The Non-Obese Diabetic (NOD) Mouse as a Model of Human Type 1 Diabetes

ArticleinMethods in molecular biology (Clifton, N.J.) 933:3-16 · August 2012with27 Reads
DOI: 10.1007/978-1-62703-068-7_1 · Source: PubMed
The non-obese diabetic (NOD) mouse spontaneously develops type 1 diabetes (T1D) and has thus served as a model for understanding the genetic and immunological basis, and treatment, of T1D. Since its initial description in 1980, however, the field has matured and recognized that prevention of diabetes in NOD mice (i.e., preventing the disease from occurring by an intervention prior to frank diabetes) is relatively easy to achieve and does not correlate well with curing the disease (after the onset of frank hyperglycemia). Hundreds of papers have described the prevention of diabetes in NOD mice but only a handful have described its actual reversal. The paradoxical conclusion is that preventing the disease in NOD mice does not necessarily tell us what caused the disease nor how to reverse it. The NOD mouse model is therefore best used now, with respect to human disease, as a way to understand the genetic and immunologic causes of and as a model for trying to reverse disease once hyperglycemia occurs. We describe how genetic approaches to identifying causative gene variants can be adapted to identify novel therapeutic agents for reversing new-onset T1D.
    • "Therefore, the idea of reducing the complexity of HLA is quite appealing to help us to understand the HLA mode of inheritance and provide insights into the complex nature of these correlations. Consistent with this concept, the non-obese diabetic (NOD) mice, that spontaneously develop T1D and have served as a useful animal model for understanding the immunological foundation, genetic basis, and treatment, of T1D [86], are genetically homogenous (created from inbred colonies), while humans are diverse; therefore, these mice are very useful for studying the correlation between the genetic variations and clinical phenotypes of the disease. The human equivalents are those Arab inbred communities living in areas where the incidence and prevalence are very high and that are considered to be genetically homogenous. "
    [Show abstract] [Hide abstract] ABSTRACT: Type 1 diabetes (T1D) is a complex autoimmune disorder that results from the T cell-mediated destruction of the pancreatic β cells and is due to interactions between environmental and genetic factors. Although Arabs have one of the highest global incidence and prevalence rates of T1D, unfortunately, there is a dearth of information regarding the genetic epidemiology of T1D in the Arab world. Arabs share several HLA haplotypes with other ethnic groups, which confer either susceptibility or protection to T1D, but they have specific haplotypes that are distinctive from other ethnicities. Among different Arab countries, several non-HLA genes were reported to be associated with susceptibility to T1D, including CTLA4, CD28, PTPN22, TCRβ, CD3z, IL15, BANK1, and ZAP70. In Arab countries, consanguinity, endogamy, and first-cousin marriage rates are some of the highest reported worldwide and are responsible for the creation of several inbreeding communities within the Arab world that have led to an increase in homozygosity of both the HLA haplotypes and non-HLA genes associated with either protection or susceptibility to T1D among Arabs. Homozygosity reduces the HLA complexity and is expected to facilitate our understanding of the mode of inheritance of HLA haplotypes and provide valuable insight into the intricate genotype-phenotype correlations in T1D patients. In this review, based on literature studies, I will discuss the current epidemiological profile and molecular genetic risks of Arabs with T1D.
    Full-text · Article · Mar 2016
    • "This preclinical model has been critical to our understanding of autoimmune diabetes yet there are caveats that have complicated translating efficacy into the clinic including differences in cell replication; islet structure; severity and composition of the immune infiltrate in the islets; and the main T-cell subset involved [21]. In fact, diabetes can be prevented or cured in the NOD, yet we have not seen such successes in human studies202122 . Often, the interpretation of efficacy is complicated by the prevalent lowrate of reproducibility associated with published preclinical results. "
    [Show abstract] [Hide abstract] ABSTRACT: The standard of care (SoC) for Type 1 diabetes (T1D) today is much the same as it was in the early 1920s, simply with more insulin options -fast-acting, slow-acting, injectable, and inhalable insulins. However, these well-tolerated treatments only manage the symptoms and complications, but do nothing to halt the underlying immune response. There is an unmet need for better treatment options for T1D that address all aspects of the disease. For decades, we have successfully treated T1D in preclinical animal models with immune-modifying therapies that have not demonstrated comparable efficacy in humans. The path to bringing such options to the clinic will depend on the implementation and standard inclusion of biomarkers of immune and therapeutic efficacy in T1D clinical trials, and dictate if we can create a new SoC that treats the underlying autoimmunity as well as the symptoms it causes. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jun 2015
    • "Also, the antihyperglycemic activity of this protein was established by inducing diabetes in animals, and not in non-obese diabetic (NOD) mice, the spontaneous model of type 1 diabetes. The NOD mice represent one of the primary experimental models of T1DM for screening of therapeutics as these mice share many immunological and pathophysiological similarities to human insulin-dependent diabetes mellitus [13]. The present study reports comparative sequence analysis, prediction of secondary structural components, 3-dimensional structural model using in silico homology modeling and antihyperglycemic activity of the rADMc1 in non-obese diabetic (NOD) mice. "
    [Show abstract] [Hide abstract] ABSTRACT: Momordica charantia is a well known medicinal plant used in the traditional medicinal system for the treatment of various diseases including diabetes mellitus. Recently, a novel protein termed as ADMc1 from the seed extract of M. charantia has been identified and isolated showing significant antihyperglycemic activity in type 1 diabetic rats in which diabetes was induced. However, the structure of this protein has not yet been analyzed. Homology modeling approach was used to generate a high quality protein 3D structure for the amino acid sequence of the ADMc1 protein in this study. The comparative assessment of secondary structures revealed ADMc1 as an all-alpha helix protein with random coils. Tertiary structure predicted on the template structure of Napin of B. Napus (PDB ID: 1SM7) with which the ADMc1 showed significant sequence similarity, was validated using protein structure validation tools like PROCHECK, WHAT_CHECK, VERIFY3D and ProSA. Arrangement of disulfide bridges formed by cysteine residues were predicted by the Dianna 1.1 server. The presence of multiple disulfide bond confers the stable nature of the ADMc1 protein. Further, the biological activity of the ADMc1 was assessed in non-obese diabetic (NOD) mice which are spontaneous model of type 1 diabetes. Significant reduction in the blood glucose levels of NOD mice was observed up to 8 h post administration of the rADMc1 protein. Overall, the structural characterizations with antihyperglycemic activity of this seed protein of Momordica charantia demonstrate its potential as an antidiabetic agent.
    Article · Aug 2013
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