| Objective:Diabetes Mellitus(DM)is the most important metabolic disease and is widely recognized as one of the leading causes of death.Around 150 million people around the world have diabetes,which is almost five times higher than estimated 10 years ago,and by 2030 this number could double.It can affect almost every organ system in the body.The World Health Organization(WHO)has declared diabetes to be epidemic and predicts that most of the growth will be contributed by Southeast Asia and the Western Pacific.The pathogenesis of Type 2 DM(Type 2 DM,T2DM)is related to insulin resistance and insulin secretion defect.At present,it is generally believed that on the basis of insulin resistance,insulin secretion defect due to genetic and environmental factors is the main cause of the pathogenesis of T2DM.Insulin deficiency following pancreatic B-cell loss is a common feature of both type 1 and type 2 diabetes.Current treatments are usually the administration of exogenous insulin or oral hypoglycemic agents,but these methods are not completely satisfactory for most patients.Establishing an ideal animal model is of great significance for further study of T2DM.The construction of T2DM animal models in large animals has always been a research difficulty.In the past,insulin resistance was mainly induced by high-fat diet,and then the islet B cells were destroyed by intravenous low-dose injection of STZ,followed by high-fat diet feeding again.This method takes a long time to build the model,the animal diet is not well controlled,and it is easy to fail.This study intends to inject STZ directly into the pancreas of pigs through fine needle injection under the guidance of endoscopic ultrasound,which can successfully build a T2DM model in a short time and optimize the animal modeling process.2020 ADA diabetes diagnosis and treatment standards also include bariatric surgery into the treatment standard,confirming that by changing the flow of food and affecting the patient’s endocrine mechanism,the purpose of treating type 2 diabetes can be finally achieved.At present,there are three main methods of surgical weight loss:the first is gastric bypass surgery,the principle is to change the structure of the gastrointestinal tract,close most of the gastric function,reduce the space of the stomach and the length of the small intestine;the second is Sleeve gastrectomy,by reducing stomach volume,reduces the secretion of hormones that stimulate hunger;the third is gastric banding,which reduces stomach volume through gastric banding,which can control food intake.Their common features are:changing the way food passes through the digestive tract,slowing gastric emptying,shortening the small intestine,and reducing absorption.But there are some problems:First,the changes of the gastrointestinal tract,the large gastric pouch can no longer be checked by gastroscopy,and only CT examinations or laparoscopic exploration can be performed.For patients with a family history of gastric cancer or repeated gastric ulcers Patients need careful consideration.Second,the operation is relatively complicated,and requires high technical level of the doctor,and the skill of laparoscopy is high,so not all doctors are suitable for this operation.Third:Because of the irreversibility of this operation,some patients lose weight too quickly and too lightly,which leads to malnutrition,and some patients cannot regain normal weight,resulting in2 injuries.Fourth:Serious complications such as severe electrolyte imbalance and even liver failure occur after surgery,as well as poor compliance,regaining weight,and post-operative eating of a large amount of high-calorie diet,resulting in unsatisfactory weight loss,resulting in unsatisfactory hypoglycemic effect.Therefore,it is necessary to find a balance between reducing body weight and reducing blood sugar;at the same time,it is necessary to develop new minimally invasive treatment measures to avoid the occurrence of the above-mentioned adverse events such as malnutrition and achieve the purpose of treating diabetes.In this study,after the establishment of the T2DM model,the experimental animals were subjected to endoscopic ultrasound-guided gastroenterostomy.The duodenum and proximal jejunum were left open to change the flow of food,so as to reduce body weight and improve blood sugar.And to explore the mechanism of endoscopic ultrasound-guided gastroenterostomy on blood sugar regulation.Methods:In this study,18 Bama miniature pigs were randomly divided into basal diet,high-fat group and high-fat plus pancreatic injection of streptozotocin group after 1 week of adaptive feeding,with 6 pigs in each group.Six Bamaha minipigs in the high-fat plus pancreas-injected streptozotocin group underwent endoscopic ultrasound-guided fine-needle injection after 1 month of high-fat feeding.Then the contents of triglyceride,total cholesterol,fasting blood glucose,fasting insulin and glycosylated hemoglobin in serum were detected monthly.Do an intravenous glucose tolerance test once a month to detect changes in blood glucose at 0 min,30 min,60 min and 120 min.Modeling success was judged with FBG>7.0 mmol/l.Calculate the insulin resistance index,greater than2.69 can judge insulin resistance.After successful modeling,the animal model was subjected to endoscopic ultrasound-guided gastroenterostomy and pyloric closure,and then continued high-fat feeding.Serum triglyceride,total cholesterol,fasting blood glucose,fasting insulin and glucagon were detected monthly.element content.Do an intravenous glucose tolerance test once a month to detect changes in blood glucose at 0min,30 min,60 min and 120 min.The changes of blood glucose and insulin in the model pigs after operation were observed.Liver and pancreas samples were collected,and the changes of liver and pancreas were observed by HE staining.Serum samples were collected to verify the hypoglycemic mechanism through gastrointestinal hormones,bile acid metabolism,and inflammatory response.Results:1.All endoscopic ultrasound-guided fine-needle injections were successfully completed.With the progress of the experiment,the body weight of miniature pigs in each group showed an upward trend,and the high-fat group increased rapidly.One month after the injection of STZ,the body weight growth of minipigs slowed down,and triglyceride and cholesterol decreased sharply,and then as the experiment progressed,body weight,triglyceride and cholesterol all showed an upward trend.One month after injection,the fasting blood glucose of minipigs was 10.14±1.23mmol/l,and the fasting insulin was 6.94±2.12 m IU/L.Continuous observation to 5 months after injection,the fasting blood glucose was 12.13±3.00mmol/l,and the fasting insulin was 15.15±4.11m IU/l.L,the glycated hemoglobin showed an increasing trend,the insulin resistance index was 8.17±0.48,and the modeling was successful.2.All endoscopic ultrasound-guided gastroenterostomy and pyloric closure were successfully completed.The weight of the miniature pigs in the operation group decreased significantly after the operation,which was lower than that in the normal feeding group and the high-fat group at the end of the experiment.Triglycerides and cholesterol showed a downward trend.Preoperative fasting blood glucose was11.51±3.41mmol/l,fasting insulin was 17.40±6.26m IU/L,3 months after operation,fasting blood glucose was 7.80±1.62mmol/l,fasting insulin was 8.19±1.62m IU/L,and preoperative insulin resistance index was 9.07±6.53,3 months postoperative insulin resistance index was 2.94±1.13,preoperative fasting glucagon was 15.57±3.11 pg/m L,3 months postoperative fasting glucagon was 11.44±1.70 pg/m L,showing a downward trend.3.At 3 months after operation,HE staining showed that the steatosis of liver cells was reduced,the pancreatic acinus was dense,and the pancreatic fat vacuoles were reduced.One month after operation,the GIP value of the operation group decreased significantly,and with the progress of the experiment,it showed a significant downward trend;the GLP-1 value increased significantly,and gradually increased with the progress of the experiment;the total bile acid value was significantly The reactivity of TNF-α,IL-1α,IL-1βand IL-6 increased at 1 month after operation,and then decreased with the progress of the experiment,and was lower than the preoperative level at the end of the experiment.Conclusions:1.Innovatively proposed individualized pancreatic injection modeling,and obtained the formula of pancreatic injection dosage(mg/kg)=fasting blood glucose x[10+(10-fasting blood glucose)~2-fasting blood glucose],and the unit of fasting blood glucose is mmol/l.2.The study successfully constructed a T2DM model through high-fat feeding combined with endoscopic ultrasound-guided direct injection of STZ into the pancreas,which greatly shortened the modeling time.Moreover,the model is stable,and the experimental results are consistent with expectations,indicating that we have successfully established an ideal T2DM minipig model.3.Endoscopic ultrasound-guided gastroenterostomy was successfully performed on a pig T2DM animal model,and the duodenum and proximal jejunum were removed,confirming that endoscopic ultrasound-guided gastroenterostomy can reduce body weight and improve glucose metabolism in T2DM pigs(Fasting blood glucose,random blood glucose and glucose tolerance),effectively relieve insulin resistance and improve insulin sensitivity.4.After surgery,the steatosis of liver cells was reduced,the pancreatic acinar was dense,and the pancreatic fat vacuoles were reduced.5.Endoscopic ultrasound-guided gastroenterostomy can down-regulate GIP and increase GLP-1 in T2DM model pigs,thereby improving blood sugar.6.Endoscopic ultrasound-guided gastroenterostomy can increase the concentration of bile acid in pigs with T2DM,and then induce the increase of GLP-1 secretion and improve blood sugar.7.Endoscopic ultrasound-guided gastroenterostomy can reduce inflammatory factors and play an important role in lowering blood sugar. |
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