Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
Pharmacology. 2011;88(5-6):275-83. doi: 10.1159/000331879. Epub 2011 Nov 4.
The potential utility of 5'-adenosine monophosphate-activated protein kinase (AMPK)-activating agents, such as metformin, in inducing angiogenesis, could be a promising approach to promote healing of gastric ulcers complicated by diabetes mellitus. The aim of the present study was to assess the effect of a drug that activates AMPK, namely metformin, in gastric ulcer healing in streptozotocin-induced diabetic rats.
Forty male Wistar albino rats were made diabetic by intraperitoneal (i.p.) streptozotocin injection and 10 rats were injected i.p. by a single dose of physiological saline. Six weeks following streptozotocin or saline injection, gastric ulcers were induced by serosal application of acetic acid. Three days after acetic acid application, rats were divided into group 1 (nondiabetic control), group 2 (streptozotocin-injected rats), groups 3-5 (streptozotocin-injected rats treated with metformin or metformin and an inhibitor of AMPK, namely compound C or pioglitazone) for 7 days following acetic acid application.
Administration of metformin, but not pioglitazone, resulted in a significant decrease in the gastric ulcer area, a significant increase in epithelial regeneration assessed histologically, a significant increase in the number of microvessels in the ulcer margin, a significant increase in gastric vascular endothelial growth factor concentration and gastric von Willebrand factor as well as a significant increase in gastric phospho-AMPK. Compound C, an inhibitor of AMPK, blocked metformin-induced changes in assessed parameters suggesting that the effect of metformin was mediated mainly through activation of AMPK.
Our results suggest the feasibility of a novel treatment strategy, namely drugs activating AMPK, for patients in whom impairment of ulcer healing constitutes a secondary complication of diabetes mellitus.
5'-腺苷单磷酸激活的蛋白激酶（AMPK）激活剂，如二甲双胍，具有诱导血管生成的潜力，这可能是促进糖尿病合并胃溃疡愈合的一种很有前途的方法。本研究旨在评估一种激活 AMPK 的药物，即二甲双胍，对链脲佐菌素诱导的糖尿病大鼠胃溃疡愈合的影响。
40 只雄性 Wistar 白化大鼠通过腹腔内（i.p.）注射链脲佐菌素诱导糖尿病，10 只大鼠通过单次腹腔注射生理盐水。注射链脲佐菌素或生理盐水 6 周后，通过浆膜应用醋酸诱导胃溃疡。醋酸应用 3 天后，将大鼠分为第 1 组（非糖尿病对照组）、第 2 组（链脲佐菌素注射大鼠）、第 3-5 组（链脲佐菌素注射大鼠用二甲双胍或二甲双胍和 AMPK 抑制剂，即化合物 C 或吡格列酮治疗），在醋酸应用后 7 天。
二甲双胍的给药，而不是吡格列酮，导致胃溃疡面积显著减少，组织学评估的上皮再生显著增加，溃疡边缘的微血管数量显著增加，胃血管内皮生长因子浓度和胃血管性血友病因子以及胃磷酸-AMPK 显著增加。AMPK 的抑制剂化合物 C 阻断了二甲双胍诱导的评估参数的变化，表明二甲双胍的作用主要是通过激活 AMPK 介导的。
我们的结果表明，一种新的治疗策略，即激活 AMPK 的药物，对于溃疡愈合受损构成糖尿病继发并发症的患者是可行的。
