Hatfieldmccaffrey2941

Safe and reliable large animal diabetes models are a key prerequisite for advanced preclinical studies on diabetes. Chemical induction is the standard model of diabetes in rodents but is often critiqued in higher animals due to reduced efficacy, relevant side effects, and inadequate mortality rate. In this chapter, we aim to describe both pharmacological and surgical approaches for reproducible and safe diabetes models in minipigs and primates. In addition, genetically modified pig models for diabetes research are described.Studies performed in humans and animal models have implicated the environment in the etiology of type 1 diabetes (T1D), but the nature and timing of the interactions triggering β cell autoimmunity are poorly understood. Virus infections have been postulated to be involved in disease mechanisms, but the underlying mechanisms are not known. It is exceedingly difficult to establish a cause-and-effect relationship between viral infection and diabetes in humans. Thus, we have used the BioBreeding Diabetes-Resistant (BBDR) and the LEW1.WR1 rat models of virus-induced disease to elucidate how virus infection leads to T1D. The immunophenotype of these strains is normal, and spontaneous diabetes does not occur in a specific pathogen-free environment. However, β cell inflammation and diabetes with many similarities to the human disease are induced by infection with the parvovirus Kilham rat virus (KRV). KRV-induced diabetes in the BBDR and LEW1.WR1 rat models is limited to young animals and can be induced in both male and female rats. Thus, these animals provide a powerful experimental tool to identify mechanisms underlying virus-induced T1D development.Virus infections have been linked to the induction of autoimmunity and disease development in human type 1 diabetes. Experimental models have been instrumental in deciphering processes leading to break of immunological tolerance and type 1 diabetes development. Animal models have also been useful for proof-of-concept studies and for preclinical testing of new therapeutic interventions. This chapter describes two robust and clinically relevant mouse models for virus-induced type 1 diabetes; acceleration of disease onset in prediabetic nonobese diabetic (NOD) mice following Coxsackievirus infection and diabetes induction by lymphocytic choriomeningitis virus (LCMV) infection of transgenic mice expressing viral neo-antigens under control of the rat insulin promoter (RIP).There are now a number of different mouse models for type 1 diabetes. The best known is the nonobese diabetic (NOD) mouse which has a genetic susceptibility to autoimmune diabetes with some features that are similar to human type 1 diabetes. Etoposide The mice also have a propensity to other autoimmune diatheses, including autoimmune thyroid disease and sialadenitis. In addition, it is well known that environmental factors affect the incidence of disease in these mice. While there are other rodent models, including numerous transgenic and knockout models, as well as those that express human proteins, none of these develop spontaneous diabetes over a period of time, when the natural history can be studied. We focus here on the unmanipulated NOD mouse and discuss features of the husbandry and investigation of the mice that allow for use of these long-studied mice in the pathogenesis of an autoimmune type of diabetes.Rat models of human type 1 diabetes have been shown to be of great importance for the elucidation of the mechanisms underlying the development of autoimmune diabetes. The three major well-established spontaneous rat models are the BioBreeding (BB) diabetes-prone rat, the Komeda diabetes-prone (KDP) rat, and the IDDM (LEW.1AR1-iddm) rat. Their distinctive features are described with special reference to their pathology, immunology, and genetics and compared with the situation in patients with type 1 diabetes mellitus. For all three established rat models, a distinctive genetic mutation has been identified that is responsible for the manifestation of the diabetic syndrome in these rat strains.Diabetes is a major public health problem it is estimated that 420 million people are affected globally. Monogenic forms of diabetes are less common, but variants in monogenic diabetes genes have been shown to contribute to type 2 diabetes risk. In vitro and in vivo models of monogenic forms of diabetes related to the endoplasmic reticulum (ER) stress response provided compelling evidence on the role of ER stress and dysregulated ER stress signaling on β cell demise in type 1 and type 2 diabetes. In this chapter, we describe the genetics, background, and phenotype of ER stress-related monogenic diabetes mouse models, and we comment on their advantages and disadvantages. We conclude that these mouse models are very useful tools for monogenic diabetes molecular pathogenesis studies, although there is a variability on the methodology that is used. Regarding the use of these models for therapeutic testing of ER stress modulators, a specific consideration should be given to the fact that they recapitulate some, but not all, the phenotypic characteristics of the human disease.The polygenic background of selectively bred diabetes models mimics the etiology of type 2 diabetes. So far, three different rodent models (Goto-Kakizaki rats, Nagoya-Shibata-Yasuda mice, and Oikawa-Nagao mice) have been established in the diabetes research field by continuous selective breeding for glucose tolerance from outbred rodent stocks. The origin of hyperglycemia in these rodents is mainly insulin secretion deficiency from the pancreatic β-cells and mild insulin resistance in insulin target organs. In this chapter, we summarize backgrounds and phenotypes of these rodent models to highlight their importance in diabetes research. Then, we introduce experimental methodologies to evaluate β-cell exocytosis as a putative common defect observed in these rodent models.Many animal models that are currently used in appetite and obesity research share at least some main features of human obesity and its comorbidities. Hence, even though no animal model replicates all aspects of "common" human obesity, animal models are imperative in studying the control of energy balance and reasons for its imbalance that may eventually lead to overt obesity. The most frequently used animal models are small rodents that may be based on mutations or manipulations of individual or several genes and on the exposure to obesogenic diets or other manipulations that predispose the animals to gaining or maintaining excessive weight. Characteristics include hyperphagia or changes in energy metabolism and at least in some models the frequent comorbidities of obesity, like hyperglycemia, insulin resistance, or diabetes-like syndromes. Some of the most frequently used animal models of obesity research involve animals with monogenic mutations of the leptin pathway which in fact are useful to study specific mechanistic aspects of eating controls, but typically do not recapitulate "common" obesity in the human population.