治療第2型糖尿病新型口服藥－DPP-IV抑制劑

New Oral Hypoglycemic Agents for the Management of Type 2 Diabetes Mellitus-DPP-IV Inhibitors

陳建良(Chien-Liang Chen) ； 謝昌勳(Chang-Hsun Hsieh) ； 郭台生(Tai-Sheng Kuo) ； 林自強(Tzu-Chiang Lin)

《內科學誌》 18卷1期 (2007/02) Pp. 20-28

https://doi.org/10.6314/JIMT.2007.18(1).03

摘要

治療第2型糖尿病常需要透過單獨或合併使用不同作用機轉的降血糖藥物，傳統降血糖藥物不但無法完全矯正第2型糖尿病的病態生理，而且可能會有體重增加、發生低血糖、和胃腸不適等副作用。此外，隨著糖尿病病程的進展，胰島β細胞功能及質量逐漸變少，常使得降血糖藥物逐漸降低效力，這些都是目前治療第2型糖尿病所須面對的瓶頸。腸降糖素(incretin)是腸道所產生的肚肽荷爾蒙，除了加弦葡萄糖依賴性胰島素的分泌(glucose dependent insulin secretion)外，還會抑制昇糖素的分泌、抑制冑排空速率、抑制食慾以及減輕體重等作用。在動物的實驗顯示，腸降糖素尚會刺激胰島β細胞增殖和抑制細胞凋亡(apoptosis)。腸降糖素類似物(incretin mimetics)的研發，雖能克服被二肽基肽酶(dipeptidyl peptidase-IV, DPP-IV)分解而延長其半衰期，但皆須經由皮下注射，因此降低病患的方便性及接受度。DPP-IV抑制劑是研發中的口服降血糖藥物，可以避免內生性的glucagon-like peptide-1(GLP-1)被分解，以增加內生性GLP-1的濃度。DPP-IV抑制劑也可以加強胰島素的分泌，抑制昇糖素的分泌，能降低空腹及餐後血糖，而且沒有增加體重和水腫等不良反應，發生低血糖的機會也較低。在動物實驗顯示，還可以改善胰島β細胞的功能，增加胰島β細胞的質量。但DPP-IV之胜肽蛋白分解不具特異性，有許多肚月太荷爾蒙也會受DPP-IV作用分解，因此可能會造成這些肚朕荷爾蒙濃度的上升，以及DPP-IV抑制劑亦有可能會造成異常的免疫反應。此類藥物未來是否能安全有效地長期使用於第2型糖尿病病患，還需要長時問大型臨床研究來証實。

關鍵字

腸降糖素 ； 葡萄糖依賴性胰島素的分泌 ； 二肽基肽酶 ； Glucagon-like peptide-1 GLP-1

並列摘要

Oral hypoglycemic agents frequently exhibit reduced efficacy over time, leading to inadequate glycemic control. Moreover, these agents may be associated with adverse side effects that include weight gain, hypoglycemia, and gastrointestinal discomfort. Incretins are peptide hormones secreted from the gastrointestinal tract that appear to have multiple mechanisms of action, including glucose-dependent enhancement of insulin secretion, suppression of inappropriately high glucagon secretion, slowing of gastric emptying and decreased food intake. Furthermore, animal studies have demonstrated preservation or restoration of/3-cell mass with incretin treatment. Inhibition of DPP-IV activity prevents the rapid breakdown and stabilizes the postprandial levels of bioactive endogenous incretins, thereby prolonging their physiologic actions. Treatment with DPP-4 inhibitors diminished postprandial glucose excursion, fasting plasma glucose and was well tolerated with neutral weight effect and a low incidence of hypoglycemia event in subjects with type 2 diabetes. Meanwhile, there is some concern about off-target actions with nonselective inhibition of DPP-IV and probably abnormal immune response. Therefore, it needs long-term, large scaled clinical trials to demonstrate the efficacy and safety of this new antihyperglycemic agent.

並列關鍵字

Increti ； Glucose dependent insulin secretion ； Dipeptidyl peptidase-IV, DPP-IV ； Glucagon-like peptide-1 GLP-1