| The incidence and prevalence of diabetes mellitus (especially type 2 diabetes) is increasing, but the situation of control of diabetes and its complications is not optimistic, therefore, the study about how to prevention and treatment of diabetes and its complications is still very urgent. Vascular disease is the basic lesions of a variety of complications of diabetes, endothelial cell injury is the basis of diabetic vascular disease, from the functional and morphological changes of vascular endothelial cells to explore the prevention and treatment of diabetes and its complications, and should have important medical value and social significance.The gastrointestinal tract plays an important role in maintaining glucose homeostasis, the movement of the stomach (gastric emptying/gastric motility) control carbohydrate intake, The intestine is the first place of the absorption of glucose utilization, gastrointestinal mucosa also secrete a variety of hormones to regulate glucose, together with insulin and glucagon and other factors to regulate blood glucose homeostasis. There is a close link between blood glucose balance and gastric motility/gastric emptying, it is common that diabetic patients have gastric motility disorders. The exact mechanism of diabetic gastric motility disorders is inconclusive, need to continue to exploration.Researchers have developed a number of important treatment by adjusting the gastrointestinal tract to achieve improved glycemic control of diabetic patients. Glucagon-like peptide-1 (GLP-1) due to have the capacity of enhancing glucose-stimulated insulin secretion, slowing gastric emptying and inhibition of glucagon secretion, it became an important target for the treatment of diabetes. GLP-1 receptor agonists reduce blood glucose through activate GLP-1 receptors, it have similar pharmacological properties, more resistant to degradation and longer half-life compared with native GLP-1, being gradually used in clinical. Exendin-4 is the first mammalian GLP-1 receptor strong agonists. It is still controversial that whether GLP-1 and its receptor agonists regulate blood glucose through prolong gastric emptying. Few studies investigate the effects of GLP-1 and its receptor agonists on diabetic gastric motility from the perspective of the gastric vascular structure and function. The discrepancy between GLP-1 receptor agonists and other hypoglycemic agents in the treatment of type 2 diabetes (T2DM) have not fully understood.We explored the role and mechanism of GLP-1 receptor agonists in the prevention and treatment of type 2 diabetes and its gastric motility disorders, based on the close relationship of gastrointestinal tract and blood glucose balance. Including two part, one part was the evidence-based evaluation of GLP-1 receptor agonist treatment for diabetes, another was the relationship between early period gastric motility disorders and gastric vasculopathy in type 2 diabetic rats and the effects of Exendin-4 on them.Objective(1) To study the efficacy and safety of GLP-1 receptor agonists versus long-acting insulin analogues in type 2 diabetic patients who have not achieved treatment goals with oral hypoglycemic agents.(2) To investigate the effects of Exendin-4 on early period gastric motility disorder in type 2 diabetic rats, and the relationship with gastric vasculopathy.Methods(1) Using the methods of evidence-based medicine, comprehensive collection of randomized controlled trials (RCTs) which were≥3 months in duration, compared GLP-1 receptor agonists with long-acting insulin analogues in patients with T2DM. The Cochrane Handbook was used to evaluate the methodological quality, extract valid data and Meta analysis. The endpoint outcomes were mortality, diabetes-related adverse events and health-related quality of life. The intermediate outcomes included glycemic control, plasma lipids levels, weight, blood pressure, adverse effects, costs and so on. (2) Adopt high carbohydrate-fat diet combined small dose streptozotocin injection induced type 2 diabetic rat model, make use of some experimental techniques such as radionuclide gastric emptying, immunohistochemistry and enzyme-linked immunosorbent/RIA; observe the changes of the glucose and lipids metabolism (fasting glucose-FBG, glycated serum protein-GSP, triglycerides-TG, total cholesterol-TC, free fatty acids-FFA and insulin-INS were key indicators), gastric emptying (gastric half-emptying time and gastric emptying rate), gastric microvascular structure, gastric vascular endothelial function (endothelial nitric oxide synthase-NOS3, nitric oxide-NO, and soluble endothelial protein C receptor-sEPCR were representative indicators), gastric tissue oxidative stress (malondialdehyde-MDA and superoxide dismutase-SOD as the representative index), GLP-1, gastric leptin and gastrin in early period type 2 diabetic rats. And the effect of Exendin-4 on these changes.Results(1) Five multicenter RCTs that met the inclusion criteria were identified. They were all open-label designs with long-acting insulin analogues arm, predefined outcomes were reported, and ITT analysis was performed. One trial was unclear on the randomization procedure and allocation concealment. Not sure if a publication bias exists. No data was found with regard to mortality or diabetes-associated complications, and few data were found on quality of life. The results of the meta-analysis suggest that long-acting insulin analogues was significantly better in reducing the fasting blood glucose (P< 0.001], but exhibits greater incidence of nocturnal hypoglycemia (P= 0.002) and influenza (P= 0.04). GLP-1 receptor agonists are more conducive to reduce body weight (P< 0.001), postprandial blood glucose (P< 0.001) as well as LDL-C (P< 0.001), but have more gastrointestinal side-effects (P< 0.001). There was no significant difference between GLP-1 receptor agonists and long-acting insulin analogues in reducing HbA1c level and the overall incidence of hypoglycemia.(2) The early period type 2 diabetic rats have higher blood glucose and lipids, gastric motility abnormalities (gastric half-emptying time was shortened, gastric emptying rate was accelerated), destruction of the gastric microvascular structure (both ultrastructural and microvessel density), gastric vascular endothelial cell dysfunction (the expression of NOS3 and the level of NO in stomach were decreased, the serum concentration of sEPCR was increased); more gastric tissue lipid oxidation end-product malondialdehyde (MDA), less antioxidant superoxide dismutase (SOD); lower the serum level of GLP-1, the concentration and expression of Leptin and Gastrin in stomach; when compared with normal rats.The type 2 diabetic rats which were early treated by Exendin-4, FBG、GSP and FFA were decreased, the serum level of insulin was increased; the gastric emptying rate was delayed, gastric half-emptying time became longer; the concentration of MDA in gastric tissue was decreased, SOD was increased; the expression of NOS3 and the level of NO in stomach was increased; the serum content of sEPCR was decreased; the injury of gastric microvascular ultrastructure was improved, gastric microvessel density was increased; the expression and concentration of Leptin and Gastrin were enhanced, and the serum level of GLP-1 was increased, when compared with non-treatment type 2 diabetic control rats.Treated and untreated normal rats have no changes on gastric motility, gastric vascular endothelial function and ultrastructure, gastric tissue oxidative stress, the levels of GLP-1, Gastrin and Leptin. Multiple stepwise regression analysis showed that the level of NO in gastric tissue was the most relevant factor to the gastric half-emptying time.Conclusions(1) Compared with long-acting insulin analogues, GLP-1 receptor agonists did not have a significant difference in regard to reducing HbA1c levels and they were significantly associated with decreased body weight but increased gastrointestinal adverse events. It remains unclear whether GLP-1 receptor agonists influence mortality or diabetes-associated complications in patients with T2DM. More trials with longer follow up are needed to better answer the exact long-term efficacy and safety of this new class of hypoglycemic drugs.(2) Gastric vascular endothelial cell injury may be the initiating factor for the gastric motility disorder in the early stage type 2 diabetic rats. Exendin-4 can improve blood glucose and lipid and gastric motility disorders, gastric microvascular endothelial injury, gastric tissue oxidative stress, and the concentration of GLP-1, gastric Leptin and Gastrin. Exendin-4 regulate gastric emptying function may be through gastric vascular endothelial function. |
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