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2006 Diabetes Research Highlights

Adeli, Khosrow

Molecular Structure and Function, Research Institute
& Department of Paediatric Laboratory Medicine
The Hospital for Sick Children

The incidence of insulin resistant states such as obesity and type 2 diabetes have been increasing at an alarming rate in recent years in both paediatric and adult populations. Our research program aims to elucidate the key genetic and environmental factors that link insulin resistance, lipoprotein abnormalities, and cardiovascular disease. We are investigating the underlying cellular and molecular mechanisms of the development of metabolic dyslipidaemia in insulin-resistant states. Using diet-induced animal models of insulin resistance and obesity, we are investigating the link between the insulin signaling pathway and deregulation of hepatic and intestinal lipoprotein metabolism. We also use these models to study the cellular and molecular mechanisms of hypolipidaemic and insulin-sensitizing drugs. Regulation of hepatic and intestinal apolipoprotein B gene expression is also under intense investigation, particularly at the posttranscriptional levels of protein translocation and intracellular degradation.

  1. Federico L., Xia Z., Naples M., Taylor D., and Adeli K. Intestinal Insulin Resistance and Aberrant Production of Apolipoprotein B48 Lipoproteins in an Animal Model of Insulin Resistance: Evidence for activation of PTP-1B, ERK, and SREBP-1c in the fructose-fed hamster intestine. Diabetes 2006, 55(5):1316-26
  2. Avramoglu-Kohen R, Basciano H, and Adeli K. Lipid and lipoprotein metabolism in insulin resistant states. Clin. Chem. Acta 2006, 368(1-2):1-19.

Belsham, Denise D.

Departments of Physiology, Obstetrics & Gynecology, and Medicine

Recently several researchers in the diabetes field have made the provocative proposal that diabetes is "a disease of the hypothalamus", a specific part of the brain controlling food intake. This statement may be over-reaching, but in the past few years it has been well-established that coordinated regulation of gene expression from the hypothalamus is critical to maintain energy balance. Recent studies suggest that in addition to regulating food intake, hypothalamic circuits also regulate insulin action, providing some insight into the potential link between type 2 diabetes mellitus and obesity; therefore research is essential to determine the contribution of the hypothalamus. Major efforts are currently underway in our laboratory to dissect the brain pathways involved, with the hope of discovering novel targets for the treatment of these complex disorders. We have generated 38 clonal hypothalamic cell lines with unique phenotypic profiles. Since they express many neuropeptides associated to the control of feeding behaviour, they can be used to study complex cell biology involved in the regulation of proteins linked to the control of feeding and energy homeostasis, such as neurotensin and neuropeptide Y (NPY). We have recently published a study on a novel leptin signal transduction pathway controlling neurotensin gene expression (Leptin signaling in neurotensin neurons involves STAT, MAP kinases ERK1/2, and p38 through c-Fos and ATF1. Cui et.al., FASEB J. 2006 Dec;20(14):2654-6). Further, we have also described how estrogen, a potential anorectic hormone, regulates NPY gene expression (Coordinate regulation of neuropeptide Y and agouti-related peptide gene expression by estrogen depends on the ratio of estrogen receptor (ER) alpha to ERbeta in clonal hypothalamic neurons. Titolo et.al., Mol Endocrinol. 2006 Sep;20(9):2080-92). We have many ongoing studies to understand the control of hypothalamic neuropeptides by nutrients and hormones, such as leptin, insulin, glucose, glucocorticoids, and estrogen.

Bendeck,Michelle

Department of Laboratory Medicine and Pathobiology

The focus of research in the Bendeck lab is on atherosclerosis. During the past year we have published a paper reporting the interaction of smooth muscle cells with type VIII collagen, a matrix protein upregulated after vascular injury, which enables cell migration by acting as a slippery substrate. These results elucidate the function of type VIII collagen in the vessel wall, and suggest that inhibition of type VIII collagen may be a good target to reduce vessel thickening in atherosclerosis. (Adiguzel et al. Migration and growth are attenuated in vascular smooth muscle cells with type VIII collagen-null alleles. Arteriosclerosis, Thrombosis and Vascular Biology 26: 56-61; 2006). Doxycycline is an antibiotic with MMP inhibitory activity, and it increases cell-cell and cell-matrix adhesion of smooth muscle cells. The net effect of doxycycline was to inhibit cell growth and migration, making it an attractive candidate for the treatment of atherosclerosis and restenotic vascular disease. (Franco et al. Doxycycline alters vascular smooth muscle cell adhesion, migration, and reorganization of fibrillar collagen matrices. American Journal of Pathology 168: 1697-1709 (2006).

Brubaker, Patricia

Department of Physiology

Research in the Brubaker lab is focused on the intestinal glucagon-like peptides, GLP-1 and GLP-2, which are released into the circulation following nutrient ingestion. GLP-1 has recently been approved in the USA for the treatment of patients with type 2 diabetes, due to its ability to stimulate insulin secretion, enhance beta cell growth and reduce food intake. GLP-2 is also in clinical trials for the treatment of intestinal insufficiency and inflammation, due to its actions to increase the growth and function of the intestine. A recent study has demonstrated that the effects of GLP-1 to enhance both insulin secretion and beta cell mass in vivo are balanced, such that the effects on insulin secretion may counter-act those on mass under certain conditions. Role of phosphatidylinositol 3-kinasegamma in the beta-cell: interactions with glucagon-like peptide-1. Endocrinology. 2006 Jul;147(7):3318-25. Epub 2006 Mar 30. Furthermore, studies on the regulation of fatty acid-induced GLP-1 release from the intestinal L cell have demonstrated an essential role for the atypical isoform of protein kinase C, PKCzeta, which may lead to new approaches to enhance circulating levels of GLP-1 in patients with type 2 diabetes. Protein kinase C{zeta} is required for oleic acid-induced secretion of glucagon-like peptide-1 by intestinal endocrine L cells. Endocrinology. 2006 Nov 16; [Epub ahead of print]. Finally, the actions of GLP-2 to stimulate intestinal growth were demonstrated to require the actions of another intestinal growth factor, insulin-like growth factor-1, thereby establishing the existence of paracrine mediators of GLP-2 action in vivo. The essential role of insulin-like growth factor-1 in the intestinal tropic effects of glucagon-like peptide-2 in mice. Gastroenterology. 2006 Aug;131(2):589-605

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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:
1) 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.
2) 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 will give us greater insights into the fundamental mechanisms of hypoglycemic seizures and hypoglycemic brain damage. (Two papers have been submitted and two more are in preparation.)

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 mellitus (DM) than in their non-diabetic peers. Eating disorders in individuals with DM are often persistent, can seriously compromise metabolic control, and increase the risk of both hospitalization and diabetes-related medical complications, particularly retinopathy and neuropathy. Little is known about the mechanisms of risk for eating disturbances 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. We aim to delineate the clinical course of eating disorders in girls and young women with type 1 diabetes, 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. Colton PA, Olmsted MP, Daneman D, Rydall AC, Rodin GM. Natural History and Predictors of Disturbed Eating Behaviour in Girls with Type 1 Diabetes. Diabetic Medicine, 2007 Feb 12, in press.

Connelly, Philip W.

Division of Endocrinology, Departments of Medicine and Laboratory Medicine and Pathobiology

The diabetes-related research in my laboratory has focused on studies of adipokines and inflammatory proteins in the Sandy Lake Oji-Cree (Elevated C-reactive protein in Native Canadian children: an ominous early complication of childhood obesity. Diabetes Obes Metab. 2006 Sep;8(5):483-91) and in studies of women with gestational diabetes (Low serum levels of high-molecular weight adiponectin in Indo-Asian women during pregnancy: evidence of ethnic variation in adiponectin isoform distribution. Diabetes Care. 2006 Jun;29(6):1377-9). We have observed that hs-CRP, an acute phase protein that predicts cardiovascular disease, is elevated in aboriginal children with obesity, with a prevalence similar to that for adults from the same population. These, and analyses of other risk factors in (Nontraditional cardiovascular risk factors in pediatric metabolic syndrome. J Pediatr. 2006 Feb;148(2):176-82) the children from the Sandy Lake cohort indicate significant early metabolic abnormalities and a high prevalence of multiple risk factors ("metabolic syndrome"). We believe that these early changes will lead to the complications of diabetes in early adulthood and need to be addressed with lifestyle and medical intervention. The inclusion of Caucasians, Chinese and Indo-Asians in our cohort of women with gestational diabetes has allowed us to identify ethnicity * specific effects on adiponectin concentration and the proportion of adiponectin in the high molecular weight form (Ethnicity modifies the effect of obesity on insulin resistance in pregnancy: a comparison of Asian, South Asian, and Caucasian women. J Clin Endocrinol Metab. 2006 Jan;91(1):93-7. Epub 2005 Oct 25). We hypothesize that abnormalities in adipokines and adiponectin in particular, will explain the increased prevalence of insulin resistance and susceptibility for Type 2 diabetes that is seen in Indo-Asians. We hypothesize that women in the group with the lowest concentrations of adiponectin with develop Type 2 diabetes within 5 years of follow-up. If this proves to be correct, then this new knowledge could be used for the early identification of women at risk for diabetes. These women could then be a focus for treatments known to reduce the development of diabetes, such as weight loss and pharmacologic therapy.

Danska, Jayne

Professor, Department of Immunology and Department of Medical Biophysics

Our research aligns North American and European investigators with expertise in autoimmune mechanisms and genetic control of T1D in humans and rodent models; the role of exposure to commensal bacteria in regulating the differentiation of the immune system; the genetics of T1D in high incidence Canadian and Scandinavian populations; and large prospective population studies of genetic and environmental T1D risk factors. Our goals are: 1) Leverage mechanistic and genome-wide analyses in spontaneous diabetic rodents to dissect interaction between defined genetic and environmental risk factors in disease progression. 2) Analyze impact of gestational environment on infant immune system and susceptibility to T1D. 3) Test positional and functional candidate genes obtained in rodent models for association with human T1D. Our ultimate objective is to integrate these data on genetic polymorphisms, immune function, exposure to intestinal microorganisms during gestation and early childhood to identify risk factors in T1D that are amenable to therapeutic intervention strategies. We have made considerable progress in defining complex genetic contributions to T1D in the NOD mouse and BB rat models, in defining the role of commensal bacteria on immunological development and function, in establishing family-based genetic studies of Type 1 diabetes, and in design and execution of large, international, prospective population-based studies toward identification of genetic and environmental factors contributing to T1D risk. The idd4 locus displays sex-specific epistatic effects on type 1 diabetes susceptibility in nonobese diabetic mice. Diabetes. 2006 Dec;55(12):3611-9 and Molecular analysis of the Idd4 locus implicates the interferon response in Type 1 diabetes susceptibility of the NOD mouse. Journal of Immunology 2006 Mar 1; 176: 2976-2990.

Dosch, Hans-Michael

Department of Immunology

In type 1 diabetes, T cell-mediated death of pancreatic beta cells produces insulin deficiency. However, what attracts or restricts broadly autoreactive lymphocyte pools to the pancreas remains unclear. We report that TRPV1(+) pancreatic sensory neurons control islet inflammation and insulin resistance. Eliminating these neurons in diabetes-prone NOD mice prevents insulitis and diabetes, despite systemic persistence of pathogenic T cell pools. Insulin resistance and beta cell stress of prediabetic NOD mice are prevented when TRPV1(+) neurons are eliminated. TRPV1(NOD), localized to the Idd4.1 diabetes-risk locus, is a hypofunctional mutant, mediating depressed neurogenic inflammation. Delivering the neuropeptide substance P by intra-arterial injection into the NOD pancreas reverses abnormal insulin resistance, insulitis, and diabetes for weeks. Concordantly, insulin sensitivity is enhanced in trpv1(-/-) mice, whereas insulitis/diabetes-resistant NODxB6Idd4-congenic mice, carrying wild-type TRPV1, show restored TRPV1 function and insulin sensitivity. Our data uncover a fundamental role for insulin-responsive TRPV1(+) sensory neurons in beta cell function and diabetes pathoetiology. TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes. Cell 2006 Dec 15;127(6):1123-35.

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Drucker, Daniel J.

Department of Medicine, Division of Endocrinology & Metabolism

The Drucker lab is carrying out studies focused on understanding the factors regulating proglucagon gene expression in the gut and pancreas, as well as the actions of the glucagon-like peptides, GLP-1, and GLP-2, on their target tissues. The first GLP-1R agonist, exendin-4, has been approved for the treatment of type 2 diabetes, and DPP-4 inhibitors that lower blood glucose through prevention of incretin degradation were approved for the treatment of T2DM in October 2006. The lab is interested in understanding the biological implications surrounding the immunogenicity of GLP-1R agonists such as Exenatide (synthetic exendin-4) as described in Lymphocytic Infiltration and Immune Activation in Metallothionein Promoter-Exendin-4 (MT-Exendin) Transgenic Mice. Diabetes. 2006 Jun;55(6):1562-70. As GLP-1R activation promotes cell proliferation and inhibits apoptosis, the effects of sustained GLP-1R activation on the growth and apoptosis of human pancreatic cancer cells was examined in Activation of glucagon-like peptide-1 receptor signaling does not modify the growth or apoptosis of human pancreatic cancer cells. Diabetes 2006 May;55(5):1369-79. Finally, we continue to be interested in elucidating novel actions of GLP-1R signaling on the islet  -cell. Our studies have uncovered a link between GLP-1R activation and ER stress, providing an understanding of how GLP-1R agonists improve insulin biosynthesis and secretion yet reduce apoptosis in vulnerable stressed -cells, as outlined in GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress. Cell Metab. 2006 Nov;4(5):391-406

Elsholtz, Harry

Department of Laboratory Medicine & Pathobiology

Our lab studies the molecular biology of pituitary hormones. Prolactin and growth hormone regulate key reproductive events and somatic growth, respectively, and can have direct effects on pancreatic islet cell development and function. Prolactin receptor deficient mice exhibit reduced islet beta cell mass, decreased insulin gene expression, and an impaired insulin response to glucose. We have investigated regulation of the prolactin gene, and identified pathways that lead to transcriptional repression. The catecholamine dopamine for example, binds to D2 type receptors and inhibits prolactin transcription by a G-protein specific, MAP kinase dependent pathway. We are using gene silencing techniques (siRNA) to target and identify critical components of this regulatory mechanism, including 'downstream' kinases that mediate MAP kinase (ERK 1/2) effects at the level of transcription. In related studies, we are investigating the chromatin-associated events that determine how endocrine signals control prolactin gene transcription. Chromatin immunoprecipitation and PCR are used to characterize early and late epigenetic changes in the prolactin promoter region and distal enhancer in response to dopamine, glucocorticoids, and inhibitors of MAP kinase signaling. Understanding how the selective recruitment/ dismissal of DNA-binding transcription factors and co-regulatory proteins alters histone modification and transcriptional initiation of the prolactin gene is a goal of this work.

Fantus, I. George

Department of Medicine

Our laboratory is involved in two 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.

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 we observed that more glucose metabolized by the HBP which stimulated intracellular protein O-glycosylation 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. Some studies suggested that bradykinin might increase insulin sensitivity. 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 which we discovered, consists of a bradykinin-stimulated signaling pathway that inhibits members of a family of enzymes called MAPKs (mitogen-activated protein kinases), which when activated cause insulin resistance (2). Inhibiting these enzymes could improve insulin resistance, lower blood glucose and, in a selected subset of people with HBP, even prevent type 2 diabetes.

  1. Goldberg, H.J., Whiteside, C.I., Hart, G.W., Fantus, I.G. Posttranslational, reversible O-glycosylation is stimulated by high glucose and mediates plasminogen activator inhibitor-1 (PAI-1) gene expression and Sp1 transcriptional activity in glomerular mesangial cells. Endocrinology 147: 222-231, 2006.

  2. Beard, K.M., Lu, H., Ho, K., Fantus I.G. Bradykinin augments insulin-stimulated glucose transport in rat adipocytes via an endothelial nitric oxide synthase (eNOS)-protein kinase G (PKG)-dependent signalling pathway. Diabetes 55:2678-2687, 2006

Giacca, Adria

Departments of Physiology and Medicine

Dr. Giacca's work is on the role of energy excess in the causing type 2 diabetes, atherosclerosis and cancer. She is working on the hypothesis that energy excess leads to these diseases through similar mechanisms which involve oxidative stress and inflammation. Her laboratory uses infusion of glucose and fat in rats and mouse models to determine the mechanisms whereby excess nutrients oppose the action of insulin and stress the pancreatic beta cell producing insulin, which ultimately causes diabetes (Goh et al. LIPID- INDUCED {beta} CELL DYSFUNCTION IN VIVO IN MODELS OF PROGRESSIVE {beta} CELL FAILURE, Am J Physiol Endocrinol Metab. 2006 Sep 26; [Epub ahead of print]). This is to identify targets to prevent and treat type 2 diabetes. She is also addressing the effect of glucose and fat, and insulin on atherosclerosis and cancer (Tran et al. Hyperinsulinemia, but not other factors associated with insulin resistance, acutely enhances colorectal epithelial proliferation in vivo, Endocrinology. 2006 Apr;147(4):1830-7. Epub 2006 Jan 12).

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Greenwood, Carol

Department of Nutritional Sciences

Our research is focused on the role of type 2 diabetes (non-insulin dependent) as a risk factor for cognitive decline and dementia with aging. It is increasingly recognized that diet- and obesity-related chronic diseases, including type 2 diabetes, hypertension and cardiovascular disease, increase dementia risk. Our animal-based studies are aimed at understanding the biologic mechanisms underlying this association, with evidence suggesting that disruptions to brain insulin signaling may be a key contributor. To complement these studies, our human-based work includes an examination of the impact of meal, or food, consumption on cognition since many older adults with type 2 diabetes experience transient decreases in cognitive function following meal ingestion. Consumption of both higher quality, lower glycemic-index, carbohydrate foods and antioxidant vitamins at the meal help offset this meal-induces decline experienced. These studies aim to understand the biologic means whereby food ingestion interferes with cognitive function in those with diabetes and to identify food strategies which minimize this decline.

  1. Winocur G, Greenwood CE, Piroli G, Grillo CA, Reznilov, LR, Reagan LP, McEwen BS. Memory impairment in obese Zucker rats: an investigation of cognitive function in an animal model of insulin resistance and obesity. Behavioral Neuroscience 119(5):1389-95, 2005.

  2. Papanikolaou Y, Palmer H, Binns MA, Jenkins DJA, Greenwood CE. Minimizing meal-induced cognitive decline in adults with type 2 diabetes through low-glycemic index carbohydrate foods. Diabetologia 49(5): 855 - 862, 2006.

Grynpas, Marc

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

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.

Halperin, Mitchell

Emeritus Professor of Medicine

The major emphasis in these studies relates to the prevention of cerebral edema in patients with diabetic ketoacidosis. In the first paper where the first author is Maccari, the question addressed is how can a patient with ketoacidosis develop such a severe degree of metabolic acidosis and have such a low arterial PCO2 with no obvious hyperventilation. Issues of CO2 production rate and the degree of buffering in skeletal muscle are addressed. In the invited editorial on the importance of the PCO2 in patients with diabetic ketoacidosis, we illustrate how to assess whether the brain in patients with DKA arte likely to have a larger H+ load and its possible impact on the development of cerebral edema.In the paper on erythropoietin, we explore the relationship between the high GFR early in diabetes mellitus and its relationship to the production of erythropoietin. These data also help explain why anaemia is likely to develop in patients that take ACE inhibitors.

  1. Maccari, C, Davids, MR, Kamel, KS, Halperin, ML. The patient with a severe degree of metabolic acidosis: a deductive analysis. Quart J Med 99: 475-485, 2006

  2. Halperin, ML, Kamel, KS, Maccari, C, Carlotti, APCP, Bohn, D. Strategies to reduce the danger of cerebral edema in a pediatric patient with diabetic ketoacidosis. Pediatric Diabetes, 7: 191-195, 2006
  3. Halperin, ML, Cheema-Dhadli, S, Lin, S-H, Kamel, KS. Properties that permit the renal cortex to be the oxygen sensor for the release of erythropoietin: Clinical implications. Clinical J Am Soc Nephrol, 1: 1049-1053, 2006

Hamilton, Jill

Department of Pediatrics
Division of Endocrinology, Hospital for Sick Children

My research interests include the clinical and biochemical manifestations of insulin resistance in the pediatric age group. Recent studies include: (i) evaluation of adjunctive therapy (oral agents used to treat type 2 diabetes) in youth with type 1 diabetes, insulin resistance and suboptimal diabetes control, (ii) psychosocial and treatment factors related to metabolic control in youth with type 2 diabetes; (iii) risk for diabetes and metabolic syndrome and pathophysiologic mechanisms related to the development of hypothalamic obesity in children treated for craniopharyngioma; (iv) early life risk factors for the development of obesity and diabetes in infants born to women with gestational diabetes.

  1. Zdravkovic V, Hamilton JK, Daneman D, Cummings EA. Pioglitazone as adjunctive therapy in adolescents with type 1 diabetes. J Pediatr. 2006 Dec;149(6):845-849. PMID: 17137905 [PubMed - in process].
  2. Ahmet A, Blaser S, Stephens D, Guger S, Rutkas JT, Hamilton J. Weight gain in craniopharyngioma--a model for hypothalamic obesity. J Pediatr Endocrinol Metab. 2006 Feb;19(2):121-7. PMID: 16562584 [PubMed - indexed for MEDLINE]

Hanley, Anthony

Department of Nutritional Sciences

1. Limited information is available regarding risk factors and metabolic consequences associated with metabolic syndrome in Aboriginal Canadian communities. We examined lifestyle factors associated with metabolic syndrome (MetS) and explored the relationships between MetS and non-traditional cardiovascular disease risk factors [adiponectin, leptin, C-reactive protein (CRP), interleukin-6 (IL-6), and serum amyloid A (SAA)] in an isolated Aboriginal Canadian community. Data were obtained from 360 non-diabetic adults participating in a population-based study. MetS was diagnosed according to the criteria of the National Cholesterol Education Program, the World Health Organization, and the International Diabetes Federation. The study showed that higher percentage body fat and lower physical activity and fitness were associated with a higher prevalence of MetS in this Aboriginal community and that hypoadiponectinemia was independently associated with MetS. (Liu J, Young TK, Zinman B, Harris SB, Hanley AJG. Lifestyle variables, non-traditional cardiovascular risk factors and metabolic syndrome in Native Canadians. Obesity Research 2006;14:500-8.)

2. Indigenous communities experience both a heavy burden and an early onset of diabetes, metabolic syndrome and related conditions. In this context, we studied the relationships between nontraditional cardiovascular (CV) risk factors and components of the metabolic syndrome in 236 Aboriginal Canadian children aged 10 to 19 years. Using an age- and sex-specific case definition, 18.6% of the children met criteria for pediatric metabolic syndrome. Our results showed that nontraditional CV risk factors accompany the accrual of traditional risk factors early in the progression to pediatric metabolic syndrome. Furthermore, inclusion of these factors in factor analysis suggests that 5 core traits underlie the early development of an enhanced CV risk factor profile in Aboriginal children. (Retnakaran R, B Zinman, PW Connelly, SB Harris, AJG Hanley. Non-traditional cardiovascular risk factors in pediatric metabolic syndrome: insights from factor analysis. Journal of Pediatrics 2006;148:176-82. )

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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 shown that the sequences necessary for regulation of expression of the human proglucagon gene differ from those previously 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. 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 can not use the rat gene as a model, and that we need to better understand the regulation of the human gene. (Zhou L, Nian M, Gu J, Irwin DM. Intron 1 sequences are required for pancreatic expression of the human proglucagon gene. Am J Physiol Regul Integr Comp Physiol. 2006 Mar;290(3):R634-4).

Jin, Tianru

Departments of Medicine and Laboratory Medicine and Pathobiology

Hormone production and the genesis of hormone producing cell are tightly controlled by temporal and spatial expression of transcription factors (TFs). Signaling pathways, whose activities are turned on and off in response to physiological, pathological and pharmacological stimulators, may modify the expression and/or function of TFs. In addition, a TF needs co-factors, which are TFs per se, to exert its regulatory functions on gene expression. My laboratory is interested in exploring how signaling molecules coordinate with TFs in regulating hormone production in gut/pancreatic endocrine cells. In 2006, we have completed the following research:

1) We isolated hamster Brn-4 cDNA and demonstrated that it functions as a co-factor of the caudal homeodomain protein Cdx-2, in regulating proglucagon gene expression. Brn-4 synergizes with Cdx-2 in activating the expression of proglucagon gene promoter, and its own activation domain is not required for this synergistic effect. Furthermore, we demonstrating the binding of Brn-4 to the proglucagon gene promoter and assessed its interaction with Cdx-2. (Wang P, Liu T, Li Z, Ma X, Jin T. Redundant and synergistic effect of Cdx-2 and Brn-4 on regulating proglucagon gene expression. Endocrinology. 2006 Apr;147(4):1950-8. Epub 2005 Dec 22).

2) We assessed the function of the Paired homeodomain protein Pbx1 as a co-factor of Cdx-2 in regulating proglucagon gene expression, and discovered the existence of additional interaction domain on Cdx-2 that interacts with Paired HD proteins. (Liu T, Branch DR, Jin T. Pbx1 is a co-factor for Cdx-2 in regulating proglucagon gene expression in pancreatic A cells. Mol Cell Endocrinol. 2006 Apr 25;249(1-2):140-9. Epub 2006 Mar 29). We examined the expression of the Epac molecule in gut proglucagon producing cells and demonstrated that Epac serves as an effector of the second messenger cAMP in activating proglucagon gene expression. (Lotfi S, Li Z, Sun J, Zuo Y, Lam PP, Kang Y, Rahimi M, Islam D, Wang P, Gaisano HY, Jin T. Role of the exchange protein directly activated by cyclic adenosine 5'-monophosphate (Epac) pathway in regulating proglucagon gene expression in intestinal endocrine L cells. Endocrinology. 2006 Aug;147(8):3727-36. Epub 2006 Apr 27).

Klip, Amira

Departments of Biochemistry, Physiology and Peadiatrics

We study the mechanisms whereby insulin and exercise, separately, increase glucose uptake by muscle cells. This occurs largely by gains in glucose carrier molecules at the cell surface, either through an increase in externalization or retardation in endocytosis back to intracellular storage sites. Most of our work is carried out in a muscle cell line expressing tagged glucose transporters (GLUT4myc), allowing us to follow GLUT4myc location by immunofluorescence, immunoelectron microscopy and biochemical analyses. Recently we found that: a) The most distal insulin signal, the Rab-GAP AS160 that is phosphorylated by Akt, is also a target of AMPK and PKC. A non-phosphorylatable mutant of AS160 prevented not only the insulin-induced but also the depolarization-induced gain in surface GLUT4. This work was carried out by postdoctoral fellow Farah Thong along with Dr. Phil Bilan, and published in Diabetes vol 56 (2007, in press). b) Insulin signalling branches downstream of PI3-kinase into a Rac-dependent arm leading to actin remodelling and an Akt-dependent arm. Both are required for GLUT4 translocation, and two agents that cause insulin resistance in cells and in vivo (ceramide and reactive oxygen species) affect Rac more readily than Akt, effectively reducing GLUT4 translocation. This work, led by doctoral student Lellean Jebailey, was published in Diabetes vol 56 (2007, in press).

Lam, Tony

Departments of Physiology and Medicine

  1. Lam TKT, Gutierrez-Juarez R, Pocai A, Bhanot S, Tso P, Schwartz GJ, Rossetti L: Brain glucose metabolism controls the hepatic secretion of triglyceride-rich lipoproteins. Nature Medicine, in press
  2. Lam TKT*, Chen S*, Park E, Burdett E, Wang PYT, Wiesenthal SR, Lam L, Tchipashvili V, Fantus IG,Giacca A: Oleate-induced decrease in hepatocyte insulin binding is mediated by Protein Kinase C-d. Biochem Biophys Res Commun 346(3):931, 2006. Epub Jun 9 2006. (*Co-first author)
  3. Pocai A, Lam TKT, Obici S, Gutierrez-Juarez R, Muse ED, Arduini A, Rossetti L: Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in over-fed rats. J Clin Invest 116(4):1081, 2006. Epub Mar 9 2006.
  4. He W, Lam TKT, Obici S, Rossetti L: Molecular disruption of hypothalamic nutrient sensing induces obesity. Nature Neuroscience 9(2):227, 2006. Epub Jan 15 2006.
  5. Lam TKT, Gutierrez-Juarez R, Pocai A, Rossetti L: Regulation of blood glucose by hypothalamic pyruvatemetabolism. Science 309(5736):943, 2005.
  6. Lam TKT, Schwartz GJ, Rossetti L: Hypothalamic sensing of fatty acids. Nature Neuroscience 8(5):579,2005.
  7. Pocai A, Lam TKT, Gutierrez-Juarez R, Obici S, Schwartz GJ, Bryan J, Aguilar-Bryan L, Rossetti L: Hypothalamic KATP channels control hepatic glucose production. Nature 434(7036):1026, 2005.
  8. Lam TKT, Pocai A, Gutierrez-Juarez R, Obici S, Bryan J, Aguilar-Bryan L, Schwartz GJ, Rossetti L: Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nature Medicine 11(3): 320, 2005. Epub Feb 27, 2005.

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Langille, B. Lowell

Departments of Laboratory Medicine and Pathobiology and Obstetrics and Gynecology

Vascular disorders underlie the most severe complications of diabetes especially atherosclerosis. Our laboratory examines how the functions of vascular cells, endothelium and vascular smooth muscle, contribute to these disorders. Current work in the laboratory examines how physical forces influence remodeling of arterial tissues in ways that influence vascular pathologies. In 2006, we published work demonstrating that proliferative repair after endothelial injury to the endothelial cells that line arteries was very sensitive to the frictional forces exerted on the cells by blood flow, and we also showed that these forces control opening and narrowing of arteries through effects on both endothelium and other arterial tissues. Additional studies examine responses of arterial tissue to injury that inevitably occurs when angioplasty and stents are used to open atherosclerotic arteries. Endothelium is lost and underlying smooth muscle migrate inward, a frustrated repair process, that ultimately narrows the artery and compromises blood flow. We are now studying the inter-cellular signals that control these responses with particular attention focusing on signals that are generated by a molecule on the surface of smooth muscle cells, called N-cadherin, that normally controls how these smooth muscle cells adhere to each other.

  1. McCue S, Dajnowiec D, Jackson MR, Langille BL. Shear Stress Regulates Forward and Reverse Planar Cell Polarity of Vascular Endothelium In Vivo and In Vitro. Circ Res 98:939-946, 2006

  2. Quan A, Ward ME, Kulandavelu S, Adamson SL, Langille BL. Endothelium-independent flow-mediated dilation in the mouse carotid artery. Journal of Vascular Research 43:383-391, 2006.

Leong-Poi, Howard

Department of Medicine

My lab is interested in the effects of diabetes and the metabolic syndrome on endothelial progenitor cell (EPC) function, specifically the implications for the therapeutic use of bone-marrow derived EPCs to restore blood flow to ischemic tissues. Diabetes and the metabolic syndrome are associated with impaired number and function of circulating EPCs, but its effect on bone marrow (BM)-derived EPCs have not been well characterized. In our recent studies, we compared the number and function of EPCs derived from the BM and peripheral circulation in rodent models (obese Zucker (OZ), and Zucker diabetic fatty (ZDF)) of the metabolic syndrome and diabetes. We found that circulating EPC number was significantly reduced in OZ and ZDF rats when compared to lean rats, however BM EPC number remained unchanged. BM EPC differentiation and migratory potential were reduced in OZ and ZDF rats when compared to lean control animals, while apoptosis rates were increased. In invivo testing in a mouse model of hindlimb ischemia, BM-derived EPCs from OZ and ZDF rats showed markedly impaired angiogenic potential, with virtually no improvement in hindlimb perfusion. Thus, BM EPCs develop phenotypic and functional impairment in the presence of diabetes and the metabolic syndrome, which may limit their therapeutic potential in these disease states. This data was presented in abstract form at the International Society for Heart Research (ISHR) and the Canadian Cardiovascular Congress, and is currently in manuscript form to be submitted.

Lewis, Gary

Departments of Medicine and Physiology
Head, Division of Endocrinology and Metabolism, University Health Networkand Mount Sinai Hospital

We have shown in the past few years that fructose feeding and high fat feeding of the Syrian Golden hamster is associated with whole body and molecular evidence of insulin resistance, enhanced hepatocyte and intestinal enterocyte de novo lipogenesis, upregulation of microsomal triglyceride transfer protein (MTP) in both the liver and intestine, increased intracellular apoB stability and facilitated assembly of apoB-containing lipoproteins leading to both hepatic and intestinal oversecretion. Recently we have turned our attention to studying primarily intestinal and secondarily hepatic lipoprotein production rates in relation to insulin resistance in humans. We have recently shown, for the first time in humans, that intestinal lipoprotein production is increased in insulin resistant humans and correlates with hyperinsulinemia. We went on to examine the effect of insulin sensitization of humans with the PPARgamma agonist, rosiglitazone. In contrast to the Syrian Golden hamster, we found that there is dissociation between the insulin sensitizing effects of rosiglitazone and the anticipated reduction in production of apoB100 and B48 secretion, and that this effect was due to direct stimulation of de novo lipogenesis by rosiglitazone. In ongoing studies we are examining hormonal and inflammatory factors regulating intestinal (and hepatic) lipoprotein production in humans. Other active areas of research in the Lewis laboratory include studies of the mechanism of HDL lowering in insulin resistant states using a combination of animal models and cell culture techniques, the effect of fatty acids on pancreatic beta cell function in humans and the mechanism of action of incretin hormones, GLP1 and GIP, in mice.

  1. Duez,H., Lamarche,B., Uffelman,K.D., Valero,R., Cohn,J.S., and Lewis,G.F. 2006. Hyperinsulinemia is associated with increased production rate of intestinal apolipoprotein B-48-containing lipoproteins in humans. Arterioscler.Thromb.Vasc.Biol. 26:1357-1363
  2. Xiao C, Giacca G, Carpentier A, Lewis GF. Differential effects of monounsaturated, polyunsaturated and saturated fat ingestion on glucose-stimulated insulin secretion, sensitivity and clearance in overweight and obese, non-diabetic humans. Diabetologia 49(6):1371-9, 2006

Matthews, Stephen G.

Professor of Physiology, Obstetrics and Gynaecology, and Medicine
See research highlights under Vranic, M.

Ng, Dominic

Departments of Medicine, Physiology, and Laboratory Medicine and Pathophysiology

My lab focuses on two main areas of research:
1) Ongoing research studying novel linkage between lipoprotein metabolism and glucose homeostasis in a monogenic low HDL syndrome using the murine model of LCAT deficiency. Recent studies in my lab suggests novel physiologic linkage between LCAT, a major modulator of HDL cholesterol levels, and fatty acid metabolism, glucose and energy homeostasis. We reported a profound alteration in fatty acid metabolism in LCAT deficient mice and this novel observation may partially explain the glucose-lipid links. Several phenotypes seen in the animal models are apparently paradoxical and may provide a window of opportunity for discovery of novel metabolic regulatory pathways. Ongoing studies include examining the interaction between these genetic-based phenotypes and various diets in the development of atherosclerosis and diabetes.

2) A new area of research exploring the role of lipoproteins, especially HDL, in diabetes. We are investigating the interaction of HDL in the modulation of the insulitis process. We will focus on the effect of HDL on the various effector arms of the immune-mediated inflammatory process in murine models of diabetes. Coordinated alteration of hepatic gene expression in fatty acid and triglyceride synthesis in LCAT-null mice is associated with altered PUFA metabolism. Am J Physiol Endocrinol Metab. 2006 Jan;290(1):E17-E25.

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Parra, Esteban J.

Department of Anthropology

In 2006, Dr. Parra and his collaborators made substantial advances in the development of a genome-wide panel of genetic markers for gene mapping applications in Hispanic/Latino populations. This panel is comprised of more than 2,000 markers and will make it possible to identify type 2 diabetes susceptibility genes in the Mexican population using a mapping strategy known as admixture mapping. Dr. Parra's research group has also characterized the admixture proportions and dynamics of a sample of type 2 diabetes patients and controls from Mexico City and evaluated the implications of this history of admixture for admixture mapping applications. A manuscript describing this work has recently been published in the journal Human Genetics. Finally, polymorphisms in two type 2 diabetes candidate genes (TCF7L2 and MGEA5) were also characterized in this sample, and two manuscripts are currently in press reporting the results of these two studies (the manuscripts will be published in the journals Clinical Genetics and American Journal of Human Biology, respectively). This work has confirmed TCF7L2 as an important type 2 diabetes susceptibility gene. Martinez-Marignac VL, Valladares A, Cameron E, Chan A, Perera A, Globus-Goldberg R, Wacher N, Kumate J, McKeigue P, O'donnell D, Shriver MD, Cruz M, Parra EJ. Admixture in Mexico City: implications for admixture mapping of Type 2 diabetes genetic risk factors. Hum Genet. 2007 Feb;120(6):807-19. Epub 2006 Oct 26. PMID: 17066296 [PubMed - in process]

Poussier, Philippe

Departments of Medicine and Immunology

The cause of autoimmune type 1A diabetes (T1D) remains unknown. A powerful approach to gain insights into the pathogenesis of the human disease has been to study inbred laboratory animals that spontaneously develop T1D. We study one of these models called the BB rat. We have developed unique lines of BB-derived rats in which isolated chromosomal regions (loci) convey powerful effects on specific steps of the diabetogenic process. Using these congenic lines that exhibit differential susceptibility to T1D, our overall objectives are to identify novel T1D susceptibility genes, to characterize the mechanisms through which these genes contribute to disease development, and to determine whether these genes are associated with human T1D. In the last eighteen months, we have identified five novel T1D-susceptibility loci in the BB rat model. The size of one of them, on chromosome 8 has been reduced to <5Mb (manuscript submitted) and we are currently sequencing and assessing the candidate T1D-susceptibility genes situated in this interval. We have also identified a non-synonymous, single nucleotide polymorphism (SNP) in a T lymphocyte-specific protein tyrosine phosphatase on chromosome 2 that is associated with T1D and age of onset of the disease in the BB rat. Importantly, this gene has recently been shown to be associated with human T1D, thyroid autoimmune diseases, lupus erythematosous, and rheumatoid arthritis. The BB rat allelic variant compromises the binding affinity of the phosphatase with its main substrate, a src family kinase, and we are studying the functional consequences of this altered interaction on T cell function and disease pathogenesis. We, through our BB rat studies, and our collaborators at the Hospital for Sick Children working on the NOD mouse model, have tested candidate genes identified in these rodent models for association with human T1D in the three large cohorts of T1D families representing >4,500 individuals. Preliminary analysis shows very significant association of human T1D with one gene that was tested based on the results of our BB rat studies. (Mordes, J.P., Poussier, P. , Blankenhorn, E.P., and Greiner, D.L. Rat models of type 1 diabetes: Genetics, environment and autoimmunity. . IN: E. Shafrir, and A.A.F. Sima (ed.). Animal Models in Diabetes. CRC Press (in press) 2006).

Prud'homme, Gerald

Department of Laboratory Medicine and Pathobiology

We designed a DNA vaccine which specifically generates protective regulatory T cells in autoimmune NOD-mouse type 1 diabetes. This vaccine incoporates an preproinsulin-GAD65 fusion protein (two target antigens of the disease), and a mutant B7 molecule which binds the immuninhibitory molecule CTLA-4. This vaccine was preventative, but our recent ongoing work shows that it can be used to treat diabetic NOD mice , when applied early after onset of disease. In collaboration with Dr. Qinghua Wang (St. Michael's Hospital, Toronto), we constructed an effective GLP-1-Fc encoding plasmid, which induces therapeutic levels of GLP-1-Fc following i.m. electroporation-enhanced gene transfer in diabetic mice. This gene therapy ameliorated disease in db/db mice (type 2 diabetes), and protected islet cells against the toxic effects of streptozotocin. Gene transfer was shown to increase beta cell mass and was also protective NOD mice, provided the autoimmune process was controlled.

  1. Glinka, Y., Y. Chang and G. J. Prud'homme. Protective regulatory T cell generation in autoimmune diabetes by DNA covaccination with islet antigens and a selective CTLA-4 ligand. Molecular Therapy (2006) Oct;14(4):578-87. PMID: 16790365 [PubMed - indexed for MEDLINE].

  2. Kumar, M., K. Hunag, Y. Glinka, G. J Prud'homme, Q. Wang. Gene therapy of diabetes using a novel GLP-1/IgG1-Fc fusion construct normalizes glucose levels in db/db mice. Gene Therapy (2007) 14:162-172. PMID: 16943856 [PubMed - in process]

  3. Soltani N, Kumar M, Glinka Y, Prud'homme GJ, Wang Q. In vivo expression of GLP-1/IgG-Fc fusion protein enhances beta-cell mass and protects against streptozotocin-induced diabetes. Gene Therapy. (2007) Ms in press.

  4. Prud'homme, G.J., Y. Glinka, A.S. Khan, R. Draghia-Akli. Electroporation-enhanced nonviral gene transfer for the prevention or treatment of immunological, endocrine and neoplastic diseases. Current Gene Thererapy (2006) Apr;6(2):243-73. PMID: 16611045 [PubMed - indexed for MEDLINE].

  5. Prud'homme, G. J., R. Draghia-Akli, Wang, Q. Plasmid-based gene therapy of diabetes. Gene Therapy (2007) Jan 11; [Epub ahead of print] PMID: 17215847.

Quaggin, Susan

Department of Medicine

The focus of research in our lab is to understand the role of angiogenic factors in the pathogenesis and progression of glomerular disease that includes diabetic nephropathy. Numerous studies have reported changes in the level of vascular growth factors such as VEGF-A and Angiopoietin-1 and 2 in the glomeruli of patients and rodents with diabetic nephropathy. In order to dissect the role of these factors, we have generated a number of genetic tools and mouse transgenic lines that permit us to manipulate the ligands and receptors of these signaling pathways in vivo. In 2006, we received NIH funding to pursue these studies as part of the AMDCC consortium. Listed below are publications and funding obtained related to these goals:

  1. Quaggin, S.E., Coffman, T.M. (2007) (Editorial) Toward a mouse model of diabetic nephropathy: Is endothelial nitric oxide synthase the missing link. Journal of the American Society of Nephrology. 18(2):364-366.

  2. Quaggin, S.E. A new piece in the nephrotic puzzle. (2006) (Review) Nature Genetics. 38(12):1360-1361

  3. Ding, M., Cui, S., Binnie, M., Jothy, S. Chengjin, L., Haigh, J., Nagy, A., Haase, V, Steer, B., Marsden, P., Rastaldi, M.P., Cohen, C.D., Kretzler, M. and S.E. Quaggin. (2006) Loss of the Tumor Suppressor VHL Leads to de Novo Glomerular Expression of CXCR4 and Rapidly Progressive Glomerulonephritis in Mice. 2006; Nature Medicine. 12(9):1081-1087.

  4. Jones, N., Blasutig, I.M., Eremina, V, Ruston, J.M., Bladt, F., Li, H., Huang, H., Larose, L. Li, S.S.-C., Takano, T., Quaggin, S.E., Pawson, T. (2006) Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes. Nature. 440(7085):818-823.

  5. Takemoto, M., He, L., Norlin, J., Patrakka, J., Xiao, Z., Petrova, T., Bondjers, C., Asp, J., Wallgard, E., Sun, Y., Samuelsson, T., Mostad, P., Lundin, S., Miura, N., Sado, Y., Alitalo, K, Quaggin, S.E., Tryggvason, K., Betsholtz, C. (2006) Large-scale identification of genes implicated in kidney glomerulus development and function. EMBO J. 25(5):1160-1174.

  6. Eremina, V., Cui, S., Gerber, H-P., Ferrara, N., Haigh, J., Nagy, A., Jothy, S. and Quaggin, S.E. (2006) VEGF-A Signaling in the Podocyte-Endothelial Compartment is Required for Mesangial Cell Migration and Survival. JASN, 17(3):724-35

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 in the years following the pregnancy. We are studying factors that lead to the development of type 2 diabetes within a large observational study involving >700 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 2006, we demonstrated that ethnicity modifies the effect of obesity on insulin resistance and identified adiponectin as a possible contributor in this context (Ethnicity modifies the impact of obesity on insulin resistance in pregnancy: a comparison of Asian, South Asian and Caucasian women. Journal of Clinical Endocrinology and Metabolism 2006; 91:93-97). We also found that the metabolic implications of a diagnosis of impaired glucose tolerance in pregnancy vary depending on the pattern of abnormal glucose values on the oral glucose tolerance test. (Impaired glucose tolerance of pregnancy is a heterogeneous metabolic disorder as defined by the glycemic response to the oral glucose tolerance test. Diabetes Care 2006; 29:57-62.)

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Shah, Baiju

Department of Medicine

  1. Shah BR, Hux JE, Laupacis A, Zinman B, Booth GL. Use of vascular risk modifying medications for diabetic patients differs among physician specialties. Diabetic Med 2006;23:1117-23.

  2. Park-Wyllie LY, Juurlink DN, Kopp A, Shah BR, Stukel TA, Stumpo C, Dresser L, Low DE, Mamdani MM. Outpatient gatifloxacin therapy and dysglycemia in older adults. New Engl J Med 2006;354:1352-61.

Silverman, Mel

Department of Medicine

My laboratory continues to work on two major projects, directly relevant to the objectives of BBDC. The first is the investigation of the role of Munc13 in the pathogenesis of diabetic nephropathy; our recent results indicate that munc13 which is member of protein kinase C super family, when activated serves as an effector of Rab34 - a newly recognized golgi-localized RabGTPase (Diacylglycerol (DAG) activated hmunc13 serves as an effector of the GTPase Rab34. P. Speight and M. Silverman. Traffic.2005; 6: 1-8). Most recently we have been following up the role of Rab34 with respect its golgi function and have obtained interesting results indicating that Rab34 is implicated in golgi-mediated protein secretion. The manuscript is under review by MBC. The second major project is the continuing structure function studies of Na+/glucose co-transporter (SGLT1). We continue to use cysteine mutagenesis and substituted cysteine inaccessibility method to identify functionally-relevant residues in the SGLT. Our most recent work have discovered for the first time, the sugar binding site in SGLT1 and have proposed the new model to account for the mechanism of Na+/glucose cotransport based on this work in our earlier studies which localized the Na+ binding site. Three manuscripts are currently under review by JBC.

  1. Huntley SA, Krofchick D, Silverman M. A glutamine to glutamate mutation at position 170 (Q170E) in the rabbit Na+/glucose cotransporter, rSGLT1, enhances binding affinity for Na+. Biochemistry. 2006 Apr 11;45(14):4653-63.
  2. Lysine 157 in the high affinity sodium/glucose cotransporter is crucial for sugar binding. Tiemin Liu and Mel Silverman. JBC (under revision)
  3. Inhibitor binding/debinding kinetics measured for the T156C mutant of the rabbit Na+/glucose cotransporter (rSGLT1). Daniel Krofchick, Bryan Lo, and Mel Silverman. JBC (submitted)
  4. Threonine 156 forms part of the sugar binding site in the rabbit Na+/glucose co-transporter (rSGLT1). Bryan Lo, Daniel Krofchick, Pam Speight, Sharon Lewinski, and Mel Silverman. JBC (submitted)
  5. Golgi-bound Rab34 is a novel member of the secretory pathway. N. Goldenberg, S. Grinstein and M. Silverman. Mol. Bio. Cell. (under revision)

Stewart, Donna E.

Professor, Department of Psychiatry and Faculty of Medicine, University of Toronto
Professor and Chair of Women's Health, University Health Network

Our research program is carrying outstudies to better understand psychosocial and behavioural dimensions that may affect diabetes self-management and health outcomes. We areinvestigatinghow self-management education programs and resources are being used and delivered in Canada; specifically, 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 and gender 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.

A recent study from our program suggests those who do not speak English, are born outside of Canada, have a lower level of education, or are older use fewer diabetes resources. Notably, the characteristics of individuals who are less likely to use resources or a variety of resources reflect the basic determinants of health (i.e., age, sex, ethnicity or primary language spoken, and education). The practical implications of our findings suggest we need to develop resources that are equitably accessible and of interest to all patients, particularly for individuals who do not speak English, who have lower education and literacy levels, and who areolderadults. Furthermore, imparting the skills on how to find and utilize currently existing resources to assist in chronic disease self-management should be promoted as a core aspect of self-management education. (Use of diabetes resources in adults attending a self-management education program. Patient Educ Couns. 2006 Dec;64(1-3):322-30.)

van der Kooy, Derek

Department of Medical Genetics and Microbiology

The search for putative precursor cells within the pancreas has been a focus of extensive research, largely due to their potential use in the generation of new b cells for therapeutic cell replacement strategies in the treatment of diabetes. We have reported the clonal identification of pancreas-derived multipotent precursor (PMP) cells isolated from the adult mouse pancreas that are capable of clonal proliferation to produce large colonies and differentiation to produce cell types of both the pancreatic and neural lineages. The in vivo identity of the PMP cells remains unknown, and it has been suggested that insulin-expressing cells retain the capacity to divide in a limited manner. We investigated whether the PMP cells may actually express insulin in vivo using transgenic mice expressing GFP under control of the insulin promoter. FACS sorting revealed that the vast majority of the PMP cells arose from the insulin-positive fraction. This suggests that while the majority of the native insulin-expressing cells are differentiated b cells, a subset of them actually represent a precursor population with more extensive capabilities. Next, we sought to determine whether the human pancreas contained cells analogous to those we identified in mice. Using purified, dissociated human islets, we found that a rare population of highly proliferative cells was present. The primary colonies produced could be passaged to produce secondary colonies.

Volchuk, Allen
Assistant Professor, Departments of Biochemistry/ Physiology/ Medicine

In 2006 we have been studying the role stress in the endoplasmic reticulum has in contributing to chronically elevated free fatty acid-induced apoptosis (death) of pancreatic beta-cells. We have shown that elevated free fatty acids cause stress in this cellular organelle and that this contributes to causing pancreatic beta-cell death. In addition, in more recent studies we have shown that making cells resistant to stress in the endoplasmic reticulum prevents pancreatic beta-cell death. These studies enhance our understanding of how risk factors such as obesity, which is characterized by elevated free fatty acid levels, may contribute to diabetes progression. During 2006 we were also part of a collaborative effort with researchers at the University of Toronto and the Hospital for Sick Children on studies 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. The results of these studies will appear in the journal Diabetes in early 2007. Karaskov E, Scott C, Zhang L, Teodoro T, Ravazzola M, Volchuk A. Chronic palmitate but not oleate exposure induces endoplasmic reticulum stress, which may contribute to INS-1 pancreatic beta-cell apoptosis. Endocrinology. 2006 Jul;147(7):3398-407. Epub 2006 Apr 6.

Vranic, Mladen / Matthews, Stephen G.

Professor of Physiology and Medicine / Professor of Physiology, Obstetrics and Gynaecology, and Medicine

In our continuing work in hypoglycemia, we analyzed the deficiencies of the counterregulatory responses in diabetic rats. In the present paper (Effects of insulin treatment without and with recurrent hypoglycemia on hypoglycemic counterregulation and adrenal catecholamine-synthesizing enzymes in diabetic rats. KE Inouye et al., Endocrinology 2006 Apr;147(4):1860-70) , we reported that 3-week insulin treatment restores the deficient epinephrine response, which was correlated with normalization of 2 key adrenomedullary enzymes that regulate epinephrine synthesis. In contrast, the hypothalamo-pituitary-adrenal (HPA) axis retained increased activity as evidences by analysis of stress hormones and their receptors. This led to elevated fasted corticosterone, which can have a deleterious effect on the brain and peripheral tissues. In response to hypoglycemia, the release of corticosterone was diminished, and most significantly, completely abolished with antecedent hypoglycemia. This defect was associated with a lack of response of expression of hippocampal mineralocorticoid receptors.

The other project involved the mechanism of the effect of exercise in delaying development of diabetes in ZDF rats, which are a model of metabolic syndrome and type 2 diabetes. In addition to improvement of glucose tolerance and blood glucose levels, we also analyzed β-cell mass and the replication of β-cells in the pancreas (MA Kiraly et al., Metabolism, 2007 in press).

Wang, Qinghua

Departments of Physiology and Medicine

Hyperglycemia is a hallmark of diabetes mellitus and is mostly a result of insufficient insulin secretion and/or excessive secretion of glucagon. Excessive secretion of glucagon is a major contributor to the diabetic hyperglycemia in type 2 diabetes. We are studying pancreatic islet function under physiological and diabetic conditions. In particular, we are investigating the molecular mechanism(s) of intra-pancreatic hormonal regulation, i.e., the mechanism(s) by which insulin suppresses glucagon secretion from the glucagon-secreting the alpha cells. Our recent study suggests that the "insulin resistance" occurs in the alpha cells may contribute to hyperglycemia in type 2 diabetes (Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system. Cell Metab. 2006 Jan;3(1):47-58). Our aim is to identify the molecular defects that cause diabetes and to develop novel therapies for prevention and treatment of diabetic hyperglycemia (Gene therapy of diabetes using a novel GLP-1/IgG1-Fc fusion construct normalizes glucose levels in db/db mice. Gene Ther. 2006 Aug 31; [Epub ahead of print]).

Wen, Xiao-Yan

Department of Medicine

Emerging evidence demonstrates that zebrafish is a superior genetic model organism in revealing molecular control of vertebrate embryonic development because of its embryonic transparency, rapid embryonic development and short generation time. Many of the transcription factors involved in human and murine pancreas development are also expressed during zebrafish pancreas formation. We are developing transgenic zebrafish models to study pancreas development and regeneration. For this study, we cloned a 2 kb zebrafish insulin promoter and fused it to a RFP (Red Fluorescent Protein) reporter gene in a Sleeping Beauty (SB) transposon vector. After microinjection of this vector together with SB transposase mRNA into fertilized zebrafish eggs, RFP expression can readily be visualized under fluorescent microscope in the developing pancreas starting from 48 hours post fertilization till young adult fish. This transgenic zebrafish strain with pancreas tagged by RFP will serve as an ideal model to study pancreas development and regeneration as zebrafish are transparent in all the embryonic developmental stages. Experiments are currently in progress to develop in vivo knockdown of selected genes in developing pancreas to assess their contribution to pancreas development. Time controlled cell ablation of pancreas beta cells is also being developed to study pancreas regeneration process after injury.

Westall, Carol

Department of Ophthalmology and Vision Sciences

Our aim is to identify the sites of earliest damage in the retina in patients with diabetes. In collaboration with Dr. Shelley Boyd (St Michael's Hospital) funding from the Juvenile Diabetes Research Foundation enables our group to investigate non-invasive measures of neuro-retinal function in early diabetes. We will evaluate four nerve function tests together to see how well they detect early diabetic damage and how well they predict subsequent vascular damage. In 2006 the measures were evaluated on controls without diabetes and test data collection started at the end of the year. 2007 will be a time of intense recruitment and data collection. Of great excitement is the awarding of CFI funding for the SickKids Centre for the Investigation of Neuroplasticity and Developmental Disorders (PI, O.Carter Snead). This funding will pave the way to identify structural changes in the retina of patients with early diabetes and will subsequent correlations between structure and function will open up new avenues of identifying the earliest indicators of damage to the retina in diabetes.

Wheeler, Michael B.

Departments Physiology and Medicine
Head of the Endocrinology and Diabetes Research Group

Type 2 diabetes (T2D) is a disease characterized by loss of insulin sensitivity in peripheral tissues and islet dysfunction in the pancreas. The latter involves impairment in insulin and glucagon secretion from the beta and alpha cells respectively. The primary focus of our lab therefore, is to understand the mechanisms that control islet function in an attempt to develop new strategies to treat T2D. We employ a multidisciplinary approach, which includes genomic and proteomic scans, molecular biology, real-time cellular imaging and patch-clamp electrophysiology to identify target proteins involved in the regulation of insulin or glucagon secretion. Understanding how islets sense and respond to glucose is a major focus of the lab. Thus we are very interested in specific proteins that regulate glucose-dependent insulin and glucagon secretion. For example, we discovered that uncoupling protein-2 is involved in mitochondrial ATP production in beta cells and we have shown it to be a negative regulator of insulin secretion. We also discovered VILIP-1, a neuronal Ca2+ sensor protein expressed in beta cells, which enhances insulin secretion in a cAMP-dependent manner. Further, we have demonstrated that the KATP channel, a key modulator of insulin secretion, is highly sensitive to changes in intracellular pH. We have also recently provided the first evidence for the functional expression of HCN potassium channels in pancreatic beta cells and are working towards determining their role in islet function. We have also shown that insulin receptor signaling is essential for glucose to regulate glucagon secretion and alpha cell survival. In collaboration with Dr. Qinghua Wang we have shown that GABA secreted from beta cells is a key factor in islet glucose sensing. In order to establish a relationship between islet dysfunction and insulin resistance, we are also using novel genetic mouse models and an integrated genomic and proteomic approach to identify novel proteins that regulate islet function and potentially cause T2D.

  1. Hyperpolarization-activated cyclic nucleotide-gated channels in pancreatic beta-cells. Mol Endocrinol. 2007 Mar;21(3):753-64. Epub 2006 Dec 7. El-Kholy W, MacDonald PE, Fox JM, Bhattacharjee A, Xue T, Gao X, Zhang Y, Stieber J, Li RA, Tsushima RG, Wheeler MB.
  2. The neuronal Ca2+ sensor protein visinin-like protein-1 is expressed in pancreatic islets and regulates insulin secretion. J Biol Chem. 2006 Aug 4;281(31):21942-53. Epub 2006 May 26. Dai FF, Zhang Y, Kang Y, Wang Q, Gaisano HY, Braunewell KH, Chan CB, Wheeler MB.
  3. Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system. Cell Metab. 2006 Jan;3(1):47-58. Xu E, Kumar M, Zhang Y, Ju W, Obata T, Zhang N, Liu S, Wendt A, Deng S, Ebina Y, Wheeler MB, Braun M, Wang Q.
  4. Insulin resistance causes increased beta-cell mass but defective glucose-stimulated insulin secretion in a murine model of type 2 diabetes. Diabetologia. 2006 Jan;49(1):90-9. Epub 2005 Dec 15. Erratum in: Diabetologia. 2006 Mar;49(3):614 Asghar Z, Yau D, Chan F, Leroith D, Chan CB, Wheeler MB.

Wojtowicz, J. Martin

Department of Physiology

Diabetes and hippocampal neurogenesis. 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 contribution of the new neurons to learning and memory is still unknown. Studies in our laboratory have shown that neurogenesis is essential for contextual fear memory (Winocur et al., 2006). 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 (Becker and Wojtowicz, 2006). We now have new data demonstrating that type I diabetes decreases cell differentiation into neurons. These changes are expected to have severe consequences on hippocampal learning and memory. The mechanism of these changes will be investigated in future studies. G. Winocur, J. M. Wojtowicz, M. Sekeres, J. S. Snyder, and S. Wang. Inhibition of neurogenesis interferes with hippocampus-dependent memory function. Hippocampus 16 (3):296-304, 2006 and S. Becker and J. M. Wojtowicz. A model of hippocampal neurogenesis in memory and mood disorders. Trends Cogn Sci., 2006.

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Wolever, Thomas

Department of Nutritional Sciences

My research interests have to do with the role of diet in the prevention and management of type 2 diabetes. The clinical utility of the glycemic index continues to be questioned because of concerns that it does not apply in mixed meals because of the confounding effects of fat and protein. To address this, we showed that about 90% of the variation in glycemic responses of 14 different breakfast meals of varied composition was accounted for by the amount of carbohydrate they contained and the glycemic index (Wolever TMS, Yang M, Zeng XY, Atkinson F, Brand-Miller JC. Food glycemic index, as given in GI tables, is a significant determinant of glycemic responses elicited by composite breakfasts. Am J Clin Nutr 2006;83:1306-1312.). Indeed, the effects of fat and protein on glucose responses have not been studied systematically, and so we have begun to do so. Our first study showed that the blood glucose lowering effects of fat and protein depended on a person's insulin sensitivity, body weight and dietary fiber intake (Moghaddam E, Vogt JA, Wolever TMS. The effects of fat and protein on glycemic responses in non-diabetic humans vary with waist-circumference, fasting plasma insulin and dietary fiber intake. J Nutr 2006;136:2506-11.). I have a CIHR grant to pursue this research. In a rather different vein, I was involved in a project to measure insulin sensitivity using the FSIGTT in schizophrenic patients under the care of Dr. Tony Cohn from CAMH before and after therapy. We did this because it was thought that the drugs used to treat schizophrenia cause obesity and diabetes. However, we found, unexpectedly, that schizophrenic patients are profoundly insulin resistant before treatment (Cohn TA, Remington G, Zipursky RB, Azad A, Connolly P, Wolever TMS. Insulin resistance and adiponectin levels in drug-free patients with schizophrenia: a preliminary report. Can J Psychiatry 2006;51:382-386), and therefore are at increased diabetes risk because of their condition rather than the drugs used to treat it.

Woo, Minna

Departments of Medicine, IMS and Medical Biophysics

Primary interest in the Woo lab is to elucidate molecular determinants of pancreatic beta cell survival and cell death using genetic mouse models. We have recently shown that PTEN, a potent negative regulator of the PI3K signaling pathway plays an important role in providing survival and growth signals in the pancreatic beta cells. Using the Cre-loxP system we have shown that beta cell mass is increased in mice where PTEN is deleted specifically in the beta cells. These mice are protected from STZ-induced diabetes. Additionally, the rat insulin promoter driven deletion of PTEN also resulted in partial deletion of PTEN in the hypothalamus. The deletion of PTEN in these as yet undefined insulin transcribing neurons resulted in a small body phenotype in addition in an increase in insulin sensitivity. Given that defects in beta cell mass and insulin sensitivity are the two major challenges to be conquered in type 2 diabetes, this mouse model provides a powerful genetic tool to further elucidate mechanisms that lead to development of type 2 diabetes as well as novel integrative approaches to treatment of type 2 diabetes. Essential role of Pten in body size determination and pancreatic beta-cell homeostasis in vivo. Mol Cell Biol. 2006 Jun;26(12):4511-8.

Woodgett, Jim

Department of Medical Biophysics

The diabetes research carried out in the Woodgett lab focuses on examining the role of an enzyme termed GSK-3 in insulin resistance and Type II Diabetes. There are two forms of this enzyme termed GSK-3α and GSK-3β which regulate the function of numerous other proteins in response to insulin. In animal models of Type II Diabetes and obesity the activity and expression of GSK-3 is higher than in normal animals. Interestingly, administration of drugs that inhibit these enzymes to animals with diabetes results in improvements in both glucose homeostasis and insulin sensitivity. Using an approach that allows us to inactivate the genes for these enzymes in specific tissues, we have generated a series of isoform- and tissue-specific GSK-3α/β mouse models. Inactivation of GSK-3α leads to improved glucose homeostasis as a result of enhanced basal and glucose-stimulated liver glycogen storage. While animals in which GSK-3β has been inactivated in the liver do not display any metabolic phenotypes, the deletion of this isoform in skeletal muscle causes enhanced glucose and insulin sensitivity. Together, these models are providing unique insights into the tissue- and isoform- specific roles of GSK-3α/β in insulin resistance and Type II Diabetes as well as allowing us to assess the short and long term effects of drugs designed to control these proteins.

Young, Kue

Department of Public Health Sciences

Received 7.7 million dollars team grant from CIHR as principal investigator, to develop and sustain a 5-year collaborative research program on chronic diseases prevention (including diabetes) in northern indigenous populations, including surveillance, genetics, and community-level interventions. Liu J, Hanley AJ, Young TK, Harris SB, Zinman B. Characteristics and prevalence of the metabolic syndrome among three ethnic groups in Canada. Int J Obes (Lond). 2006 Apr;30(4):669-76. PMID: 16302011.

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.

  1. Zinman B, Harris SB, Gerstein HC, Young TK, Raboud JM, Neuman J, Hanley AJG. Preventing type 2 diabetes using combination therapy: design and methods of the Canadian Normoglycemia Outcomes Evaluation (CANOE) trial. Diabetes, Obesity, and Metabolism (epub ahead of print) doi: 10.1111/j.1463-1326.2005.00540.x. 2005. published in 8:531-537, Sept issue of 2006.

  2. Kahn SE, Zinman B, Haffner SM, O'Neill MC, Kravitz BG, Yu D, Freed MI, Herman WH, Holman RR, Jones NP, Lachin JM, Viberti GC and the ADOPT Study Group. Obesity is a major determinant of the association of C-Reactive Protein levels and the metabolic syndrome in Type 2 diabetes. Diabetes 55: 2357-2364, August 2006.

  3. DREAM Trial Investigators. Effect of Ramipril on the incidence of diabetes. NEJM 355(15): 1551-1562, 2006 Sept 2006

  4. DREAM Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomized control trial. The Lancet 368: 1096-1105. Sept 2006.

  5. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz, BG, Lachin JM, O'Neill MC, Zinman B, Viberti G. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. NEJM Dec 4, 2006 (epub ahead of print).