Metformin Improves Cardiac Functional Recovery After Ischemia in Rats

Legtenberg, Roger J.; Houston, R.; Oeseburg, B.; Smits, Paul

doi:10.1055/s-2002-26705

Cited by 46 publications

(35 citation statements)

References 7 publications

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“…Regarding dosage, 125 g/kg is 286-fold less than the maximum antihyperglycemic dose (2,500 mg/day) of metformin, making the current study the first to clearly demonstrate that a subtherapeutic dose of metformin can provide cardioprotection. Regarding the time of administration, we demonstrate that in contrast to previous studies (20,21), which reported the cardioprotective effects of a chronic administration or constant perfusion of metformin, an acute administration of metformin given once either before ischemia or at the time of reperfusion can provide protection. These findings are of clinical relevance since they demonstrate that acute metformin treatment could potentially be initiated at the time of coronary artery reperfusion to patients experiencing myocardial ischemia.…”

Section: Discussioncontrasting

confidence: 89%

“…However, a closer look at the UKPDS studies reveals that metformin reduced A1C values in treated patients to the same extent as in the other cohort of patients treated with conventional therapies, suggesting that metformin might have additional cardioprotective actions beyond its antihyperglycemic effects (7). This notion is further supported by the observation that metformin does not affect glucose values in nondiabetic rodents (20) yet improves cardiac function following in vitro global ischemia (21). This is further supported by the findings of the current study, which is the first to provide strong evidence that a single administration of metformin to nondiabetic and diabetic mice profoundly reduces infarct size without lowering blood glucose levels.…”

Section: Discussionsupporting

confidence: 84%

“…Studies using the isolated perfused working heart model have reported that metformin at concentrations known to lower blood glucose provides cardioprotection in diabetic hearts against increasing preload and in nondiabetic hearts against global ischemia (20,21). However, questions regarding the protective mechanisms of metformin in in vivo models of myocardial ischemia-reperfusion (I/R) remain to be answered.…”

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confidence: 99%

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Acute Metformin Therapy Confers Cardioprotection Against Myocardial Infarction Via AMPK-eNOS–Mediated Signaling

et al. 2008

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OBJECTIVE-Clinical studies have reported that metformin reduces cardiovascular end points of type 2 diabetic subjects by actions that cannot solely be attributed to glucose-lowering effects. The therapeutic effects of metformin have been reported to be mediated by its activation of AMP-activated protein kinase (AMPK), a metabolite sensing protein kinase whose activation following myocardial ischemia has been suggested to be an endogenous protective signaling mechanism. We investigated the potential cardioprotective effects of a single, low-dose metformin treatment (i.e., 286-fold less than the maximum antihyperglycemic dose) in a murine model of myocardial ischemia-reperfusion (I/R) injury.RESEARCH DESIGN AND METHODS-Nondiabetic and diabetic (db/db) mice were subjected to transient myocardial ischemia for a period of 30 min followed by reperfusion. Metformin (125 g/kg) or vehicle (saline) was administered either before ischemia or at the time of reperfusion.RESULTS-Administration of metformin before ischemia or at reperfusion decreased myocardial injury in both nondiabetic and diabetic mice. Importantly, metformin did not alter blood glucose levels. During early reperfusion, treatment with metformin augmented I/R-induced AMPK activation and significantly increased endothelial nitric oxide (eNOS) phosphorylation at residue serine 1177.CONCLUSIONS-These findings provide important information that myocardial AMPK activation by metformin following I/R sets into motion events, including eNOS activation, which ultimately lead to cardioprotection. Diabetes 57:696-705, 2008 M etformin is one of the most commonly prescribed antihyperglycemic agents for the treatment of type 2 diabetes (1). Its major effects in terms of blood glucose are mediated through a reduction in hepatic glucose output and an increase in insulin-dependent peripheral glucose utilization (2). The therapeutic effects of metformin, however, are not limited to its ability to lower blood glucose, as evidence supports direct vascular effects (3,4). Additionally, two large-scale clinical trials have reported that metformin improves vascular function and reduces mortality and cardiovascular end points of type 2 diabetic subjects (5,6) by actions that cannot be attributed entirely to its antihyperglycemic effects (7).Recent studies suggest that the pleotropic effects of metformin may be mediated by its activation of AMPactivated protein kinase (AMPK) (1,8,9), a protein kinase that is activated in response to alterations in cellular energy levels (10). Its activation is mediated by increases in AMP-to-ATP ratios through mechanisms involving allosteric regulation of AMPK subunits, making it a better substrate for upstream AMPK kinases (AMPKK) and a worse substrate for competing protein phosphatases (11). Metabolic activators of AMPK include ischemia, oxidative stress, exercise, and glucose deprivation (12). When activated, AMPK stimulates fatty acid oxidation (13), promotes glucose transport (14), accelerates glycolysis (15), and inhibits triglyceride (16) and ...

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Section: Discussioncontrasting

confidence: 89%

Section: Discussionsupporting

confidence: 84%

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confidence: 99%

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Acute Metformin Therapy Confers Cardioprotection Against Myocardial Infarction Via AMPK-eNOS–Mediated Signaling

et al. 2008

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“…For type-2 diabetics, oral agents (sulfonylurea or oral hypoglycemic agents, Metformin, DPP-4 inhibitors, SGLT-2 inhibitors, thiazolidinediones) can be used alone or in combination with insulin; these treatments can be shifted to insulin with metformin if they remain uncontrolled on oral agents. Metformin should be prescribed to type-2 diabetic patients (if not contraindicated) because metformin has cardiovascular protective effects, reduces insulin resistance, increases insulin sensitivity, and decreases the serum lipids while elevates HDL-C as has been demonstrated by research studies [63][64][65][66][67][68][69][70]. It is recommended following best available guidelines for the management of diabetes and its complications [71,72].…”

Section: Discussionmentioning

confidence: 99%

Association of Serum Lipids with High Blood Pressure and Hypertensionamong Diabetic Patients. Mathematical Regression Models to PredictBlood Pressure from Lipids. An Experience from 12-year Follow Up ofmore than 9000 Patients' Cohort

Aziz¹

2017

Gen Med

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Dyslipidemia and hypertension alone predispose to the risk of coronary artery disease, especially if the patient is diabetic. This risk is increased and multiplied when both dyslipidemia and hypertension coexists. There is a lack of studies and significant data for the correlation or association of blood pressure with serum lipids. The studies conducted in the past showed the conflicting results with poor associations. Furthermore, these studies were not conducted on diabetic subjects and lack regression models or mathematical linear equations. Hence, we conducted a prospective, observational cohort study on 9340 diabetic subjects for the duration of 12 year (2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015)(2016)(2017), with the aim to find significant associations, correlations between serum lipids (total cholesterol, triglycerides, LDL-C, HDL-C and Non-HDL-C) and blood pressure (systolic and diastolic). Our data has demonstrated that total cholesterol, triglycerides, and LDL-C were significantly correlated with systolic and diastolic BP, and raised among hypertensive patients as compared to non-hypertensive ( p<0.001 for all lipids). The highest correlations were found between Non-HDL-C with systolic and diastolic blood pressures (r=0.414 and r=0.415, respectively with p<0.001). However, HDL-C was inversely correlated with systolic and diastolic BP and was raised among non-hypertensive patients. Regression models and mathematical linear equations were developed to estimate increasing blood pressure by the given serum lipid levels. All regression models were significant (p<0.0001). We concluded and developed regression models, for the first time in medical research that high lipid levels contribute to the development of increase systolic and diastolic blood pressures. With triglycerides, total-cholesterol, and HDL-C, Non-DHL-C levels should also be calculated in diabetology clinics and general practice. Screening should be done for diabetic patients to detect high blood pressure (or HTN) and elevated serum lipids, and early initiation of management to prevent diabetes complications.

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“…It has been previously shown that several tissues endangered by oxidative imbalance associated with T2D, particularly the myocardium (38,44), endothelial cells (5,48), and the brain (13), could be protected by metformin administration. Surprisingly, there are scarce data regarding the antioxidant effect of metformin in the fatty liver, despite the fact that steatosis is a hallmark of T2D and that the fatty liver is highly susceptible to oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Metformin prevents ischemia reperfusion-induced oxidative stress in the fatty liver by attenuation of reactive oxygen species formation

Cahová

Páleníčková

Daňková

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Z, Oliyarnyk O, Kazdova L. Metformin prevents ischemia reperfusion-induced oxidative stress in the fatty liver by attenuation of reactive oxygen species formation. Am J Physiol Gastrointest Liver Physiol 309: G100 -G111, 2015. First published June 4, 2015; doi:10.1152/ajpgi.00329.2014.-Nonalcoholic fatty liver disease is associated with chronic oxidative stress. In our study, we explored the antioxidant effect of antidiabetic metformin on chronic [high-fat diet (HFD)-induced] and acute oxidative stress induced by short-term warm partial ischemia-reperfusion (I/R) or on a combination of both in the liver. Wistar rats were fed a standard diet (SD) or HFD for 10 wk, half of them being administered metformin (150 mg·kg body wt Ϫ1 ·day Ϫ1 ). Metformin treatment prevented acute stress-induced necroinflammatory reaction, reduced alanine aminotransferase and aspartate aminotransferase serum activity, and diminished lipoperoxidation. The effect was more pronounced in the HFD than in the SD group. The metformin-treated groups exhibited less severe mitochondrial damage (markers: cytochrome c release, citrate synthase activity, mtDNA copy number, mitochondrial respiration) and apoptosis (caspase 9 and caspase 3 activation). Metformin-treated HFD-fed rats subjected to I/R exhibited increased antioxidant enzyme activity as well as attenuated mitochondrial respiratory capacity and ATP resynthesis. The exposure to I/R significantly increased NADH-and succinate-related reactive oxygen species (ROS) mitochondrial production in vitro. The effect of I/R was significantly alleviated by previous metformin treatment. Metformin downregulated the I/R-induced expression of proinflammatory (TNF-␣, TLR4, IL-1␤, Ccr2) and infiltrating monocyte (Ly6c) and macrophage (CD11b) markers. Our data indicate that metformin reduces mitochondrial performance but concomitantly protects the liver from I/R-induced injury. We propose that the beneficial effect of metformin action is based on a combination of three contributory mechanisms: increased antioxidant enzyme activity, lower mitochondrial ROS production, and reduction of postischemic inflammation. metformin; oxidative stress; mitochondrial respiration; liver injury; 31 P MR spectroscopy METFORMIN IS AN ORAL ANTIHYPERGLYCEMIC drug widely used in the treatment of Type 2 diabetes (T2D) (7). There is evidence that metformin also protects against oxidative stress in various tissues, although the antioxidant activity of metformin is not well understood. It has been shown that hyperglycemia is associated with increased reactive oxygen species (ROS) formation due to superoxide overproduction from the mitochondrial electron transport chain as a consequence of increased glycolysis (8). It has been hypothesized that the antioxidative effect of metformin is simply the consequence of its glucoselowering effect and subsequent decrease in superoxide anion production (3). Nevertheless, metformin has also displayed antioxidative characteristics in several models of oxidative stress without hyperglycemia (2,19,20,2...

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Metformin Improves Cardiac Functional Recovery After Ischemia in Rats

Cited by 46 publications

References 7 publications

Acute Metformin Therapy Confers Cardioprotection Against Myocardial Infarction Via AMPK-eNOS–Mediated Signaling

Acute Metformin Therapy Confers Cardioprotection Against Myocardial Infarction Via AMPK-eNOS–Mediated Signaling

Association of Serum Lipids with High Blood Pressure and Hypertensionamong Diabetic Patients. Mathematical Regression Models to PredictBlood Pressure from Lipids. An Experience from 12-year Follow Up ofmore than 9000 Patients' Cohort

Metformin prevents ischemia reperfusion-induced oxidative stress in the fatty liver by attenuation of reactive oxygen species formation

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