OBJECTIVES : To summarize the major findings that have come from studies of BB rats and related models of diabetes and to develop recommendations for new directions in diabetes research.
THE PROGRAM: This is a multidisciplinary meeting that will bring together internationally recognized leaders in diabetes research whose work has shaped our present understanding of this disease and its complications. The meeting will permit diabetes investigators from diverse fields and trainees to interact on the occasion of the anniversary of this unique discovery.
BACKGROUND : The BioBreeding (BB) Rat was discovered in 1974 at the former BioBreeding Laboratories near Ottawa, Canada and was the first animal model of spontaneous, autoimmune type 1 diabetes. Since then there have been more than 1,400 scientific papers published on various aspects of diabetes pathogenesis, genetics, immunology, environmental agents, metabolism and complications.
The model was first characterized by Errol Marliss and colleagues when he was at the University of Toronto, in collaboration with researchers at the University of Massachusetts. Around the same time, a nucleus of BB rats was shipped to the University of Massachusetts Medical School where an NIH-funded colony was established. The NIH colony was later transferred to a private company, Biomedical Research Models, Inc. (info@biomere.com) which currently houses BB and related rat strains. Animals are also available from Taconic (custserv@taconic.com), Health Canada (jocelyn_souligny@hc-sc.gc.ca) and individual researchers in countries around the world.
The BB rat has been instrumental in studies demonstrating the role of various immune system components including immune stem cells, thymic maturation, gut immune dysfunction, a new family of immune regulatory genes, dysregulated cytokine balance and participation of the innate immune system. Other important studies have revealed the etiology of pancreatic islet inflammation (insulitis), the role of dietary antigens and viruses, defects in the early development and maintenance of islet mass, enhanced apoptosis, novel changes in the islet proteome, and links between the dysregulated immune system and pancreas biology.
The BB rat has also been used as the basis for developing new models of diabetes and autoimmunity. There are several strains of BB rats: BBDP (diabetes-prone), BBDR (diabetes-resistant), BBZDR, BB/Lew, BB nude rats, BB transgenics and numerous congenic animals. The rat genome was published recently, there is an expanded array of rat reagents and technologies point to exciting new possibilities.
There have been important metabolic observations to date that have the potential for application to the human disease. The fact that the rat develops total insulin deficiency has made it ideal for studies of the metabolic impacts of this state and of different levels of insulin replacement. This includes effects on muscle protein metabolism, regulation of glucagon secretion, endothelial nitric oxide production, lipid metabolism, vitamin status, aspects of brain function, bone alterations, and many others. There have been important contributions to understanding the mechanisms of diabetic complications. These include neuropathy, as well as retinopathy, nephropathy, reproductive dysfunction, gastrointestinal tract dysfunction, and more.
Data from these animals have been used as the basis for several major studies in human patients or those at high risk, including the first trial demonstrating effects of early immunosuppression in newly diagnosed patients, the Canada-Europe cyclosporin A trial, the current TRIGR study (trial to reduce IDDM in the genetically at risk) and others. Therapeutic interventions and preventive strategies proposed for use in humans are more likely to be successful if verified not only in the NOD mouse, whose diabetes is easily modified, but also in the BB rat where diabetes incidence is more difficult to alter. The BB rat has been used for trials of many drugs, not only for diabetes prevention, but for treatment of the diabetes and its complications.
