糖尿病 z-bo 2020-12-02 680

　　Introduction: WTO reports that diabetes is one of the most common public health problems. It will affect 220 million people worldwide in 2020. The increase in the global prevalence of diabetes is an important social issue because diabetes is A complex multifactorial origin disease.

　　 With population growth, aging, urbanization, and increasing obesity and physical inactivity, the prevalence of diabetes is increasing worldwide. Unlike the West, the elderly are the most affected, and the proportion of diabetes in young to middle-aged adults in Asian countries has increased disproportionately. This may have long-term adverse effects on a country’s health and economy, especially in developing countries.

　　 Experimental model: Experimental diabetes is usually induced in laboratory animals through several methods, including: chemical, surgical and genetic (immune) manipulation. Most diabetes experiments are conducted in rodents, although some studies are still conducted on larger animals.

　　 Animal models for screening anti-diabetic drugs can be roughly divided into the following three types:

　　A Method of inducing experimental diabetes

　　B gene diabetic animal

　　C hybrid model

　　The methods of inducing experimental diabetes can be further divided into the following categories:

　　A Dog pancreatectomy

　　B Alloxan Diabetes

　　C Diabetes induced by streptozotocin

　　D Hormone-induced diabetes

　　E virus-induced diabetes

　　F Other diabetes compounds

　　G Insulin deficiency caused by insulin antibodies

　　 Genetic diabetic animals can be further divided into the following categories:

　　A Spontaneously diabetic rats

　　B Spontaneous diabetic mice

　　C Chinese Hamster

　　D Other species with hereditary diabetes symptoms

　　E genetically modified animals

　　Miscellaneous model

　　A Animal model of invertebrates

　　B Metabolic disorders caused by diet

　　 Dog pancreatectomy: Polyuria, polydipsia, polyphagia, and severe diabetes occur after pancreatectomy in dogs. Through the injection of pancreatic gland extract, the high blood sugar level of the dogs whose pancreas was removed, further proved the existence of hormones in the pancreas.

　　Method Male Beagle dogs weighing 12-16 kg were anesthetized by intravenous injection of 50 mg/kg sodium pentobarbital. Make a moderate incision along the midline from the xiphoid process to the umbilicus. Enter the abdomen through the white thread to ligate the bleeding vessel. Carefully clean the sickle ligament and ligate blood vessels. Through the pylorus along the stomach with the right hand, reach the pancreas and duodenum to start the operation. First, the lepto-end mesenteric cut process itself is free, and the pancreatic tissue is stripped from the inferior pancreaticoduodenal artery and vein. Carefully remove the blood vessels along the broken line between the pancreas, the pancreaticoduodenal vessels and the intestinal wall. The pancreas is the pancreaticoduodenal vessels separated from the duodenum and preserved intact. Ligation of small blood vessels in the pancreas. The dissection is performed from both sides of the duodenum. In the area of the accessory pancreatic duct, the connected glandular tissue is very firm, so take it out carefully so as not to leave residual pancreatic tissue. The pancreatic duct is clean, double ligated and cut off at the junction. Peel off gradually until you encounter a lobule containing the main pancreatic duct. The glandular tissue firmly adheres to the duodenum. Blunt separation of the pancreatic duct and blood vessel ligation are performed by pancreatic duct ligation. The duodenum is partially returned to the abdominal cavity. Cut the pancreatic body and tail mesentery. Double ligation and cutting of small blood vessels. The pancreatic tissue is bluntly separated from the splenic blood vessel, and the pancreatic branch of the splenic blood vessel is double-ligated and cut. The pylorus of the pancreas is the last to be dissected. Finally, all the pancreatic tissue is removed. Examine the pancreatic remnant again in the surgical area. The intraperitoneal injection of 5 ml of 1% procaine solution is to prevent intussusception of the intestine. 250,000 units of penicillin saline solution was dripped into the abdominal cavity. First suture the abdominal wall and subcutaneous suture, and finally suture the skin continuously eversion. After the operation, the animal will undergo the following treatments through the jugular vein catheter for 3-4 days: After the operation, the animal will receive the following treatment through the jugular vein catheter for 3-4 days: 1000 glucose solution 10% ml 10 IU human insulin, 3 ml 24% trimethoprim Aminopyrimidine solution, 2 ml of 50% Analgin 400 IU secretin. On the third day, milk was provided for the animals. After the animals pass the first dairy product, they cook dry food containing trypsin once a day. A single daily dose of 34 IU insulin is injected subcutaneously. Vitamin D3 is given as an intramuscular injection of 1 ml every three months.

　　 Alloxan Diabetes: The increase in blood sugar and diabetes caused by alloxan management has been described in many species, such as dogs, rabbits, rats and other species. Guinea pigs have found resistance to alloxan. The most commonly used species have described dosages and treatment regimens. Three stages are observed in most species: an initial rise in glucose followed by a decline, possibly due to islet insulin depletion, followed by a continuous rise in blood sugar. Alloxan generally produces greater toxicity due to the conversion of its anion group.

　　 Method: Inject 150 mg/kg alloxan (5 g/100 ml, pH 4.5) into the ear vein for 10 minutes into rabbits weighing 2 to 3.5 kg. This result causes hyperglycemia and uric aciduria in 70% of animals. The remaining animals die or have only temporary hyperglycemia. Wistar or SD rats weighing 150-200 grams are injected subcutaneously with 100-175 mg/kg alloxan. Male Beagle dogs weighing 15-20 kg are injected intravenously with 60 mg/kg alloxan. Subsequently, the animals received 1,000 ml of a 5% glucose solution containing 10 IU of insulin every day for a week, and the canned food was ad libitum. Thereafter, a single daily dose of 28 IU insulin was injected subcutaneously. The method was improved: rats were injected with 200 mg/kg alloxan on days 2, 4 and 6.

　　 Streptozotocin-induced diabetes: Rakieten et al reported the diabetes-induced activity of antibiotic bacteriocin. STZ toxicity is especially β-pancreatic islet cells. Most experimental animals use rats to induce diabetes, and STZ has become a valuable tool used by diabetes researchers. PARP knockout mice are resistant to STZ-induced diabetes.

　　 Method: Use male Wistar rats weighing 150-220 grams. STZ (60 mg/kg) is injected intravenously. The serum insulin value drops to 4 times, six to eight hours after injection, leading to the hypoglycemic phase after persistent hyperglycemia. The severity and onset of diabetes symptoms depends on the STZ dose. After a dose of 60 mg/kg for 24-48 hours, symptoms of 800 mg% hyperglycemia, diabetes and ketonuria appeared. Histological observation of β cells. After 10-14 days, the stable state is allowed to use animals for pharmacological tests.

　　 Hormone-induced diabetes: growth hormone-induced diabetes The effect of pure pituitary growth hormone in cats on diabetes has been reported. Adult dogs and cats with repeated injections of growth hormone induced all symptoms of diabetes including severe ketonuria and ketemia, while rats did not show any signs of diabetes after similar treatment, but the growth accelerated.

　　 Glucocorticoid-induced diabetes Cortisone can cause hyperglycemia and diabetes in rats. In guinea pigs and rabbits with experimental diabetes, glucocorticoids can be obtained without forced feeding. Stimulating the adrenocorticotropic hormone to produce adrenocorticotropic hormone in rats has the ability to secrete steroids to induce steroid diabetes.

　　 Virus-induced diabetes Virus infection and β-cell-specific autoimmune diseases may induce juvenile diabetes (type I) diabetes. Encephalomyocarditis virus D subtype infection and the destruction of pancreatic β cells (emc-d) can induce diabetes. The susceptible strain that causes insulin-dependent diabetes in mice is similar to that of humans. If animals are pretreated with cyclosporine, an effective immunosuppressive drug, it increases the severity and incidence of diabetes.

　　 Insulin deficiency caused by insulin antibodies: Guinea pig anti-insulin serum can induce a transient diabetic syndrome. Guinea pig anti-insulin serum induces unique effects. This is due to the neutralizing effect of insulin antibodies of endogenous insulin secreted by the injected animals. This leads to a state of insulin deficiency. , With larger doses can induce ketemia and acidosis, ketonuria, and diabetes. After a few hours, the diabetic syndrome is reversible with a lower dose.

　　Method: Male guinea pig weighing 300~400 g. 1 mg of bovine insulin was injected subcutaneously in divided doses. Inject monthly. 10 ml of blood was taken out from each animal by heart puncture every month. 0.25-1.0 ml guinea pig anti-insulin serum was injected intravenously in rats. Anti-insulin serum induced a dose-dependent increase in blood glucose concentration, up to 300 mg.

　　 hereditary diabetic animals: it is described that rodents exhibit spontaneous diabetes on a genetic basis. Due to the discovery of leptin and its downstream signal transduction cascade, new insights into the genetics of diabetes and obesity animal disease models have been obtained. Many genetic diabetic animal models show defects in the leptin pathway, and various mutations cause leptin deficiency.

　　 Spontaneous diabetic rats: Spontaneous diabetes in these rats has been reported:

　　Biological breeding rat (BB): BB rat is a spontaneous diabetes model. It is due to insulin deficiency and autoimmune destruction of pancreatic beta cells. The onset of clinical diabetes generally occurs between 60-120 days of age. After a few days of hypoinsulinemia, severe hyperglycemia ketosis exists. The immunosuppressant mycophenolate mofetil can prevent the development of diabetes in BB rats. Kloting and Vogt reported a diabetic tendency of a BB rat.

　　WBN/KOB rat: Wistar strain animal, named WBN/KOB. Shows impaired glucose tolerance and diabetes at 21 weeks of age. A decrease in the number and size of islets was observed after 12 weeks of age. Yagihashi observed fibrinous exudation and degeneration of pancreatic tissue in the exocrine area. The degeneration of male rats at 16 weeks of age mainly occurs around the pancreatic islets and pancreatic ducts. These mice suffer from demyelination, mainly motor neuropathy.

　　 Cohen diabetic rats: Cohen diabetic rats are characterized by hyperglycemia, diabetes and hyperinsulinemia rats. For hypoinsulinemia, insulin resistance develops later. The number and sensitivity of insulin receptors in Cohen rats decreased. When fed a diet rich in sucrose or other refined sugars, but not a starch or solid diet, rats developed diabetes-related complications.

　　 GK (GK) rats: GK rats are non-obese and insulin resistant. GK rats are highly genetic Wistar rats that spontaneously develop type II diabetes. 2 to 4 weeks after birth, glucose-stimulated insulin secretion defects, peripheral insulin resistance and hyperinsulinemia, accompanied by damaged skeletal muscle glycogen synthase activation. Accompanied by chronic activation of diglyceride-sensitive protein kinase C.

　　 Zucker obese rats: the classic model Zucker obese hyperinsulinemic rats. Obesity appears due to a simple early autosomal recessive inheritance (FA). Obese rats showed peripheral insulin resistance similar to human diabetes. However, their blood sugar levels are usually normal throughout their lives.

　　 Zucker diabetic obese rats (ZDF/DRT-FA): Peterson originally obtained Zucker diabetic obese rats from Zucker obese rats. This strain suffers from hyperglycemia of approximately 20 mmol/L. Males and females become diabetic at 6-8 weeks and 9-11 weeks, respectively. Lee described lipotoxic beta cells as the cause of diabetes. Due to high blood sugar, diabetes and obesity, calorie loss leads to extreme bulimia. High blood sugar is characteristic of these animals.

　　 WDF/TA-FA rats: Wistar obese rats are genetically obese and hyperglycemia. Velasquez et al. transferred the Zucker rat obesity gene to Wistar Kyoto. OLETF rat: The characteristics of OLETF rat are: (1) late onset of hyperglycemia (18 weeks of age), (2) chronic disease course, (3) mild obesity, (4) male inheritance, (5) islet hyperplasia, ( 6) Renal complications (nodular lesions).

　　ESS rat: The animal showed abnormal glucose tolerance test from 2 months. The syndrome is a mild type of diabetes that does not reduce the life span of animals.

　　 Spontaneously diabetic mice:

　　KK mice: The urine glucose and blood glucose levels of mice seven months or older are 320 mg%. The insulin content of the pancreas increased, but the histological observation of β-cells and islet hypertrophy revealed that the liver section showed a decrease in glycogen and an increase in lipid content.

　　KK-AY mice: The blood glucose, insulin levels and glycosylated hemoglobin levels of mice gradually increased from 5 weeks of age. β-cell degranulation and glycogen infiltration. Increased fat production in the liver and adipose tissue.

　　NOD mice: NOD mice are insulin-dependent diabetes models and develop autoimmune destruction of pancreatic β-cells and secondary hypoinsulinemia. Mice between 100 and 200 days old suffer from diabetes. Without insulin treatment, NOD mice survived more than one month. They usually die of ketosis. Baeder et al. reported that the use of an immunomodulatory drug or soluble interleukin-1 receptor can prevent the occurrence of diabetes. Verdaguer et al. observed that insulin-dependent diabetes in NOD mice is the result of CD4 + and CD8 + T cell-dependent autoimmune processes against pancreatic β-cells.

　　 Obese hyperglycemic mice: Bleisch et al. observed genetically obese mice with genetic diabetes. These mice had diabetes, the non-fasting blood glucose level was 300 mg%, but no ketonuria and coma were observed. One of the most interesting functions is insulin resistance. Increased insulin content. No pathological changes in the kidneys and other organs.

　　 Hamster: The blood sugar level of diabetic hamsters is elevated, normally 110 mg%, up to 600 mg%. The symptoms of diabetes in hamsters are severe polyuria, urine sugar, urine ketones, and urine protein. Insulin injections and oral hypoglycemic drugs can improve the symptoms of diabetes. Histopathological changes of pancreas, liver and kidney. The number of islets is reduced and the islet cells are abnormal.

　　 Conclusion: However, every newly synthesized drug enters the market and must pass experimental animal research before being used by humans. The characteristics of diseases and pathological changes in small animals (rats or mice) are similar to those of humans. Therefore, before conducting clinical research, human life is more precious than animals. Therefore, pre-clinical research always does this. Using smaller animal models, such as mice, will also reduce the experimental cost of test compounds. Carry out a detailed investigation of these diabetic animal species to better understand similar conditions in humans, and discover new targets and drugs for the treatment of type 2 diabetes.