Role of Activation of 5′-Adenosine Monophosphate-Activated Protein Kinase in Gastric Ulcer Healing in Diabetic Rats

Abstract

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Anti‐aging pharmacology in cutaneous wound healing: effects of metformin, resveratrol, and rapamycin by local application

“…Several intriguing issues arise with our present findings that are interesting to be addressed in future studies. As stated, it should be cautious that systemic administration of these agents may result in more unpredictable side effects and failed therapeutics in the skin, potentially underlying differential effects of MET by local and systemic applications (Baraka & Deif, ; Ochoa‐Gonzalez et al ., ). Therefore, topically targeting AMPK by MET may become a feasible approach to the chronic nonhealing wounds in both young and aged population, or function as a useful supplement to current treatments such as glucocorticoids (Hofman et al ., ) and epidermal growth factor (EGF) (Brown et al ., ).…”

“…MET, a biguanide agent and AMPK activator, has long been used to treat diabetic hyperglycemia, which substantially impairs wound healing (Madiraju et al ., ). However, controversial results exist regarding whether AMPK activation by MET improves healing of diabetic wounds, in that negative effects on foot ulcers (Ochoa‐Gonzalez et al ., ) and positive effects on gastric ulcers (Baraka & Deif, ) upon oral administration of MET have both been reported, suggesting differential effects of MET by systemic and local applications. RSV, a natural polyphenol in red wine and grapes, stimulates both Sirt1 and AMPK pathways, leading to activation of the metabolic regulator peroxisome proliferator‐activated receptor gamma coactivator‐1 alpha (PGC‐1α) (Park et al ., ).…”

Metformin reduces gastric cancer risk in patients with type 2 diabetes mellitus

“…Metformin may also induce apoptosis in human gastric cancer cells via the inhibition of survivin mediated by mTOR through the activation of AMPK [ 56 ] or via the inhibition of hypoxia inducible factor 1α and pyruvate kinase M2 signaling pathway [ 57 ]. Metformin may exert a gastric mucosal protection effect [ 58 ] and significantly improve gastric ulcer healing mediated by an activation of AMPK [ 59 ].…”

A comparison of epithelial-to-mesenchymal transition and re-epithelialization

“…As a result, one would expect metformin to inhibit wound healing. However, metformin sped overall wound healing and epithelialization, in particular, in ulcers [234]. The apparently disparate results may reflect an underlying complexity in how metabolism affects tumors vs. normal tissue.…”