Knop Filip K, Holst Jens J, Vilsbøll Tina
Department of Internal Medicine F, Gentofte Hospital, University of Copenhagen, Niels Andersens Vej 65, DK-2900 Hellerup, Denmark.
IDrugs. 2008 Jul;11(7):497-501.
Type 2 diabetes mellitus (T2DM) is a progressive disease characterized by insulin resistance, a steady decline in glucose-induced insulin secretion (most likely caused by a progressive decrease in functional beta-cell mass), and inappropriately regulated glucagon secretion; in combination, these effects result in hyperglycemia. In 1958, sulfonylurea (SU) was introduced to the market as one of the first oral treatments for T2DM. Since then, the ability of SU to stimulate the release of insulin from pancreatic beta-cells by the closure of ATP-sensitive K+-channels has been employed as one of the most widespread treatment options for T2DM. However, SUs are associated with weight gain and a risk of hypoglycemia, and the one-track antidiabetic mechanism of SUs often results in patients being treated with additional antidiabetic drugs. In recent studies, SU has proven to be associated with increased beta-cell apoptosis, suggesting that SU may actually accelerate the progressive decrease in beta-cell mass, thereby promoting the need for insulin replacement. In contrast, the newly developed incretin-based therapies for T2DM employ the beta-cell-preserving properties of incretin hormones - glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). More importantly, incretin-based therapies potentiate glucose-stimulated insulin secretion and may restore reduced glucose-induced insulin secretion in T2DM. Furthermore, the insulinotropic effects of GLP-1 and GIP are glucose-dependent, reducing the risk of hypoglycemia. GLP-1 inhibits glucagon secretion and decreases gastrointestinal motility, in turn reducing food intake and body weight. This feature review focuses on the challenges and feasibilities of replacing SU with incretin-based therapy in patients with T2DM.
2型糖尿病（T2DM）是一种进行性疾病，其特征为胰岛素抵抗、葡萄糖诱导的胰岛素分泌稳步下降（很可能是由于功能性β细胞量逐渐减少所致）以及胰高血糖素分泌调节不当；这些效应共同导致高血糖。1958年，磺脲类药物（SU）作为首批用于T2DM的口服治疗药物之一投放市场。从那时起，SU通过关闭ATP敏感性钾通道来刺激胰腺β细胞释放胰岛素的能力，一直被用作T2DM最广泛的治疗选择之一。然而，SU与体重增加和低血糖风险相关，而且SU单一的抗糖尿病机制常常导致患者需要加用其他抗糖尿病药物。在最近的研究中，已证明SU与β细胞凋亡增加有关，这表明SU实际上可能加速β细胞量的逐渐减少，从而促使患者需要进行胰岛素替代治疗。相比之下，新开发的基于肠促胰岛素的T2DM治疗方法利用了肠促胰岛素激素——胰高血糖素样肽1（GLP-1）和葡萄糖依赖性促胰岛素多肽（GIP）的β细胞保护特性。更重要的是，基于肠促胰岛素的治疗方法可增强葡萄糖刺激的胰岛素分泌，并可能恢复T2DM患者降低的葡萄糖诱导的胰岛素分泌。此外，GLP-1和GIP的促胰岛素作用是葡萄糖依赖性的，可降低低血糖风险。GLP-1抑制胰高血糖素分泌并降低胃肠蠕动，进而减少食物摄入量和体重。本专题综述重点关注在T2DM患者中用基于肠促胰岛素的治疗方法替代SU的挑战和可行性。
