment of the long term complications of diabetes, principally diabetic nephropathy and heart failure. This translational approach involves the use of preclinical animal models as well as human subjects, using both drug and cell-based strategies. Members of the group come from a variety of different research backgrounds including molecular biology, cardiology, nephrology and endocrinology. Recent publications include:

Greenwood, Carol

Department of Nutritional Sciences

My research interest relates to studies examining the impact of dietary practices on cognitive function with aging. Type 2 diabetes is considered a risk factor for cognitive decline and dementia, including Alzheimer's Disease. We are interested in the relationships by which diet contributes to the development of insulin resistance and/or type 2 diabetes and how this relates to cognitive function. Our animal studies show that both the chronic consumption of high fat diets and an age-related development of poor glucose tolerance are associated with cognitive deficits. These data are consistent with our human studies demonstrating that static estimates of insulin resistance and beta-cell function are correlated with measures of cognitive performance. Indeed it now appears that cognitive deficits become apparent during early stages of diabetes development (prior to attaining clinical criterion used for diagnosis) and that these deficits worsen in association with declining glucose regulatory status. The cognitive deficits observed in adults with type 2 diabetes can be further exacerbated in association with the consumption of carbohydrate foods. Indeed, we hypothesize that the hyperglycemia experienced during the post-absorptive period is contributing to this further impairment in performance. Our current studies are examining the relationship between food-induced changes in circulating blood glucose levels and cognitive function in adults with type 2 diabetes.

Grynpas, Marc

Department of Laboratory Medicine and Pathobiology and
Institute for Biomaterials and Biomedical Engineering

Effect of Vanadium Treatment on Bone Loss and Bone Quality in Rat Models of Osteoporosis and Diabetes. Vanadium is a trace element, which has been shown to have insulin enhancing properties and have effects on carbohydrate and lipid metabolism. Vanadium compounds have been proven effective in experimental diabetes and insulin-resistant hypertension. Limited trials in humans have shown the anti-diabetic potential of these agents. However, while these agents have demonstrated little toxicity at therapeutic doses in rats, they are known to accumulate in bone mineral where vanadate substitutes for phosphate. It is therefore essential to understand the long-term effects on these agents on bone quality. We have shown that vanadium compounds improve diabetes-related bone dysfunction primarily by improving the diabetic state and appeared to increase bone formation in diabetic rats (see ref. below). We are now in the process of determining the effects of these compounds on combined models of diabetes and osteoporosis. Facchini DM, Yuen VG, Battell ML, McNeill JH, Grynpas MD. The effects of vanadium treatment on bone in diabetic and non-diabetic rats. Bone. 2006;38(3):368-77.

Irwin, David M.

Department of Laboratory Medicine and Pathobiology

Regulation of expression of the human proglucagon gene. My lab is interested in the regulation of the human proglucagon gene. We have previously shown that the sequences necessary for regulation of expression of the human proglucagon gene differ from those described for the rat proglucagon gene. We have found that sequences within intron 1, rather than the upstream of the promoter are essential for expression of the human proglucagon gene in pancreatic islets. The human immediate promoter region is transcriptional silent in pancreatic islet cells, in contrast to the transcriptionally competent rat promoter region. Our comparative analyses together with site-directed mutagenesis have identified a novel site in the human promoter, which does not exist in the rat promoter, which is important for regulating islet expression. These observations imply that in order to potentially modify the expression of the human proglucagon gene, for the treatment of Diabetes or obesity that we need to better understand the regulation of the human gene. (Tsai B, Yue S, Irwin DM. A novel element regulates expression of the proximal human proglucagon promoter in islet cells. Gen Comp Endocrinol. 2007 Apr;151(2):230-9.)

Klip, Amira

Professor of Paediatrics, Biochemistry and Physiology

My lab studies the cellular and molecular mechanisms of insulin action and how they are derailed in insulin resistance/diabetes. Using a muscle cell line expressing tagged glucose transporter 4 (GLUT4) generated in our laboratory, cell imaging and gene knockdown, we defined that insulin signalling bifurcates at the level of IRS isoforms, with IRS-1 leading to GLUT4 translocation to the membrane. This is achieved through PI3-kinase and we found two bifurcations downstream of this enzyme, one leading to Rac and actin remodelling, the other to Akt, its substrate AS160 and its target Rab8A. We found that GLUT4 vesicles fuse with the membrane through VAMP2, syntaxin4 and SNAP23, and we currently study how insulin signals regulate vesicle mobilization, tethering, docking and fusion. In a mass spectrometry analysis of insulin-dependent proteins interacting with GLUT4, we identified actinin4 as a linker between remodelled actin and GLUT4 vesicles. In parallel, we study how GLUT4 traffic is regulated by muscle contraction and its signals, AMPK and PKC. Our recent work reveals that these signals reduce GLUT4 endocytosis, while insulin increases GLUT4 exocytosis, and we are investigating the molecular basis of the regulation of GLUT4 endocytosis, as a possible mechanism to bypass insulin resistance.

Lam, Tony K. T.

Departments of Physiology and Medicine

Many laboratories worldwide have dedicated major efforts to elucidate the mechanisms responsible for the development of diabetes and obesity, with particular emphasis on the mechanistic regulation of energy and nutrient homeostasis. To unveil the pathway(s) that regulate both energy and nutrient homeostasis, the central nervous system (CNS) or more specifically the hypothalamus received much attention recently. In 2007, we began to unveil the neural circuit that regulates both glucose and lipid hemostasis.

Caspi L, Wang PY, Lam TK. A balance of lipid-sensing mechanisms in the brain and liver. Cell Metab. 2007 Aug;6(2):99-104. PMID: 17681145 [PubMed - indexed for MEDLINE]
Muse ED, Lam TK, Scherer PE, Rossetti L. Hypothalamic resistin induces hepatic insulin resistance. J Clin Invest. 2007 Jun;117(6):1670-8. Epub 2007 May 24. PMID: 17525801 [PubMed - indexed for MEDLINE]
Lam TK, Gutierrez-Juarez R, Pocai A, Bhanot S, Tso P, Schwartz GJ, Rossetti L. Brain glucose metabolism controls the hepatic secretion of triglyceride-rich lipoproteins. Nat Med. 2007 Feb;13(2):171-80. Epub 2007 Feb 4. PMID: 17273170 [PubMed - indexed for MEDLINE]

Leiter, Lawrence

Departments of Medicine and Nutritional Sciences

Dr Leiter's research team focuses on the prevention of atherosclerosis, especially in diabetes; clinical trials on new dietary and pharmacologic therapies for diabetes, dyslipidemia, and obesity; and the improvement of care in patients at high risk for vascular disease, including those with diabetes. We are involved in the design and execution of large, multicenter, clinical outcome trials in the prevention of atherosclerosis. Novel nutritional and pharmacologic therapies are also being evaluated in a large collaborative research group at St. Michael's Hospital. In addition, in collaboration with the Canadian Heart Research Center, a number of Canadian registries incorporating physician practice enhancement initiatives are underway.

Lewis, Gary

Departments of Medicine and Physiology

People who have prediabetes or Type 2 diabetes are resistant to the normal action of insulin in their body (insulin resistance) and are at very high risk of developing cardiovascular disease; heart attacks, strokes and circulation problems. Part of the reason for this is that they have high levels of blood fats; triglycerides and cholesterol. For many years scientists have tried to understand exactly why the body manufactures too much fat when it becomes insulin resistant. They have focused their attention on the liver, an important site of fat production. We have recently shown that the intestine is also implicated in the high production rate of fats and contributes to the elevation of fats in the blood. Our initial observations were made in animal models of insulin resistance but until recently it was still not known whether this phenomenon also applies to humans. We recently embarked on a new line of research and have begun to conduct a series of studies designed to investigate exactly why and how the intestine overproduces fat in insulin resistant humans. We use specialized techniques called stable isotope enrichment to tag the fat particles originating in the liver and intestine in order to determine their rate of production and clearance from the circulation of humans with and without insulin resistance. We are examining factors such as fatty acids, hormones and inflammatory factors that affect the production and clearance of these particles. Hopefully, by gaining an understanding of these mechanisms, we will then be able to design appropriate treatments to try and reduce the risk of heart disease in people who are insulin resistant.

Duez H, Lamarche B, Valero R, Pavlic M, Xiao C, Szeto L, Patterson BW, Proctor S and Lewis GF. Regulation of intestinal lipoprotein production by plasma free fatty acids in humans. Diabetes (56 (Suppl 1):A238, 2007

McIntyre, Roger S.

Departments of Psychiatry and Pharmacology

Dr. McIntyre is studying neurocognitive difficulties (concentration, memory, attention, and learning) in people with Major Depressive Disorder (MDD)and Bipolar Disorder. Insulin, best known for its effect on glucose regulation, is a critical protein in the brain that balances brain chemical transmitters, stimulates brain growth, and enhances brain cell survival, learning and memory. Animal studies indicate that the administration of insulin protects the brain from injury and improves memory. This investigation will attempt to determine if intranasal insulin improves memory and other aspects of neurocognitive function in individuals with MDD who do not have any apparent depressive symptoms. If effective, intranasal insulin could become a novel and innovative treatment for neurocognitive difficulties with potential to improve a depressed individual's quality of life and function. This work is supported by The Stanley Medical Research Institute and the National Alliance for Research on Schizophrenia and Depression. McIntyre RS, Soczynska JK, Konarski JZ, Woldeyohannes HO, Law CW, Miranda A, Fulgosi D, Kennedy SH. Should Depressive Syndromes Be Reclassified as "Metabolic Syndrome Type II"? Ann Clin Psychiatry. 2007 Oct-Dec;19(4):257-64. Review. PMID: 18058283 [PubMed - indexed for MEDLINE

Norwich, Kenneth

Department of Physiology, Institute of Biomaterials & Biomedical Engineering

Our group has studied the integration of the various factors that influence levels of blood glucose. We have developed a mathematical model that emulates the manner in which the hormone insulin and the peptides GIP and GLP-1 (incretins) work together to lower blood glucose, in response to sources of glucose such as the liver and bowel which supply glucose to the blood. Diabetes mellitus is a disease in which these factors - those that lower and those that raise blood glucose - tend to lose synchrony, so understanding the interplay of the many regulatory factors is important in the diagnosis and treatment of this disease. The oral glucose tolerance test is one in which a patient drinks a sweet solution, permitting the physician to monitor the rise and subsequent fall of glucose in his or her bloodstream over the next few hours. We have been analyzing this test mathematically to discover the type of result that would herald the start of insulin resistance, a feature of type 2 diabetes. Brubaker, P.L., Ohayon, E.L., D'Allesandro, L.M., and Norwich, K. H. A mathematical model of the oral glucose tolerance test illustrating the effects of the incretins. Annals of Biomedical Engineering, 35 (7), 1286-1300, 2007.

Parra, Esteban

Department of Anthropology

We characterized polymorphisms in two candidate genes (TCF7L2 and MGEA5) in a sample of type 2 diabetes patients and controls from Mexico. These studies have been published in the journals Clinical Genetics and American Journal of Human Biology, respectively. We have also published a manuscript in the American Journal of Human Genetics, describing a genomewide admixture mapping (AM) panel for Hispanic/Latino populations. This panel will make it possible to apply AM approaches to identify genetic susceptibility factors for common diseases (including type 2 diabetes) in many admixed populations throughout the Americas. Recently, we have initiated a type 2 diabetes AM project in collaboration with the research group of Dr. Miguel Cruz, from the Mexican Institute of Social Security. For this project, we are characterizing a large sample of type 2 diabetes patients (N=1,000) and controls (N=500), using Affymetrix Genome-Wide Human SNP array 5.0.

Retnakaran, Ravi

Department of Medicine, Division of Endocrinology and Metabolism

Women with a history of diabetes in pregnancy (gestational diabetes (GDM)) are at increased risk of developing type 2 diabetes (T2DM) in the years following the pregnancy. We are studying factors that lead to the development of T2DM within a large observational study involving >900 women, with and without a history of GDM. Specific areas of research interest include (i) physiologic determinants of the metabolic defects that lead to diabetes (insulin resistance and beta-cell function), (ii) novel metabolic and cardiovascular risk factors (including fat-derived hormones, such as adiponectin, and inflammatory proteins) and (iii) the impact of ethnicity. In 2007, we demonstrated that women with GDM have low circulating levels of the high-molecular-weight form of adiponectin, which may be a factor that contributes to their risk of developing T2DM (Retnakaran R, Connelly PW, Maguire G et al. Decreased high-molecular-weight adiponectin in gestational diabetes: implications for the pathophysiology of type 2 diabetes. Diabet Med 2007; 24(3):245-52). In addition, we showed that established risk factors for GDM may be important in women with a family history of T2DM, but may not be the principal determinants of gestational hyperglycemia in women without a family history of T2DM. These findings highlight the complex relationship between family history of diabetes and GDM, and may hold implications for selective screening for GDM (Retnakaran R, Conelly PW, Sermer M et al. The impact of family history of diabetes on risk factors for gestational diabetes. Clin Endocrinol 2007;67(5):754-60.)

Rozakis Adcock, Maria

Department of Laboratory Medicine and Pathobiology

The prevalence of obesity is increasing worldwide, as is the prevalence of obesity-related co-morbidity. Obesity is associated with an increased risk of developing insulin resistance and Type II diabetes (T2D). A universal observation in both humans and rodents is that impaired insulin secretion in obesity-linked T2D is caused by a marked increase in pancreatic beta-cell destruction that outweighs the rate of beta-cell replication and renewal. Currently, it is unclear what instigates an increased rate of beta-cell death during the pathogenesis of obesity-linked T2D. However, both chronic exposure to elevated levels of free fatty acids and prolonged fluctuations of high circulating glucose levels have a prominent influence. Thus maintaining beta-cell survival is a crucial factor for preventing the onset of T2D. Our laboratory recently reported the cloning of a novel WD-containing protein, PHIP1, and demonstrated that it plays a role in suppressing free fatty acid-induced cell death in beta cells. Moreover, PHIP1 has emerged as an important element that promotes beta cell growth.

Shah, Baiju

Department of Medicine

Dr. Shah's research focuses on the quality and outcomes of diabetes care. Much of this work is done using linkage of large health care administrative data bases to examine what is actually occurring in clinical care in Ontario. He has compared the care received by patients who see diabetes specialists versus those who see family physicians, and he is currently examining the impact of diabetes education programs on patients' care and health outcomes. He is also studying physician prescribing behaviour and diabetes care in visible minority groups.

Stewart, Donna E.

Professor, Department of Psychiatry and Faculty of Medicine

Our research program is carrying out studies to better understand psychosocial and behavioural dimensions that may affect diabetes self-management and health outcomes. We are also investigating how self-management education programs and resources are being used and delivered in Canada; specifically, when are patients referred to education, who is being referred, who uses these services, predictors of program attrition and retention, and the impact on varying use of education services on health outcomes using both quantitative and qualitative methods. In addition, we are researching how sex, gender and culture may differ in how services, education and care are being delivered and used by patients and how it may affect diabetes self-care and quality of life. Studies recently published from our research program include:

Volchuk, Allen

Department of Biochemistry and Department of Physiology

In 2007 we have been studying the effect stress in the endoplasmic reticulum has in contributing to dysfunction in insulin producing pancreatic beta cells in the context of chronically elevated lipids, glucose and inflammatory cytokines. We have used molecular biology strategies to make cells more or less resistant to stress in the endoplasmic reticulum to determine the contribution of this type of cellular stress to overall beta-cell function. We hope to publish these findings in 2008. In 2007 we also completed a collaborative study with researchers at the University of Toronto and the Hospital for Sick Children examining how chronic hyperglycemia causes oxidative stress in pancreatic beta-cells in culture and in diabetic animal models. We identified that pancreatic beta-cells from diabetic animals have elevated oxidative stress, which contributes to the accumulation of protein aggregates in the cytoplasm. Such aggregates may contribute to pancreatic beta-cell dysfunction, which is a feature of type 2 diabetes. These findings provide an additional mechanism by which chronically elevated glucose leads to reduced beta-cell function. The results of these studies have been published in the journal Diabetes: Kaniuk NA, Kiraly M, Bates H, Vranic M, Volchuk A, Brumell JH. Ubiquitinated-protein aggregates form in pancreatic beta-cells during diabetes-induced oxidative stress and are regulated by autophagy. Diabetes. 2007 Apr;56(4):930-9.

Vranic, Mladen

Department of Physiology and Medicine.

In collaboration with Allen Volchuk and John Brumell, we have demonstrated that diabetes induced oxidative stress induces ubiquitination and storage of proteins into cytoplasmic aggregates that do not colocalize with insulin. Autophagy, not proteasome, plays a key role in regulating their formation and degradation. To our knowledge, this is the first demonstration that autophagy acts as a defense to cellular damage incurred during diabetes. (Kaniuk NA, Kiraly M, Bates HE, Vranic M, Volchuck A, and Brumell JH. Ubiquitinated-protein aggregates form in pancreatic ß-cells during diabetes-induced oxidative stress and are regulated by autophagy. Diabetes 56(4): 930-939, 2007.) In collaboration with Steve Matthews we show that swim training prevents hyperglycemia in ZDF rats. Mechanisms involved in the partial maintenance of the ß-cell function involve: hypertrophy and replication of ß-cell mass, and an increase of the area of GLUT 2 and protein kinase B. Formation of ubiquitinated protein aggregates, a response to cellular/oxidative stress, occurred in nonexercised 19 wk-old ZDF rats but not in lean, 6 wk-old basal, or exercised rats. Thus, improved ß-cell compensation through increased ß-cell function and mass occurs in exercised ZDF rats and is in part responsible for improved glucorregulation. (Kiraly MA, Bates HE, Kaniuk N, Yue JTY, Brummel J, Matthews SG, Riddell MC, Vranic M. Swim training prevents hyperglycemia in ZDF rats: Mechanisms involved in partial maintenance of ß-cell function. Am J Physiol Endocrinol Metab, 294: E271-83, 2008.) Stress is widely assumed to worsen Type 2 diabetes and place a role in HPA hyperactivity. In collaboration with Steve Matthews we demonstrated that intermittent restraint stress only acutely increases glycemia, but this response adapts over time. Intermittent stress leads to HPA adaptations that prevent the exacerbation of hypercorticosteronemia - which is responsible for the stress-induced amelioration of hyperglycemia that occurs independently of food intake reductions. This conclusion is supported by gene expression of stress hormones and their receptors related to HPA activity. (Bates HE, Sirek AS, Kiraly MA, Yue JTY, Goche Montes D, Matthews SG, Vranic M. Adaptation to mild, intermittent stress delays development of hyperglycemia in the ZDF rat independent of food intake: role of habituation of the HPA axis, 2008. Endocrinology, 2008 (in press).

Wheeler, Michael B.

Departments of Physiology and Medicine

The primary focus of our lab is to investigate the cellular and molecular mechanisms that control pancreatic islet function in order to better understand how islet dysfunction contributes to the development of Type 2 Diabetes (T2D) and obesity. The pancreatic islet is primarily comprised of insulin-secreting β-cells and glucagon-secreting α-cells, which function synchronously to regulate blood sugar levels. Our group employs a multidisciplinary approach, which includes genomic and proteomic scans, molecular biology, real-time cellular imaging and patch-clamp electrophysiology alongside novel genetic mouse models to identify proteins involved in the regulation of insulin and glucagon secretion. We have previously discovered that uncoupling protein-2 (UCP2) regulates insulin secretion and β-cell function. More recently, we have examined the levels of UCP2 in α-cells and discovered that UCP2 also plays a role in maintaining α-cell function, glucagon secretion and α-cell survival. With the growing link between obesity and T2D, we are also interested in the effects of free fatty acids on islet function. We have recently demonstrated the opening of a novel mitochondrial pore believed to play a role in the regulation of β-cell metabolism during the early stages of high-fat stress. As well, we have investigated the role of oxidative stress in free-fatty acid-induced decline in β -cell function. Additionally, maintenance of zinc levels is crucial for cell survival as well as α-and β-cell function. As such, another recent research project in our lab has been to investigate zinc transport pathways and the regulation of zinc levels in α-cells. With this in mind, we have demonstrated that zinc inhibits glucagon secretion and it is transported into α-cells in part through calcium channels. Members of the Wheeler lab have access to state-of-art facilities and have forged collaborations with world-class researchers. As such the Wheeler lab is an excellent training environment for undergraduates, M.Sc. and Ph.D. candidate as well as post-doctoral fellows interested in T2D research.

Wojtowicz, J. Martin

Department of Physiology

Diabetes and Neurogenesis in the Adult Brain. Does insulin have a direct effect of developing neurons in the hippocampus? Discovery of neurogenesis (production of new neurons) in adult brain changed our view of brain plasticity and its role in learning and memory. The hippocampus is crucial for certain types of memory but the exact contributions of the new neurons to learning and memory are still unknown. Studies in our laboratory have shown that neurogenesis is essential for contextual fear memory (Wojtowicz et al., 2008). Diabetic neuropathy and associated cognitive deficits such as impaired memory are well-established phenomena, especially in elderly patients. In animal models of diabetes the cognitive changes consistent with reduced synaptic plasticity have been documented. The next challenge is to examine changes in hippocampal neurogenesis during diabetes and determine whether these changes contribute to the behavioral, cognitive deficits. We now have new data suggesting that neurogenesis in severely reduced in type I diabetes (Zhang et al., 2008). These changes are expected to have severe consequences on hippocampal learning and memory. The mechanism of these changes will be investigated in future studies.

Wolever, Thomas

Department of Nutritional Sciences

My research interests have to do with the role of diet in the prevention and management of obesity and type 2 diabetes. One of the unresolved debates in this area is whether insulin resistance and hyperinsulinemia is a cause or an effect of obesity. We recently obtained evidence supporting the notion that, in adults, hyperinsulinemia is a physiological response to obesity which helps to limit further weight gain. We showed that hyperinsulinemic subjects have lower food intake and higher responses of some food intake regulatory hormones than subjects with normal plasma insulin (Abou-Samra R, Wolever TMS, Anderson GH. Enhanced food intake regulatory responses after a glucose drink in hyperinsulinemic men. Int J Obesity 2007;31:1222-31). More and more prospective studies are showing that starchy foods which are digested and absorbed slowly and elicit low blood glucose responses may reduce risk for developing type 2 diabetes. One of our aims, therefore, is to assist industry in developing carbohydrate foods with such characteristics. We published this year the results of a series of studies suggesting that a novel sweetener called sucromalt has such properties; being slowly but completely digested and absorbed from the human small intestine and eliciting low glucose and insulin responses (Grysman A, Wolever TMS, Carlson T. Effects of sucromalt on postprandial responses in humans. Eur J Clin Nutr advance online publication 22 August 2007; doi: 10.1038/sj.ejcn.1602890). This is novel because most low-glycemic ingredients currently used to replace sugars or other carbohydrates (eg. sugar alcohols, enzymatically modified dextrins or fructo-oligosaccharides) are partly or completely malabsorbed.

Woo, Minna

Department of Medicine

Insufficiency in functional pancreatic beta cells is the quintessential finding in both type 1 and type 2 diabetes. The focus of our lab is to understand the genes that are important in growth and cell death during normal physiological turnover and during progression of type 1 and type 2 diabetes. We have taken genetic approaches to elucidate these roles in vivo using genetically engineered mouse models. Caspases are primarily known for their roles in apoptosis. However, their physiological roles in tissue homeostasis are not well understood. We have shown for the first time that Caspase-8 is essential in the development of type 1 and type 2 diabetes and serves as an essential molecule in the apoptotic process during diabetes progression. Furthermore, in homeostasis, caspase-8 plays a paradoxical pro-survival role. Liadis N, Salmena L, Kwan E, Tajmir P, Schroer SA, Radziszewska A, Li X, Sheu L, Eweida M, Xu S, Gaisano HY, Hakem R, Woo M. Distinct in vivo roles of caspase-8 in beta-cells in physiological and diabetes models. Diabetes. 2007 Sep;56(9):2302-11.

Woodgett, Jim

Department of Medical Biophysics

Insulin acts by stimulating glucose uptake and metabolism in various tissues in our bodies. In type-2 diabetes, these tissues become resistant to the effects of insulin which results in inefficient clearance of glucose from the blood. In an effort to find means to re- sensitize tissues to insulin, we generated a mouse model in which we specifically inactivated an enzyme that insulin normally inhibits. The idea was that inhibiting the function of this enzyme would allow less insulin to achieve the same result. As we hypothesized, these animals were found to be highly sensitive to insulin and were particularly efficient in promoting conversion of glucose into liver glycogen. Since the animals showed no other side effects, this study suggests that chemical inhibitors of this enzyme may be safe and useful in the treatment of type-2 diabetes. MacAulay K, Doble BW, Patel S, Hansotia T, Sinclair EM, Drucker DJ, Nagy A, Woodgett JR. (2007) Glycogen synthase kinase 3alpha-specific regulation of murine hepatic glycogen metabolism. Cell Metab. 2007 Oct; 6(4):329-337.

Zinman, Bernard

Department of Medicine

Dr Zinman's research team focuses on clinical investigation related to studies examining the long-term complications of diabetes; diabetes in aboriginal communities; and the evaluation of new therapies for Type 1 and Type 2 diabetes. The long term follow up of patients recruited to the DCCT [Diabetes Control and Complications Trial] has resulted in a better understanding of the relationship of metabolic control and the long term microvascular [ kidney failure, blindness and nerve damage] and macrovascular [ heart attack and stoke] complications of diabetes. In the Leadership Sinai Centre for Diabetes new therapies are being evaluated in a clinically relevant setting and provides on opportunity to implement translational research.

Banting and Best Diabetes Centre

Faculty of Medicine

University of Toronto

Research at the University

2007 Diabetes Research Highlights

Carlen, Peter L.

Colton, Patricia

Cummins, Carolyn

Drucker, Daniel J.

Fantus, I. George

Gaisano, Herbert

Gilbert, Richard E.

Greenwood, Carol

Grynpas, Marc

Irwin, David M.

Klip, Amira

Lam, Tony K. T.

Leiter, Lawrence

Lewis, Gary

McIntyre, Roger S.

Norwich, Kenneth

Parra, Esteban

Retnakaran, Ravi

Rozakis Adcock, Maria

Shah, Baiju

Stewart, Donna E.

Volchuk, Allen

Vranic, Mladen

Wheeler, Michael B.

Wojtowicz, J. Martin

Wolever, Thomas

Woo, Minna

Woodgett, Jim

Zinman, Bernard