Smits M M, Tonneijck L, Muskiet M H A, Kramer M H H, Cahen D L, van Raalte D H
Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands.
Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.
Diabetes Obes Metab. 2016 Mar;18(3):224-35. doi: 10.1111/dom.12593. Epub 2016 Jan 5.
The gastrointestinal hormone glucagon-like peptide-1 (GLP-1) lowers postprandial glucose concentrations by regulating pancreatic islet-cell function, with stimulation of glucose-dependent insulin and suppression of glucagon secretion. In addition to endocrine pancreatic effects, mounting evidence suggests that several gastrointestinal actions of GLP-1 are at least as important for glucose-lowering. GLP-1 reduces gastric emptying rate and small bowel motility, thereby delaying glucose absorption and decreasing postprandial glucose excursions. Furthermore, it has been suggested that GLP-1 directly stimulates hepatic glucose uptake, and suppresses hepatic glucose production, thereby adding to reduction of fasting and postprandial glucose levels. GLP-1 receptor agonists, which mimic the effects of GLP-1, have been developed for the treatment of type 2 diabetes. Based on their pharmacokinetic profile, GLP-1 receptor agonists can be broadly categorized as short- or long-acting, with each having unique islet-cell and gastrointestinal effects that lower glucose levels. Short-acting agonists predominantly lower postprandial glucose excursions, by inhibiting gastric emptying and intestinal glucose uptake, with little effect on insulin secretion. By contrast, long-acting agonists mainly reduce fasting glucose levels, predominantly by increased insulin and reduced glucagon secretion, with potential additional direct inhibitory effects on hepatic glucose production. Understanding these pharmacokinetic and pharmacodynamic differences may allow personalized antihyperglycaemic therapy in type 2 diabetes. In addition, it may provide the rationale to explore treatment in patients with no or little residual β-cell function.
胃肠激素胰高血糖素样肽-1（GLP-1）通过调节胰岛细胞功能降低餐后血糖浓度，刺激葡萄糖依赖性胰岛素分泌并抑制胰高血糖素分泌。除了对胰腺的内分泌作用外，越来越多的证据表明，GLP-1的几种胃肠作用对降低血糖至少同样重要。GLP-1降低胃排空率和小肠蠕动，从而延迟葡萄糖吸收并减少餐后血糖波动。此外，有人提出GLP-1直接刺激肝脏摄取葡萄糖，并抑制肝脏葡萄糖生成，从而进一步降低空腹和餐后血糖水平。已开发出模拟GLP-1作用的GLP-1受体激动剂用于治疗2型糖尿病。根据其药代动力学特征，GLP-1受体激动剂可大致分为短效或长效，每种都具有降低血糖水平的独特胰岛细胞和胃肠作用。短效激动剂主要通过抑制胃排空和肠道葡萄糖摄取来降低餐后血糖波动，对胰岛素分泌影响很小。相比之下，长效激动剂主要通过增加胰岛素分泌和减少胰高血糖素分泌来降低空腹血糖水平，对肝脏葡萄糖生成可能还有额外的直接抑制作用。了解这些药代动力学和药效学差异可能有助于2型糖尿病的个性化降糖治疗。此外，这可能为探索在无或几乎没有残余β细胞功能的患者中进行治疗提供理论依据。
