动物模型,糖尿病 z-bo 2020-07-31 1117

　　[Modeling mechanism] Spontaneous diabetic animals, also known as spontaneous hyperglycemic animals, are naturally occurring diabetic animals or diabetic models preserved through genetic breeding and culture, and their performance is the same as human diabetic animals. Very similar to clinical symptoms. Can be used for the etiology of diabetes. Etiological research can also be used for research and screening of anti-diabetic drugs.

　　(I) Spontaneous type 1 diabetes animal model

　　[Modeling method]

　　1. OD mice Non-obese diabetic mice (non-obese diabetic (NOD) mice) are CTS (cataract sensitive subtype) diabetic mice derived from the JCL-ICR strain. Polyuria, weight loss, and a significant increase in blood sugar levels, and without insulin treatment, animals cannot survive for a month and usually die of ketosis. OD mice are mediated by T cells (including CD4 and CD8 cells), and their development is controlled by a series of T cell regulators. Beta cell damage is secondary to the autoimmune process, leading to hypoinsulinemia. The incidence of diabetes in OD mice is related to gender. The incidence of female mice is significantly higher than that of male mice, and the incidence rate is faster.

　　2, BB rats, also known as BBDP (bio-breeding diabetes) rats, are naturally-occurring genetic type C diabetes animal models screened from Wistar rats. The etiology is related to the autoimmune destruction of pancreatic β cells, causing pancreatitis and insulin deficiency. The onset of diabetes in BB rats occurred suddenly at about 60-120 days. A few days later, severe hyperglycemia, hypoinsulinemia and ketemia appeared in diabetic animals.

　　3, LEW.1NR1/ztm-iddm rat is a spontaneous mutant of Lewis rat MHC haplotype, and it is an animal model of spontaneous autoimmune type 1 diabetes. The onset is about 58 days, the incidence is 20%, and gender does not affect the incidence. It is characterized by hyperglycemia, diabetes, alcohol and polyuria. Pancreatic islets infiltrate inflammatory cells (B lymphocytes, T lymphocytes, macrophages, NK cells). B cells rapidly undergo apoptosis at the site of pancreatitis.

　　[Model Features] NOD mice, BB diabetic rats, LEW.1NR1/ztm-iddm rats are suitable models for studying spontaneous type 1 autoimmune diabetes. [Model Evaluation and Application] OD mice and type 1 human diabetes have many common features. The development of the disease is controlled by the susceptibility or resistance genes of many diseases, including most loci with complex histocompatibility. Type diabetes research. The BB diabetic rat is also an ideal animal model for type 1 diabetes, because it can simulate the natural onset, development and consequences of type 1 diabetes without the intervention or interference of external factors.

　　(II) Type 2 Spontaneous Diabetes Animal Model 1. KK mice (kkmouse) are slightly obese type 2 diabetic animals raised by Japanese scholars. After mating with C57BL/6J mice, they selfed and obtained the gene-deficient mouse Toronto2 (T2kk). When the yellow obesity gene (namely Ay) was introduced into KK mice to obtain KK-Ay mice, they had obvious obesity and diabetes symptoms compared with KK mice. After 5 weeks, blood sugar levels, blood insulin levels and HbA1c levels gradually increased. Beta cells have degranulation and glycogen infiltration, followed by islet hypertrophy and central bubbles. Fatty liver and fatty tissue increase. The insulin sensitivity of adipose tissue is lower than that of KK mice and is completely lost at 16 weeks of age. Kidney disease develops earlier, develops rapidly, and thickens the glomerular basement membrane. Mouse pituitary, liver, adrenal gland and parathyroid gland also have corresponding proliferative changes.

　　2, Ob/ob mice (ob/obmouse) are obese, hyperglycemic mice discovered by the Jackson Laboratory of the United States in 1949. They are called ob mice due to their obesity phenotype. The method of inheritance is autosomal recessive genetic inheritance. He is very obese and spontaneously causes hyperglycemia and diabetes in the early stages. The average non-fasting blood glucose level is 300 mg/dl, but he does not have ketosis or coma.

　　3. The db/db mouse diabetic mouse (C57BL/KsJdb/dbmouse) is also a spontaneous mutant mouse discovered by the Jackson Laboratory in the C57BLKS/J (BKS) inbred line in 1966. The mouse is hyperglycemic and polyuria. The phenotype of high urine glucose levels is very similar to that of human diabetic patients. Hyperinsulinemia occurs within 10 to 14 days, obesity is obvious within 3 to 4 weeks, and can reach 2-3 times that of wild mice within 10 weeks, but the length is 5% shorter than wild type, hypercholesterolemia And hypercholesterolemia. Triglyceridemia. Hyperglycemia occurs between 4 to 8 weeks. The typical clinical manifestation is diabetes, accompanied by polyphagia, diabetic thirst and polyuria.

　　4. SY mouse NSY (Nagoya-Shibata-Yasuda) mice are derived from heterotypic JC1-ICR mice based on glucose tolerance selection and reproduction, and have an age-dependent spontaneous diabetes model. After 24 weeks, glucose-stimulated insulin secretion was severely impaired, and fasting insulin levels increased. At the 48th week, the incidence of cumulative diabetes was 98% in male mice and 37% in female mice. Mice at any age have no severe obesity, extreme hyperinsulinemia, pancreatic islet hypertrophy or inflammatory changes.

　　5. Goto et al. (GK rats in Sendai, Japan) selected 18 rats with mild glucose tolerance from 211 Wistar rats through oral glucose tolerance test. After about 10 generations, hyperglycemic rats Repeatedly reproduce with people. A naturally occurring non-obese type 2 diabetic mouse strain similar to the type of diabetes is called GK (Goto-Kakizakirat) rat. This mouse strain has several susceptibility genes, the main features of which are impaired secretion of pancreatic β-cells, fasting hyperglycemia, increased liver glycogen production, liver, muscle, and diabetes (different gene codes are unusual). Lead to beta cell metabolism). Adipose tissue has moderate insulin resistance, and various complications of diabetes occur. At 18 months of age, the symptoms of GK rats include increased blood sugar, decreased heart rate, and myocardial atrophy, very similar to the progression of human type 2 diabetes with cardiac atrophy and severe myocardial hypertrophy. , Interstitial fibrosis, persistent cardiomyocytes. Apoptosis.

　　6. Obese Zuckerrat Obese Zucker rat develops diabetes within 4 to 5 weeks after birth. It is characterized by obesity, hyperglycemia, hyperinsulinemia, hyperlipidemia and moderate hypertension. [Characteristics of the model] KK mice have characteristics similar to adult obesity and diabetes, and exhibit congenital insulin resistance and obesity. As the rats get older and their eating habits change, they will develop hyperglycemia and obvious diabetic diabetes. Ob/ob and db/db mice have typical clinical manifestations of diabetes, such as extreme obesity, polyphagia, diabetic thirst and polyuria. These are ideal animal models for type 2 diabetes. The pathophysiological characteristics of SY mice are similar to human type 2 diabetes. Impaired insulin secretion and insulin resistance of pancreatic β-cells are the pathogenesis of type 2 diabetes, similar to the etiology of human type 2 diabetes. I will. SY mice are thought to be useful for studying the genetic susceptibility and pathogenesis of type 2 diabetes. The progressive loss of β-cell islet fibrosis is a characteristic of GK rat type 2 diabetes model. Obese Zucker rats can be used as a type 2 diabetic hypertension animal model [Model evaluation and application] KK-Ay rats can be used to evaluate the extrapancreatic effects of antidiabetic drugs. Ob/ob and db/db mice not only showed typical clinical manifestations of diabetes, but also showed diabetic complications, such as cardiomyopathy, peripheral neuropathy, diabetic nephropathy, diabetic retinopathy and delayed wound healing. He also showed immunodeficiency, including lymphatic organ atrophy, decreased thymus volume and decreased thymocyte count. The two mutant mice also had abnormal breathing and bone metabolism. Therefore, ob/ob and db/db mice can be used in related research, such as diabetes and obesity, metabolism, wound healing, immunity and inflammation, endocrine, reproduction. The SY mouse model can be used to study the genetic susceptibility and pathogenesis of human type 2 diabetes, and is particularly suitable for studying the role of insulin resistance in the pathogenesis. The GK rat model is an excellent model for studying the etiology and insulin resistance of type 2 diabetes. It is suitable for studying the mechanism of gastric bypass surgery in the treatment of type 2 diabetes. Obese Zucker rats are often used as models for drug research.