Campbell R Keith
College of Pharmacy, Wegner Hall #147, PO Box 646510, Washington State University, Pullman, WA 99164, USA.
Ann Pharmacother. 2007 Jan;41(1):51-60. doi: 10.1345/aph.1H459. Epub 2006 Dec 26.
To review advances in understanding the pathophysiologic basis of type 2 diabetes mellitus and the pharmacology and mechanism of action of dipeptidyl peptidase 4 (DPP-4) inhibition in correcting the underlying defects in glycemic control.
Articles were identified through MEDLINE for the period 1966 through November 2006. Abstracts and presentations from the American Diabetes Association Scientific Sessions and the European Association for the Study of Diabetes (2002-2006) were also searched for scientific reports on DPP-4 inhibitors.
Abstracts, original clinical and preclinical research reports, and review articles published in the English language were identified for review. Literature discussing glucose regulation, incretin hormones, type 2 diabetes pathophysiology, and DPP-4 inhibition were evaluated and selected based on consideration of their support for the proof of concept, mechanistic and in vivo findings, and timeliness.
The search for new and effective therapies for type 2 diabetes has led to the identification of a novel therapeutic target, the incretin hormones, which play a role in mediating glucose homeostasis via effects on glucagon and insulin secretion from pancreatic islet alpha- and beta-cells, respectively. The incretins' glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide are rapidly inactivated by the enzyme DPP-4. DPP-4 inhibitor agents act by blocking the active site of DPP-4, thereby preventing inactivation of and prolonging the duration of action of incretins, which in turn helps to correct the defective insulin and glucagon secretion that marks type 2 diabetes. Clinical studies to date indicate that DPP-4 inhibitors effectively stimulate insulin secretion, suppress glucagon release, and improve glucose control in patients with type 2 diabetes. These agents are well tolerated and have a low incidence of adverse effects.
The DPP-4 inhibitors are novel agents for the treatment of type 2 diabetes. Compounds under development in this new class of oral antidiabetic drugs may be free of the limitations of current therapies.
综述在理解2型糖尿病病理生理基础以及二肽基肽酶4（DPP-4）抑制剂在纠正血糖控制潜在缺陷方面的药理学及作用机制方面取得的进展。
通过检索1966年至2006年11月期间的MEDLINE获取相关文章。还检索了美国糖尿病协会科学会议和欧洲糖尿病研究协会（2002 - 2006年）的摘要和报告，以查找有关DPP-4抑制剂的科学报告。
识别并审阅以英文发表的摘要、原始临床和临床前研究报告以及综述文章。基于对概念验证、机制和体内研究结果的支持以及时效性的考虑，对讨论葡萄糖调节、肠促胰岛素激素、2型糖尿病病理生理学和DPP-4抑制作用的文献进行评估和筛选。
对2型糖尿病新型有效疗法的探索促使人们确定了一个新的治疗靶点——肠促胰岛素激素，其分别通过对胰岛α细胞和β细胞的胰高血糖素和胰岛素分泌产生影响，在调节葡萄糖稳态中发挥作用。肠促胰岛素胰高血糖素样肽-1和葡萄糖依赖性促胰岛素多肽会被DPP-4酶迅速灭活。DPP-4抑制剂通过阻断DPP-4的活性位点发挥作用，从而防止肠促胰岛素的失活并延长其作用持续时间，进而有助于纠正标志着2型糖尿病的胰岛素和胰高血糖素分泌缺陷。迄今为止的临床研究表明，DPP-4抑制剂可有效刺激胰岛素分泌、抑制胰高血糖素释放并改善2型糖尿病患者的血糖控制。这些药物耐受性良好，不良反应发生率低。
DPP-4抑制剂是治疗2型糖尿病的新型药物。这类新型口服抗糖尿病药物中正在研发的化合物可能不存在现有疗法的局限性。
