自发性糖尿病动物模型 z-bio 2021-03-11 246

　　[Modeling mechanism] Spontaneously diabetic animals, also known as spontaneously hyperglycemic animals, are naturally occurring diabetes in animals, or a diabetic model retained through genetic breeding and cultivation. Its performance is very similar to the clinical symptoms of human diabetes. It can be used for the cause of diabetes and The study of pathogenesis can also be used for the research and screening of anti-diabetic drugs.

　　(1) Spontaneous Type 1 Diabetes Animal Model

　　【Modeling method】

　　1. NOD mouse nonobese diabetes (NOD) mouse is a CTS (cataract susceptible subline) diabetic mouse derived from the JCL-ICR strain of mice inbred, and the onset is sudden, and the manifestation is obvious polydipsia , Polyuria, weight loss, blood sugar significantly increased, without insulin treatment, animals can not survive for a month, usually die of ketosis. NOD mice are mediated by T-cells (including CD4 and CD8 cells), and their development is controlled by a series of T-cell regulation. Beta cell damage is secondary to the autoimmune process, causing hypoinsulinemia. The incidence of diabetes in NOD mice is related to gender. The incidence of diabetes in female mice is significantly higher than that in male mice and the onset is early.

　　2. BB rat, also called BBDP (biobreeding diabetes-prone rat) rat, is a spontaneous hereditary type C diabetes animal model screened out from Wistar rats. Its pathogenesis is related to autoimmune destruction of pancreatic β-cells leading to pancreatitis and insulin deficiency. The onset of diabetes in BB rats is sudden, about 60 to 120 days of age, and a few days later, severe hyperglycemia, hypoinsulinemia and ketemia appear in diabetic animals.

　　3. LEW.1NR1/ztm-iddm rat is a spontaneous mutant strain of Lewis rat MHC haplotype, and a spontaneous autoimmune type 1 diabetes animal model. The onset is about 58 days, the incidence rate is 20%, and gender does not affect the incidence rate. It is characterized by high blood sugar, diabetes, ketonuria and polyuria. Pancreatic islets are infiltrated by inflammatory cells (B lymphocytes, T lymphocytes, macrophages, NK cells). Β-cells rapidly apoptotic in the site of pancreatitis.

　　[Model Features] NOD mice, BB diabetic rats and LEW.1NR1/ztm-iddm rats are good models for studying spontaneous autoimmune type 1 diabetes.

　　[Model evaluation and application] NOD mice and human type 1 diabetes have many common characteristics: disease development is controlled by many disease susceptibility or resistance genes, including most gene loci with complex histocompatibility, which can be used for type 1 diabetes Research. BB diabetic rats can simulate the natural onset, course development and outcome of human type 1 diabetes without the participation and interference of external factors. It is also an ideal type 1 diabetes animal model.

　　(2) Spontaneous Type 2 Diabetes Animal Model

　　1. KK mouse (kk mouse) is a mildly obese type 2 diabetic animal bred by Japanese scholars. After crossing with C57BL/6J mice, and inbreeding to obtain Toronto2 (T2kk) mice, which are congenital genetically defective mice. The yellow obesity gene (namely Ay) was transferred to KK mice, and KK-Ay mice were obtained. Compared with KK mice, they had obvious obesity and diabetes symptoms. After 5 weeks, blood sugar, blood circulating insulin levels and HbA1c levels gradually increased. β cells have degranulation and glycogen infiltration, followed by pancreatic islet hypertrophy and central air bubbles. Fatty liver and adipose tissue increase. The insulin sensitivity of adipose tissue was lower than that of KK mice, and it was completely lost at 16 weeks of age. Kidney disease occurs early, develops rapidly, and the glomerular basement membrane thickens. The mouse's pituitary gland, liver, adrenal gland and parathyroid gland also have corresponding hyperplasia changes.

　　2. The ob/ob mouse (ob/ob mouse) is an obese hyperglycemic mouse. It was discovered in 1949 by the Jackson Laboratory of the United States that it is called an ob mouse because of its obese phenotype. Its inheritance method is autosomal recessive gene inheritance. The body is extremely fat, and he spontaneously produces hyperglycemia and diabetes in the early stage. The average blood sugar level in the non-fasting state is 300mg/dl, but there is no ketosis and coma.

　　3. The db/db mouse diabetic mouse (C57BL/KsJ db/db mouse) is also a spontaneous mutant mouse discovered in the C57BLKS/J (BKS) inbred line by Jackson's laboratory in 1966. The mouse is hyperglycemic, The phenotype of polyuria and high urine glucose levels is very similar to that of human diabetic patients. Hyperinsulinemia occurs in 10 to 14 days, obesity is obvious in 3 to 4 weeks, and it can reach 2 to 3 times that of wild mice at 10 weeks, but the length is 5% shorter than wild type, and there are hypercholesterolemia and hypercholesterolemia. Triglyceridemia. Hyperglycemia appeared in 4 to 8 weeks, and showed typical clinical manifestations of diabetes with polyphagia, diabetic thirst, and polyuria.

　　4. NSY mice NSY (Nagoya-Shibata-Yasuda) mice are derived from outbred JC1-ICR mice based on glucose tolerance selection and breeding, and have an age-dependent spontaneous diabetes animal model. After 24 weeks, glucose-stimulated insulin secretion was significantly impaired, and fasting insulin levels increased. The incidence of cumulative diabetes in male mice at 48 weeks was 98%, while that in female mice was only 37%. The mouse has no severe obesity at any age, no extreme hyperinsulinemia, and no pancreatic islet enlargement or inflammatory changes.

　　5. GK rat Goto et al. in Sendai, Japan selected 18 rats with mild impaired glucose tolerance through oral glucose tolerance test from 211 Wistar rats. After about 10 generations, the rats with hyperglycemia were repeatedly selected to mate with humans. A spontaneous non-obese type 2 diabetic mouse species similar to type 2 diabetes is called GK (Goto-Kakizaki rat) rat. This mouse species has several susceptibility genes that exhibit diabetic traits (different gene codes cause abnormal β-cell metabolism), mainly manifested as impaired secretion of pancreatic β-cells, fasting hyperglycemia, increased liver glycogen production, liver, muscle, and Adipose tissue has moderate insulin resistance, etc., and various complications of diabetes appear. At the age of 18 months, GK rats had symptoms such as increased blood sugar, decreased heart rate, and myocardial atrophy, which were very similar to the development of human type 2 diabetic heart disease, and had significant myocardial hypertrophy, interstitial fibrous hyperplasia and continuous cardiomyocytes. Apoptosis.

　　6. Obese Zucker rat (Zucker rat) Obese Zucker rat develops diabetes 4 to 5 weeks after birth. It is characterized by being accompanied by obesity, hyperglycemia, hyperinsulinemia, hyperlipidemia, and moderate hypertension.

　　【Features of the model】KK mice have properties similar to adult obese diabetes, showing congenital insulin resistance and body obesity. As the mice grow older and change their dietary behaviors, they transform into hyperglycemic and diabetic overt diabetes. Ob/ob mice and db/db mice have typical clinical symptoms of diabetes, such as extreme obesity, polyphagia, diabetic thirst, and polyuria, and are ideal animal models for type 2 diabetes. The pathophysiological characteristics of NSY mice are similar to human type 2 diabetes. Impaired insulin secretion and insulin resistance of pancreatic β-cells may be the mechanism of type 2 diabetes, which is similar to the pathogenesis of human type 2 diabetes. NSY mice are believed to help people study the genetic predisposition and pathogenesis of type 2 diabetes. The progressive disappearance of β-cells islet fibrosis is a characteristic of GK rat type 2 diabetes model. Obese Zucker rats can be used as an animal model of type 2 diabetes with hypertension

　　[Model Evaluation and Application] KK-Ay mice can be used to evaluate the extra-pancreatic effects of anti-diabetic drugs. Ob/ob mice and db/db mice not only have typical clinical manifestations of diabetes, but also show complications of diabetes such as cardiomyopathy, peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, and delayed wound healing. Also exhibited immune deficiencies, including lymphatic organ atrophy, decreased thymus volume, and decreased thymocyte number. The two mutant mice also have abnormalities in the respiratory system and bone metabolism. Therefore, ob/ob mice and db/db mice can be used for related research on diabetes and obesity, metabolism, wound healing, immunity and inflammation, endocrine, reproduction and so on. The NSY mouse model is helpful for the study of the genetic tendency and pathogenesis of human type 2 diabetes, and is especially suitable for studying the role of insulin resistance in the pathogenesis. The GK rat model is a good model for studying the pathogenesis of type 2 diabetes and insulin resistance. It is suitable for the study of the mechanism of gastric bypass surgery in the treatment of type 2 diabetes. Obese Zucker rats are often used as models for pharmaceutical research.