Senior Scientist , Chronic Disease , Ottawa Hospital Research Institute

Biographical Sketch
Dr. Scott studied Chemistry at McGill University and received a PhD in Biochemistry from Queen’s University followed by postdoctoral training at the University of Alberta.  He then joined Health Canada as a Research Scientist.  In 1999, he moved to the Ottawa Hospital Research Institute where he is a Senior Scientist in the Chronic Disease and Molecular Medicine Programs.  He is a Professor in the Departments of Medicine and Biochemistry, Microbiology and Immunology at the University of Ottawa.

Research Focus -   Molecular and cellular basis of autoimmune Type 1 diabetes

The treatment for Type 1 diabetes (T1D) has not changed much since insulin was discovered in 1921.  Incidence of T1D has increased over the past 50 years and there is no cure. T1D is an autoimmune disease in which the patient's immune system destroys the insulin-producing ß-cells by a process dependent on interaction between several risk genes and environmental factors.  The identity of the players in this process and the mechanisms involved are only partially understood.  Essential questions that remain unanswered are what elements in the environment promote diabetes and how does this occur?  Successful treatment or prevention of diabetes depends on a better understanding of the environmental agents that promote this disease.

Our lab is interested in how environmental factors, particularly dietary antigens, influence the development of T1D [1].  A major focus is to understand diabetes-promoting interactions between dietary antigens, the gut immune system and the endocrine pancreas.  The aims of this work are: (i) to understand T1D pathogenesis and how it is modified by dietary proteins with a particular focus on wheat protein induced gut immune response, (ii) to determine whether it is possible to establish a more normal microenvironment to maintain islet ß-cell mass, (iii) to investigate the potential for primary prevention and treatment. Three major areas of investigation are: (1) characterization of diabetes-promoting agents in the diet [2], (2) understanding ß-cell pathways/ processes that are abnormal [3-5] and (3) characterizing abnormal immune response to dietary proteins that promote diabetes in animals and patients [6-8].

Nutritional modification of autoimmune diabetes: Dietary antigens - gut immune system - islet ß-cells

Dietary antigens  The spontaneous development of diabetes in two models of T1D, BB rats and NOD mice, is strongly influenced by the source of dietary protein [1]. Standard rodent diets that are mostly cereal-based are associated with the highest diabetes incidence whereas diets based on selected hydrolyzed proteins or other non-diabetes-promoting amino acid sources are diabetes-retardant. It is noteworthy that both BB rats and NOD mice still develop diabetes when maintained in ultra-clean, viral-antibody-free conditions where the major environmental influence is from the diet. We have identified diabetes-promoting dietary agents and we are investigating the mechanisms involved [1]. To identify diabetes-related wheat proteins, we screened approximately 1 million recombinant wheat proteins and identified a wheat storage globulin, Glb1 homologue [2]. IgG reactivity to the Glb1 homologue correlated closely with in vivo measures of pancreatic damage and islet inflammation.

Gut immune response - The Th1 cytokine pattern in islet infiltrates can be altered in diabetes-prone rats fed a protective, low antigen, hydrolyzed casein-based diet [9,10] suggesting that diet controls the islet directed inflammatory process.  In animals fed cereal-based, diabetes-promoting diets we reported an unusually high proportion of CD4⁺, IFN-gamma producing T cells in the main inductive site for the gut immune system, the mesenteric lymph nodes, MLN [6]. This was associated with decreased expression of GATA-3 rather than increased T-bet, key transcription factors controlling the balance between Th1/Th2 cytokine production [11]. Our recent data show there is a significant subset of patients who display strong pro-inflammatory, mainly Th1 cell reactivity to wheat proteins [12].  Thus, the basis of abnormal immune response to wheat antigens in diabetes-prone animals and humans continues to be a focus of our research. 

A gut-centric working model of T1D:  The gut is where dietary molecules, microbes and other non-self chemicals have their first major encounter with the largest population of immune cells in the body, the gut-associated lymphoid tissue.  Evidence is mounting from studies of diabetes-prone rodents and human patients that the gastrointestinal tract can show signs of sporadic inflammation and leakiness.  The gut and its draining lymph nodes, the MLN, and possibly the pancreatic lymph nodes, are sites where immune cells exposed to dietary and microbial antigens reside.  We hypothesize that the gut barrier and its immune system are abnormal in some susceptible individuals permitting exposure to a complex mixture of dietary and microbial antigens that somehow stimulates an abnormal immune system to mistakenly target the insulin-producing ß-cells.  This model is described in more detail in Lefebvre et al. [1].    

The target ß-cells      

Compromised regenerative capacity and abnormal metabolism?    Our data show that diets with different diabetes-promoting capacity affect the ability of the endocrine pancreas to retain sufficient ß-cells to maintain normal blood glucose.   One pathway to enhance islet mass is from islet neogenesis, a form of which is represented by extra-islet, insulin⁺ clusters of <4 cells (EIC) or the formation of neogenic tubular complexes (TC) [3].  Although both of these processes are upregulated in the pancreas of diabetes-prone rats, they are insufficient to maintain normal blood glucose levels in the face of a chronic immune attack, possibly because of a decreased capacity to expand into mature islets [5].  These processes seem to represent early but futile attempts to maintain islet mass and could be influenced by diet in some instances. Therefore, diets that influence diabetes development probably do so through combined effects on islet mass and the gut immune system.     

PrP^C and glucose homeostasis   ß-cell metabolism could be different in diabetes-prone individuals compared with those who do not develop diabetes.  For example, we recently reported that aggregates of the normal prion protein, PrP^C, occur in the cytosol of ß-cells and their formation was responsive to changes in blood glucose [4].  This suggested that PrP^C can exist in an aggregated form in vivo, and is linked with glucose homeostasis [4]. Studies are underway to ascertain the mechanism behind this phenomenon and to understand the potential link with T1D.  

Current Funding

Research is funded by the Juvenile Diabetes Research Foundation International; Canadian Institutes of Health Research; Canadian Diabetes Association

Current Research Group Members

Dr. Gen-Sheng Wang, Research Associate, gswang@ohri.ca
Dr. Alexander Strom, JDRF Postdoctoral Fellow, astrom@ohri.ca
Majid Mojibian, PhD Student, mmojibian@ohri.ca
Brigitte Sonier, PhD Student, bsonier@ohri.ca (FRSQ Scholarship)
Christopher Patrick, MSc Student, cpatrick@ohri.ca (OGS Scholarship)
Cristina Slatculescu, MSc Student, cslatculescu@ohri.ca
Jennifer Crookshank, Research Technician, jcrookshank@ohri.ca

Front Row: Gen-Sheng Wang, Brigitte Sonier, Jennifer Crookshank, Cristina Slatculescu    Back Row: Alexander Strom, Majid Mojibian, Christopher Patrick, Fraser Scott

Selected Publications

1. Lefebvre DE, Powell KL, Strom A, Scott FW: Dietary proteins as environmental modifiers of type 1 diabetes mellitus. Annu Rev Nutr 26:175-202, 2006 PubMed ID: 16848704
   
2. MacFarlane AJ, Burghardt KM, Kelly J, Simell T, Simell O, Altosaar I, Scott FW: A type 1 diabetes-related protein from wheat (Triticum aestivum). cDNA clone of a wheat storage globulin, Glb1, linked to islet damage. J Biol Chem 278:54-63, 2003 PubMed ID: 12409286
   
3. Wang GS, Rosenberg L, Scott FW: Tubular complexes as a source for islet neogenesis in the pancreas of diabetes-prone BB rats. Lab Invest 85:675-688, 2005 PubMed ID: 15765120
   
4. Strom A, Wang GS, Reimer R, Finegood DT, Scott FW: Pronounced cytosolic aggregation of cellular prion protein in pancreatic beta-cells in response to hyperglycemia. Lab Invest 87:139-149, 2007 PubMed ID: 17146448
   
5. Kauri L, Wang, G-S., Patrick, C, Bareggi, M, Hill, DJ, Scott, FW: Increased islet neogenesis without increased islet mass precedes autoimmune attack in diabetes-prone rats. Lab. Invest. In Press, 2007 PubMed ID: 17906659
   
6. Chakir H, Lefebvre DE, Wang H, Caraher E, Scott FW: Wheat protein-induced proinflammatory T helper 1 bias in mesenteric lymph nodes of young diabetes-prone rats. Diabetologia 48:1576-1584, 2005 PubMed ID: 16003532
   
7. Mojibian M, Chakir H, MacFarlane AJ, Lefebvre DE, Webb JR, Touchie C, Karsh J, Crookshank JA, Scott FW: Immune reactivity to a glb1 homologue in a highly wheat-sensitive patient with type 1 diabetes and celiac disease. Diabetes Care 29:1108-1110, 2006 PubMed ID: 16644646
   
8. Mojibian MS, A, MacFarlane, AJ, Scott, FW: Immune reactivity to a homologue of wheat storgae globulin, Glb1 in human type 1 diabetes. FASEB J. 21:A771, 2007
   
9. Scott FW, Cloutier HE, Kleemann R, Woerz-Pagenstert U, Rowsell P, Modler HW, Kolb H: Potential mechanisms by which certain foods promote or inhibit the development of spontaneous diabetes in BB rats: dose, timing, early effect on islet area, and switch in infiltrate from Th1 to Th2 cells. Diabetes 46:589-598., 1997 PubMed ID: 9075798
   
10. Scott FW, Rowsell P, Wang GS, Burghardt K, Kolb H, Flohe S: Oral exposure to diabetes-promoting food or immunomodulators in neonates alters gut cytokines and diabetes. Diabetes 51:73-78., 2002 PubMed ID: 11756325
    
11. Chakir H, Wang H, Lefebvre DE, Webb J, Scott FW: T-bet/GATA-3 ratio as a measure of the Th1/Th2 cytokine profile in mixed cell populations: predominant role of GATA-3. J Immunol Methods 278:157-169, 2003 PubMed ID: 12957404
    
12. Mojibian M, Lefebvre, DE, Chakir H, Scott, FW: T cell reactivity to wheat proteins in human type 1 diabetes. Diabetes 54(Suppl1):A79, 2005