肠促胰岛素及其他肽类在糖尿病治疗中的应用
Incretins and other peptides in the treatment of diabetes.
作者信息
Todd J F, Bloom S R
机构信息
Department of Metabolic Medicine, Imperial College London, Hammersmith Hospital, London, UK.
出版信息
Diabet Med. 2007 Mar;24(3):223-32. doi: 10.1111/j.1464-5491.2006.02071.x.
Glucagon-like peptide-1 (7-36) amide (GLP-1) is a gut hormone, released postprandially,which stimulates insulin secretion and insulin gene expression as well as pancreatic B-cell growth. Together with glucose-dependent insulinotropic polypeptide (GIP), it is responsible for the incretin effect which is the augmentation of insulin secretion following oral administration of glucose. Patients with Type 2 diabetes have greatly impaired or absent incretin-mediated insulin secretion which is mainly as a result of decreased secretion of GLP-1. However,the insulinotropic action of GLP-1 is preserved in patients with Type 2 diabetes,and this has encouraged attempts to treat Type 2 diabetic patients with GLP-1.GLP-1 also possesses a number of potential advantages over existing agents for the treatment of Type 2 diabetes. In addition to stimulating insulin secretion and promoting pancreatic B-cell mass, GLP-1 suppresses glucagon secretion,delays gastric emptying and inhibits food intake. Continuous intravenous and subcutaneous administration significantly improves glycaemic control and causes reductions in both HbA1c and body weight. However, GLP-1 is metabolized extremely rapidly in the circulation by the enzyme dipeptidyl peptidase IV(DPP-IV). This is the probable explanation for the short-lived effect of single doses of native GLP-1, making it an unlikely glucose-lowering agent. The DPP-IV resistant analogue, exenatide, has Food and Drug Administration (FDA) approval for the treatment of Type 2 diabetes and selective DPP-IV inhibitors are underdevelopment. Both approaches have demonstrated remarkable efficacy in animal models and human clinical studies. Both are well tolerated and appear to have advantages over current therapies for Type 2 diabetes, particularly in terms of the effects on pancreatic B-cell restoration and potential weight loss.
胰高血糖素样肽-1(7-36)酰胺(GLP-1)是一种肠促胰素,在餐后释放,可刺激胰岛素分泌、胰岛素基因表达以及胰腺β细胞生长。它与葡萄糖依赖性促胰岛素多肽(GIP)共同作用,产生肠促胰素效应,即口服葡萄糖后胰岛素分泌增加。2型糖尿病患者的肠促胰素介导的胰岛素分泌严重受损或缺失,这主要是由于GLP-1分泌减少所致。然而,2型糖尿病患者中GLP-1的促胰岛素作用仍然存在,这促使人们尝试用GLP-1治疗2型糖尿病患者。与现有的2型糖尿病治疗药物相比,GLP-1还具有许多潜在优势。除了刺激胰岛素分泌和促进胰腺β细胞数量增加外,GLP-1还能抑制胰高血糖素分泌、延缓胃排空并抑制食物摄入。持续静脉输注和皮下注射可显著改善血糖控制,降低糖化血红蛋白(HbA1c)水平和体重。然而,GLP-1在循环中会被二肽基肽酶IV(DPP-IV)迅速代谢。这可能是单次给予天然GLP-1效果短暂的原因,使其不太可能成为一种有效的降糖药物。抗DPP-IV的类似物艾塞那肽已获得美国食品药品监督管理局(FDA)批准用于治疗2型糖尿病,选择性DPP-IV抑制剂也在研发中。这两种方法在动物模型和人体临床研究中均显示出显著疗效。它们耐受性良好,与目前的2型糖尿病治疗方法相比似乎具有优势,特别是在对胰腺β细胞恢复和潜在体重减轻的影响方面。