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<p>Lower-extremity ischemia–reperfusion (I/R) injury triggers a systemic inflammatory and oxidative response that extends beyond the primary ischemic site, leading to remote organ damage and increased morbidity and mortality. Metformin has been reported to exert antioxidant and anti-inflammatory effects independent of its glucose-lowering properties; however, its effects on distant organ injury following limb I/R under non-diabetic conditions remain incompletely understood. Twenty-four male Wistar albino rats were randomly allocated into four groups (<i>n</i> = 6 each): control, I/R, I/R + metformin 4&#xa0;mg/kg, and I/R + metformin 8&#xa0;mg/kg. Lower-extremity ischemia was induced by infrarenal abdominal aortic clamping for 45&#xa0;min, followed by 120&#xa0;min of reperfusion. Metformin was administered intraperitoneally immediately before reperfusion. Liver, lung, and kidney tissues were collected for the assessment of total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI), along with histopathological evaluation. Compared with the control group, I/R significantly increased TOS and OSI levels and decreased TAS levels in liver, lung, and kidney tissues (<i>p</i> &lt; 0.001), accompanied by marked histopathological alterations, including hepatocellular degeneration, pulmonary edema and inflammation, and renal tubular and glomerular injury. Metformin administration was associated with significant attenuation of oxidative stress parameters and histopathological damage in all examined organs compared with the I/R group. Both doses improved TAS and reduced TOS and OSI levels; however, the 8&#xa0;mg/kg dose demonstrated more consistent biochemical improvement and more pronounced histopathological findings. In particular, higher-dose metformin was associated with reduced hepatic sinusoidal dilatation and necrosis, decreased pulmonary alveolar wall thickening and total lung injury scores, and attenuated renal tubular degeneration, inflammation, and cast formation. Metformin may attenuate remote liver, lung, and kidney injury following lower-extremity I/R in non-diabetic rats, potentially through mechanisms related to the modulation of oxidative stress. The observed dose-related effects suggest a possible systemic protective role; however, further experimental and clinical studies are required to confirm these findings and clarify the underlying mechanisms.</p>

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Potential protective effects of metformin on remote organ injury in the liver, kidney, and lung following experimental lower-extremity ischemia–reperfusion in non-diabetic rats

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月31日

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  • Hüseyin Demirtaş,
  • Alperen Kutay Yıldırım,
  • Abdullah Özer,
  • Ali Doğan Dursun,
  • Şaban Cem Sezen,
  • Ayşegül Küçük,
  • Mustafa Arslan

摘要

Lower-extremity ischemia–reperfusion (I/R) injury triggers a systemic inflammatory and oxidative response that extends beyond the primary ischemic site, leading to remote organ damage and increased morbidity and mortality. Metformin has been reported to exert antioxidant and anti-inflammatory effects independent of its glucose-lowering properties; however, its effects on distant organ injury following limb I/R under non-diabetic conditions remain incompletely understood. Twenty-four male Wistar albino rats were randomly allocated into four groups (n = 6 each): control, I/R, I/R + metformin 4 mg/kg, and I/R + metformin 8 mg/kg. Lower-extremity ischemia was induced by infrarenal abdominal aortic clamping for 45 min, followed by 120 min of reperfusion. Metformin was administered intraperitoneally immediately before reperfusion. Liver, lung, and kidney tissues were collected for the assessment of total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI), along with histopathological evaluation. Compared with the control group, I/R significantly increased TOS and OSI levels and decreased TAS levels in liver, lung, and kidney tissues (p < 0.001), accompanied by marked histopathological alterations, including hepatocellular degeneration, pulmonary edema and inflammation, and renal tubular and glomerular injury. Metformin administration was associated with significant attenuation of oxidative stress parameters and histopathological damage in all examined organs compared with the I/R group. Both doses improved TAS and reduced TOS and OSI levels; however, the 8 mg/kg dose demonstrated more consistent biochemical improvement and more pronounced histopathological findings. In particular, higher-dose metformin was associated with reduced hepatic sinusoidal dilatation and necrosis, decreased pulmonary alveolar wall thickening and total lung injury scores, and attenuated renal tubular degeneration, inflammation, and cast formation. Metformin may attenuate remote liver, lung, and kidney injury following lower-extremity I/R in non-diabetic rats, potentially through mechanisms related to the modulation of oxidative stress. The observed dose-related effects suggest a possible systemic protective role; however, further experimental and clinical studies are required to confirm these findings and clarify the underlying mechanisms.