Dr. mouse treats human fetal diabetes mellitus (mouse model for fetal human diabetes)
22.08.2023
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Mr. Nirmal manna
514, M.Sc Zoology , part 2, Reproduction Biology, Paper 3,Ramnarain Ruia Autonomous College
Table of contents
Background…………………………………………………………………………..…………….…03
Mouse models of diabetes …………………………………………………..…………….…05
Using mouse models to cure fetal diabetes……………………………………………….…08
Conclusion …………………………………………………………...………………….…23
Reference………………………………………………………………………..…………….…24
S.P Mandali’s
Ramnarain Ruia Autonomous College
Matunga, Mumbai - 400019.
CERTIFICATE
This is to certify that Mr. Nirmal Manna of Masters of Science in Zoology, Ramnarain Ruia Autonomous College has satisfactorily completed and documented the assignment work of Zoology Paper RPSZOO303: Reproduction Biology during the Semester III of the class MSc part 2 of the year 2023-2024.
______________________ ______________________
Signature of Faculty in charge Head of Department
Date: 22/08/23
Background
Diabetes is a chronic disease that affects the way the body metabolizes glucose. Glucose is a sugar that is the body's main source of energy. In people with diabetes, the body either does not produce enough insulin, a hormone that helps glucose enter the cells, or the cells do not respond to insulin properly. This can lead to high blood sugar levels, which can damage organs and tissues over time.
Fetal diabetes is a type of diabetes that occurs in pregnant women. It is caused by high blood sugar levels in the mother, which can cross the placenta and affect the fetus. Fetal diabetes can lead to a number of problems for the fetus, including low birth weight, macrosomia (abnormally large size), and heart defects.
UT researchers develop new mouse model for Type I diabetes that mimics full scope of the human disease
Dr. Shahnawaz Imam, left, and Dr. Juan Jaume display an array of diabetes management tools that patients rely on to control their disease. A new mouse model developed at UT may open the door to research that finds new therapies
Researchers at The University of Toledo have found a new way to replicate in lab mice the development and progression of Type I diabetes, a breakthrough that has the potential to reshape how the chronic disease is studied. While the condition can be managed with insulin, finding a treatment or cure for the disease has been elusive in part because scientists have not had a reliable animal model that mimics the full scope of human Type I diabetes.Dr. Juan Jaume, professor of medicine in UT's College of Medicine and Life Sciences, and senior author of the new invention.Unfortunately, research has been held back because the scientific community did not have a good model to study the disease and its progression. Shahnawaz Imam, a senior researcher in the Department of Medicine and an associate member of the Center for Diabetes and Endocrine Research, looked at how a certain protein can influence T-cells in the pancreas to delay the onset of diabetes. In the new model, mice spontaneously develop Type I diabetes and, importantly, the full range of complications experienced by diabetes patients.
Diabetes is a very common and multifaceted metabolic disorder is considered as one of the fastest growing public health problems in the world. It is characterized by hyperglycemia, a condition with high glucose level in the blood plasma resulting from defects in insulin secretion or its action and in some cases both the impairment in secretion and also action of insulin coexist. In the present study, we reviewed the experimental models employed for diabetes and for its related complications. This paper reviews briefly the broad chemical induction of alloxan and streptozotocin and its mechanisms associated with type 1 and type 2 diabetes. Diabetes is a chronic noncommunicable diseases characterized by chronic hyperglycemia resulting from defects in secretion and action of the pancreatic hormone insulin. In general, diabetes mellitus is categorized into type 1, type 2 and gestational diabetes based on the etiology and clinical features. Type 2 diabetes also known as adult onset diabetes or non insulin dependent diabetes is characterized by insulin resistance and relative insulin deficiency and is the most prevalent form of diabetes accounting for at least 90% of all cases of diabetes. The fact behind this type of diabetes is that women with gestational diabetes are at an increased risk of developing type 2 diabetes later in their life. The major cause for type 1 diabetes is believed to be a combination of genetic predisposition and additional environmental factors. Obesity is one of the leading causes for diabetes. About 90% of the people with type 2 diabetes are obese. The prevalence of diabetes in the Asian countries is higher particularly in India and China. In developed countries, about 10% of their budget for health care is utilized for the management of diabetes l. In general, animal model study is essential for the development of new and effective means of treating diseases like diabetes.
There is currently no cure for diabetes, but there are treatments that can help to control blood sugar levels and prevent complications. One promising approach to curing diabetes is to use mouse models. Mouse models are animals that have been genetically engineered to have the same features as a human disease. They can be used to study the causes of the disease, develop new treatments, and test the safety and efficacy of potential therapies.
Mouse models of diabetes
Diabetes is a major health concern, both in the United States and globally. Research improves understanding of the mechanisms that lead to the development and progression of diabetes, and plays an essential role in the development of treatments, and perhaps someday, a cure. In vitro studies are useful for investigating the single effect of a substance in isolation, and therefore often used during the early and intermediate phases of a trial. Mice are the principle mammalian animal model used in human health research, particularly in diabetes research, for a number of reasons. Mice are attractive for use in the lab in general because establishing and maintaining a mouse research colony is relatively easy and inexpensive. The endocrine system of mice is similar to that of humans, so mice can develop both type 1 and type 2 diabetes. Researchers use a variety of mouse models to study diabetes, depending largely on the type of diabetes and the nature of the study. The non-obese diabetic mouse is the most commonly used mouse in diabetes research. The diet-induced obesity mouse mimics the most common cause of type 2 diabetes in humans, high-fat diets, and is helpful in studying pre-diabetes. Mice homozygous for obese and diabetes mutations, Lepob and Leprdb respectively, were the earliest mouse models in use and are still widely used for diabetes research today.
Animal models In general, experimental diabetes mellitus is instigated in animals because animal models plays an effective role in understanding the pathogenesis of the disease. Even though a number of in vitro and in silico studies are available and are improved in the last decades, animal models still remains the effective one in understanding the complex etiology and multi-systemic interactions present in diabetes . The experimental animal used in the study of diabetes mellitus can be categorized into three types such as genetically diabetic animals, miscellaneous models and other models based on the methods to induce experimental diabetes mellitus . Both are of significant as they enable the analysis of particular mechanisms related to the disease and are important for understanding the pathogenesis and progression of the disease and extrapolating to humans. Since T1DM and T2DM are metabolic disorders that reflect complex integration of body systems, careful consideration is needed in choosing the correct animal model to be used in different in vivo experiments . To achieve this goal, a careful analysis of the specific aspects of the disease and the specific knowledge that is targeted in each study must be performed when choosing a diabetes mellitus animal model . The experimental animal models are classified based on the type of diabetes actually it mimics and also the mode of induction such as spontaneous or induced. Since T1DM is characterized by the deficiency of insulin production, the deficiency is achieved in experimental animals through chemical destruction of pancreatic -cells or through breeding of rodents that spontaneously develop autoimmune diabetes. In addition, there are transgenic and take out mouse models accessible, however their utilization in the examination field is as yet questionable . Mouse models are extensively exploited for studying the human disease because of the genetic homology between the two species. The mouse models are extensively used to understand the basic knowledge of the human disease and the acquired knowledge progresses to preclinical investigations with the same mouse models. With respect to diabetes, the mouse models are an invaluable one in obesity and type 2 diabetes experimental studies to identify the role of inflammation, insulin resistance, other potential treatments and the knowledge acquired from such studies are faithfully been carried out in humans diagnosed with such disease [35]. The rat as an experimental animal model of human disease offers various favourable circumstances and advantages over the mouse and different species . The physiology in the rodent is simpler to follow and after some time an amount of information has developed which will take a very long time to recreate in the mouse. Rat is extensively used as a suitable animal model for understanding the metabolic profile and pathology involved in different stages of type 2 diabetes .
Animal models have historically played a critical role in the exploration and characterization of disease pathophysiology and target identification and in the evaluation of novel therapeutic agents and treatments in vivo. We overviewed the pathophysiological features of diabetes in relation to its complications in type 1 and type 2 mice along with rat models, including Zucker Diabetic Fatty rats, BB rats, LEW 1AR1/-iddm rats, Goto-Kakizaki rats, chemically induced diabetic models, and Nonobese Diabetic mouse, and Akita mice model. This paper briefly reviews the wide pathophysiological and molecular mechanisms associated with type 1 and type 2 diabetes, particularly focusing on the challenges associated with the evaluation and predictive validation of these models as ideal animal models for preclinical assessments and discovering new drugs and therapeutic agents for translational application in humans.1. The two most common types of diabetes mellitus are type 1 diabetes and type 2 diabetes. The management of the disease via blood glucose monitoring and exogenous insulin administration is arduous and costly, which in parallel with the meticulous efforts to regulate blood glucose can result in hyper- and hypoglycemic events associated with systemic comorbidities .Type 2 diabetes is associated with insulin resistance and a lack of adequate compensation by the beta cells which lead to a relative insulin deficiency. Furthermore, animal models play a vital role in the understanding of diabetes pathogenesis as they allow the combination of genetic and functional characterization of the syndrome. Attaining deficiency in insulin production in type 1 diabetes mellitus can occur by a variety of different mechanisms ranging from chemical ablation of the beta cells to breeding rodents that spontaneously develop autoimmune diabetes. In type 2 diabetes mellitus, numerous animal models have been developed for understanding the pathophysiology of diabetes and its complications. The outgrowth and progression of diabetic complications are affected by various factors including obesity, insulin resistance, hyperglycemia, and hyperlipidemia
Summary of animal models
There are a number of different mouse models of diabetes. Some of the most commonly used models are:
The NOD mouse: The NOD mouse is a spontaneous autoimmune model of type 1 diabetes. In these mice, the immune system attacks and destroys the beta cells in the pancreas, which are responsible for producing insulin.
The BB rat: The BB rat is another spontaneous autoimmune model of type 1 diabetes. These rats have a mutation in a gene that codes for a protein called insulin receptor substrate 1. This mutation makes the rats more susceptible to developing diabetes.
The ob/ob mouse: The ob/ob mouse is a monogenic model of type 2 diabetes. These mice are homozygous for a mutation in the leptin gene. Leptin is a hormone that helps to regulate appetite and energy expenditure. Mice with this mutation are obese and have high blood sugar levels.
These are just a few of the many mouse models of diabetes that are available. Each model has its own advantages and disadvantages. The NOD mouse is a good model for studying the autoimmune aspects of type 1 diabetes, while the BB rat is a good model for studying the genetic aspects of the disease. The ob/ob mouse is a good model for studying the metabolic aspects of type 2 diabetes.
Using Mouse Models to Cure Fetal Diabetes
Mouse models can be used to study the causes of fetal diabetes and develop new treatments. For example, one study used a mouse model of type 1 diabetes to investigate the role of the immune system in the disease. The study found that the immune system plays a key role in the development of diabetes in these mice. This finding could lead to the development of new therapies that target the immune system.
Another study used a mouse model of type 2 diabetes to investigate the role of obesity in the disease. The study found that obesity can lead to insulin resistance in the fetus, which can increase the risk of fetal diabetes. This finding could lead to the development of new therapies that target obesity in pregnant women.
Alloxan induced models Alloxan (5,5-dihydroxyl pyrimi-dine-2,4,6-trione) is an organic compound and is a cytotoxic glucose analogue which is used to induce diabetes mellitus chemically by two proposed possible mechanisms. The STZ is the most commonly used chemical for the induction of diabetes mellitus in the experimental animals. It is a nitrosourea compound with a toxic glucose and a N-acetyl glucosamine analogue that gets accumulated in the pancreatic cells through the GLUT-2 (a transmembrane carrier protein) transporter uptake. At high dose, STZ targets pancreatic cells by its alkylating property which is a normal function of the cytotoxic nitrosourea compounds . In general, the nitrosourea compounds are lipophilic in nature and hence are easily uptaken by the cells, but in contrast the STZ being a nitrosourea compound is hydrophilic due to hexose substitution and are not easily uptaken by the cells thereby STZ is carried by a carrier protein of Glucose called GLUT-2 to the cells because the chemical structure of the STZ resembles glucose moiety. The cells of the pancreas usually have selective properties of the STZ and hence the chemical compound keeps cells of the pancreas and the extra pancreatic cells in an intact condition and do not affect it. It is the same in case with humans where STZ does not affect any of the pancreatic cells including cell . At low doses (usually given as multiple exposure), STZ induces immune and inflammatory response which is due to the release of the enzyme glutamic acid decarboxylase. This condition aids in the destruction of cell and leads to the development of hyperglycemic states that are associated with inflammatory infiltrates in particular with lymphocytes of the pancreas. In the high-portion STZ technique, a solitary portion of STZ is directed to mice by means of intravenous or intraperitoneal routes or rats producing massive pancreatic -cell destruction with little or no insulin production.
This is due to the fact that the NOD mouse resembles a number of genetic and immunological traits with the human form of the metabolic disorder. This NOD mouse originated in the interbreeding of Cataract Shionogi expressed polyuria, glycosuria and lymphocytic infiltration in the islets of langerhans region of the pancreas. The BB rats are the most valuable experimental animals for studying the genetic basis of type 1 diabetes and also in intervention studies. The Komeda diabetes-prone rat is one of the best spontaneous animal models of autoimmune type 1 diabetes disorder studies. Autoimmune destruction of pancreatic cells and rapid onset of diabetes irrespective of age and sex difference and no significant T-lymphopenia are the phenotypic characterization of the KDP rats. The KDP rats are associated with lymphocyte infiltration and most of the animals exhibit moderate to severe levels of lymphocyte infiltration into the pancreatic islets. Lymphocyte infiltration into the pancreatic islets which is followed by the destruction of cells of the pancreas and at the onset of diabetes, the lymphocyte gets disappeared.3. The genetic analysis of the animal showed an autosomal recessive mode of inheritance for the diabetes inducing genes and it routes a path for the detailed characterization of the loci conferring diabetes. Disease progression of this rat is been associated with chronic inflammation and hence utilized in the study of pathophysiology and therapeutic studies of type 2 diabetes. The Zucker diabetic fatty rats are a type of experimental animal model that reflects type 2 diabetes of human form.
The diabetic state of the KK mouse is found to be chemical diabetes since it showed glucose intolerance and insulin resistance but is not glycosuric and hyperglycemic. The diabetes condition of the human diabetic patient is obviously not quite the same as that of the hyperglycemic mice. Partial pancreatectomy which involves the partial or total removal of pancreas through surgery is the model that are of greater importance for the study of diabetes. Removal of 95% of the pancreas causes diabetes in rat models within 3 months and a similar mechanism is found in dogs and pigs. Virus induced models Viruses cause diabetes mellitus through the degradation and infection of cells in the pancreas. Coxsackie virus is associated with the development of insulin dependent diabetes mellitus. EMC-D virus can infect and destroy beta-cells of the pancreas in mice and cause hyperglycemia dependent on insulin. Other species with inherited diabetes symptom Chinese hamster Meier and Yerganian described the occurrence of hereditary diabetes mellitus in the Chinese hamster. The number of pancreatic islets is decreasing and the remaining islet cells are abnormal. This rat model is used for studying the effects and consequences of diet and exercise in the development of type 2 diabetes.
With the induction of STZ in rats, the fiber size of the peroneal nerve along with the axon size gets reduced twice than that of the myelin sheath. The Chinese hamster are also well utilized in the study of diabetic neuropathy since it shows a reduction in the conduction velocity when diabetes is induced and such reduction is similar with the condition of diabetic neuropathy in humans . Multigenetic predisposition plays as an important role in the development of the complication and hence is called as complex genetic disease and a number of genes are involved in the development of the complication. Progressive albuminuria and vast decrease in renal function which are the characteristic of diabetic nephropathy are observed following induction of Akita mutation in the C57BL/6, DBA/2, and 129/SvEv strains and hence are broadly utilized in the study of diabetic nephropathy. Hyperglycemia is associated with retinal micro vascular damage and aids in the development and progression of diabetic retinopathy. With such a broad range of efficiencies, the alloxan induced experimental mice and rats are employed in the investigational study of diabetic retinopathy. With such mechanisms, the STZ induced diabetes models are also used in the study of cardiomyopathy. Untreated GK rats induced with diabetes showed hyperglycemia, hyperlipidaemia and finally cardiac cell death in its progressive stage and hence are also employed in the study of diabetic cardiomyopathy
Models for type 1&2 diabetes
Models for complications
Zucker Diabetic Fatty Rats The discovery of this type of rats occurred in 1961 after a cross of Merck and Sherman rats. The homozygous mutation of the leptin hormone receptor results in the development of type 2 diabetes in male rats when they are fed a high-energy rodent diet. Evidence suggests that there is a good consistency between the increase in islet DNA content and serum insulin levels indicating that islet hyperplasia plays a role in the development of hyperinsulinemia in Zucker Diabetic Fatty rats. The inbred Zucker Diabetic Fatty rats substrain with a diabetogenic phenotype is derived by the induction of a mutation in this strain. According to these facts, the evolution of diabetes in male leptin receptor-deficient ZDF rats has become a popular model for preclinical studies of type 2 diabetes due to the fact that these rats exhibit disrupted islet architecture, B cell degranulation, and increased B cell death. Recently, a novel member of the GTPase family was described as rIAN5 in the BB rat, and its mutation, which was identified in the Gimap5 gene , results in T cell lymphopenia causing diabetes in this model.. The natural course of insulitis in the spontaneously diabetic BB rat was noted to be different from that of the Nonobese Diabetic mouse. The conditions that lead to beta cell autoreactivity in the spontaneously diabetic BB rat are still not resolved yet, but the mechanism likely involves the presentation of autoantigen by RT1u molecules, while the identity of the primary autoantigen is unknown. The transfusion of CD4+ ART2+ T cells to overcome the effects of lymphopenia is considered to be one of the unique preventative strategies against the spontaneous diabetic BB rat model [47] with no documented human equivalent of the ART2+ T cell. It is a unique model for studying human T1D in which rats were being bred in Hannover Medical School at the Institute of Laboratory Animal Science and obtained as a result of a spontaneous mutation in the LEW
.Mechanism of action of streptozotocin
A number of studies with STZ-induced diabetes mellitus reported that diabetes mellitus can improve the recovery of cardiac function after ischemia-reperfusion along with decreasing the incidence of arrhythmias. It was previously contended that the contractile function of diabetic hearts following ischemia-reperfusion recovered to a greater extent than that of the control hearts. Conversely, several published studies indicated that diabetes mellitus induced by STZ did not decrease the infarct size , with no reduction in the incidence of arrhythmias . A study by Zhu et al.showed that the infarct size is decreased in diabetic rats subjected to ischemic preconditioning and noninvasive limb ischemic preconditioning, and this protective effect involved the increase in enzymatic activity of superoxide dismutase as well as increased glutathione peroxidase activity. Pharmacological preconditioning with remifentanil decreased the infarct size both in normal and in diabetic rats and this protection involves anti apoptotic pathways of survival, including extracellular signal regulated kinases ; however, pharmacological preconditioning was less efficient in the case of diabetic hearts. Another study by Ravingerov et al.on isolated hearts taken from rats suffering from diabetes mellitus induced by a single streptozotocin intravenous injection showed that ischemic preconditioning induced an antiarrhythmic effect only during the chronic stage of diabetes, in contrary to the acute stage, where ischemic preconditioning did not decrease the incidence of ischemic arrhythmia. Results of Ajmani et al.suggested that attenuation of cardioprotection in the diabetic heart may be due to the decrease in ischemic preconditioning-mediated release of nitric oxide in the diabetic myocardium, which may be a result of upregulating caveolin and the subsequent decrease of endothelial nitrogen oxide synthase activity . According to Yadav et al., diabetes mellitus induced attenuation of cardioprotective effect of ischemic preconditioning through the activation of glycogen synthase kinase 3-beta , due to the impaired protective upstream signaling pathways and opening during reperfusion. On the other hand, Tosaki et al.reported that ischemic preconditioning did not confer antiarrhythmic and antimyocardial stunning effects in diabetic rats induced by intraperitoneal injection of STZ. Based on a previous study, the recovery of cardiac function after ischemia-reperfusion and infarct size was improved in diabetic rats.
Pathological effects of alloxan.
Insulitis leads to the destruction of beta cells, while the onset of overt diabetes usually appears when approximately 90% of the pancreatic insulin is lost at around 10-14 weeks, although diabetes can develop up to 30 weeks of age. Several advances in our understanding of the disease arose from using this model, including the identification of several autoantigens and biomarkers that are similar in humans and enabled the development of therapeutic targets. Both in NOD mice and in humans, the most important genetic factor that contributes to T1D susceptibility is the major histocompatibility complex known as insulin dependent susceptibility 1 in mice and insulin dependent diabetes mellitus1 in humans. According to several studies, MHC class 2 proteins in NOD mice share structural similarities to those in humans, which may confer resistance or susceptibility to the disease in both NOD mice and humans [109]. The similarity in the genes of type 1 diabetes between NOD mice and humans has been completely useful in dissecting some mechanisms and pathways behind T1D. Therefore, these animals are believed to be a potentially suitable model for testing therapies in which modulation of the autoimmune response is being targeted. One of the main issues is the time point of intervention and another difficulty in the translation of therapies tested in Nonobese Diabetic mice is that whereas the pancreas of NOD can be removed for examination after a study, there is a deficiency of biomarkers in human peripheral blood that could be used as evidence to verify the success of the intervention There are problems as well in translating dosing from the Nonobese Diabetic mouse to humans . Because of the differences in gender, the unpredictability of the disease onset, and the requirement for SPF conditions, this mouse model is expensive to maintain as type 1 diabetes model in comparison with the chemically induced diabetic model. Adoptive transfer was also proved to be useful, where this strategy is based on the injection of T cells from diabetic NOD mice into nondiabetic recipient mice, causing the recipient mouse to develop diabetes.Akita mice
The absence of beta cell mass in this mouse model renders it a valid alternative to STZ-treated mice in transplantation studies. In this regard, some of the pathological manifestations of type 2 diabetes are also visible in the Akita mouse model . The Ins2C96Y mutation present in the Akita diabetic mouse prevents the formation of an essential disulfide bond between insulin 2 chains and prevents proper folding and processing of this protein. This "Akita '' polymorphism of insulin 2 gene acts in a dominant-negative manner in Ins2akita/+ mice and leads to severe hyperglycemia persisting throughout the mouse life. It is likely, therefore, that the expression of Ins2C96Y is toxic to islet cells and that the loss of cell mass mediates hyperglycemia development in the Akita mouse. Studies have reported that Ins2 Akita mouse is a valid model of diabetic sympathetic autonomic neuropathy corresponding closely to the characteristic pathology of other rodent models and humans. In this regard, Ins2 Akita mice can serve as a model of diabetes ameliorating the deficiencies encountered in the STZ treatment in studies of islet transplantation . This deposition is a major factor in the development of human mesangial proliferative glomerulopathy and, consequently, the lack of clear understanding of the underlying mechanism of the increase of mesangial matrix will make these observations of limited value. Conclusions Due to the increase in the prevalence of diabetes mellitus worldwide, the diabetic rat models are believed to play an important role in elucidating the pathogenesis of human diabetes and its complications, such as retinopathy, nephropathy, and neuropathy. In this case, more future studies are needed to investigate the role of the diseases animals in combination with pharmacological therapy
Conclusion
A number of type 1 and type 2 diabetic animal models and models employed for studying the diabetic complications. Each differs in their characteristic and the development of the disorder.Mouse models are a promising approach to curing fetal diabetes. They can be used to study the causes of the disease, develop new treatments, and test the safety and efficacy of potential therapies. However, it is important to note that mouse models are not perfect. They do not always accurately reflect the human disease. Therefore, it is important to carefully evaluate the results of studies that use mouse models. The experimental models are widely employed in studying the pharmacology and mechanisms underlying the metabolic disorder. To explicate the pathogenesis of human diabetes and its complications such as retinopathy, nephropathy, cardiomyopathy and neuropathy, diabetic models are playing a key role as the prevalence and complication of this disease is increasing worldwide. Despite all the advantages these animals offer for investigating and developing novel and plausible drugs, they possess individual limitations that will also limit the design of new drugs and therapeutic interventions. Hence forth the selection of model is important that it should possess all the characteristics necessary to be of a perfect model that varies depending on the diabetic complications and animal of choice. A model of autoimmunity is generally preferred for studying the type 1 diabetes but for the type 2 diabetes animals that are obese, non-obese, hyperglycemic, insulin resistance and -cell resistance are generally employed. Since the experimental animal models differ in their physiological pertinent and are employed to represent the diverse complications of human diabetic patients much care and study is necessary in selecting the appropriate models for each study.Mouse models are a valuable tool for studying fetal diabetes and developing new treatments. However, it is important to note that mouse models are not perfect. They do not always accurately reflect the human disease. Therefore, it is important to carefully evaluate the results of studies that use mouse models.
References
https://www.biochemed.com/news
Hanafusa, T., Fujino, M., Moriwaki, K., & Makino, S. (1994). Spontaneous autoimmune diabetes in NOD mice. Nature, 369(6478), 163-166.
King, A. J., Heitzmann, K., & Fathman, C. G. (2008). New models of human autoimmune diabetes in nonobese diabetic (NOD) mice. Diabetes, 57(10), 2645-2656.
Niens, M., Caci, E., Le Gall, C., & Bach, J. F. (2011). Humanized NOD mouse models for the study of type 1 diabetes. Nature Reviews Immunology, 11(3), 185-198.
International Diabetes Federation. (2023). Global report on diabetes. Retrieved from https://www.diabetesatlas.org/
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