Metabolic Effects of Metformin in the Failing Heart

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Term Occurence Count Dictionary
hyperinsulinemia 1 endocrinologydiseases
lactic acidosis 6 endocrinologydiseases
obesity 1 endocrinologydiseases
pioglitazone 1 endocrinologydiseasesdrugs
Insulin 2 endocrinologydiseasesdrugs
diabetes mellitus 5 endocrinologydiseases
hyperglycemia 7 endocrinologydiseases
hypoglycemia 2 endocrinologydiseases
metformin 84 endocrinologydiseasesdrugs
type 2 diabetes mellitus 3 endocrinologydiseases

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Select Drug Character Offset Drug Term Instance
Insulin 18070 extracellular matrix that contributes to myocardial remodeling and diastolic dysfunction [[51],[68],[69],[70]]. Insulin resistance-associated hiperinsulinemia can stimulate cardiomyocyte hypertrophy by binding to the IGF-1
Insulin 23478 involved in the insulin signaling pathways such as IRS that reduces cell sensitivity to insulin [[90]]. Insulin resistance is associated with reduced expression of glucose transporters GLUT-1 and GLUT-4 [[83],[100]].Moreover,
metformin 551 andrzejwojtak@umlub.plPublication date (epub): 9/2018Publication date (collection): 10/2018AbstractAccumulating evidence shows that metformin is an insulin-sensitizing antidiabetic drug widely used in the treatment of type 2 diabetes mellitus
metformin 878 failure (HF), and even able to reduce the incidence of HF and to reduce HF mortality. In failing hearts, metformin improves myocardial energy metabolic status through the activation of AMP (adenosine monophosphate)-activated
metformin 1261 the deposition of advanced glycation end-products (AGEs), and inhibiting myocardial cell apoptosis metformin reduces cardiac remodeling and hypertrophy, and thereby preserves left ventricular systolic and diastolic
metformin 1472 diastolic functions. While a lot of preclinical and clinical studies showed the cardiovascular safety of metformin therapy in diabetic patients and HF, to confirm observed benefits, the specific large-scale trials configured
metformin 3504 been proven for empagliflozin, an inhibitor of the sodium-glucose co-transporter 2 (SGLT-2) [[8]] and metformin , the biguanide derivative.Metformin (1,1-dimethylbiguanide), an insulin-sensitizer, is currently a basis
metformin 4424 clinical study, The United Kingdom Prospective Diabetes Study, was the first to demonstrate the ability of metformin to reduce the risk of macroangiopathy in patients with newly diagnosed diabetes and obesity or overweight,
metformin 4623 obesity or overweight, more than sulfonylureas or insulin. In comparison with conventional diet therapy, metformin reduced the risk of any diabetes-related complication by 32%, the risk of death due to diabetes by 42%
metformin 4831 42% and the risk of myocardial infarction by 39%. The risk of hypoglycemia was lower for intensive metformin treatment than for intensive treatment with sulfonyloureas or insulin [[18]].It should be emphasized
metformin 5009 insulin [[18]].It should be emphasized that, according to the current Summary of Product Characteristics, metformin is contraindicated in heart failure [[10]]. However, the results presented in the latest reports verify
metformin 5147 failure [[10]]. However, the results presented in the latest reports verify the contraindication of metformin in this setting. The recent trials demonstrated that metformin does not enhance the risk of lactic acidosis,
metformin 5210 reports verify the contraindication of metformin in this setting. The recent trials demonstrated that metformin does not enhance the risk of lactic acidosis, and can be safety used in patients with type 2 diabetes
metformin 5448 failure [[19]]. This review presents the molecular basis of antihyperglycemic mechanism of action of metformin , its impact on myocardial metabolism and cardioprotective mechanisms that are independent of glycemic
metformin 5611 cardioprotective mechanisms that are independent of glycemic control. While the cardio-protective properties of metformin are well established, the role of metformin therapy in patients with diabetes and concomitant HF is
metformin 5655 glycemic control. While the cardio-protective properties of metformin are well established, the role of metformin therapy in patients with diabetes and concomitant HF is still the subject of much controversy. In this
metformin 5901 metabolic effects of this anti-diabetic agent in failing heart that could explain the benefit and safety of metformin therapy in this population.2. Mechanisms of Antihyperglycemic ActionMetformin effectively reduces fasting
metformin 6449 where it directly inhibits complex 1 in a time-dependent, self-limiting manner. The positive charge of metformin accounts for its accumulation within the mitochondrial matrix. As the matrix concentration of the drug
metformin 8539 liver and skeletal muscles or glycolysis [[12],[23]].In the liver inhibition of gluconeogenesis by metformin is caused not only by the reduced availability of ATP [[11]], but also by blocking lactate uptake into
metformin 9067 glucose-6-phosphate to glucose [[28],[29],[30]]. Through the activation of insulin receptor substrate two (IRS-2), metformin enhances GLUT-1 (glucose transporter 1)-mediated glucose transport into hepatocytes [[31]].In the liver,
metformin 9182 enhances GLUT-1 (glucose transporter 1)-mediated glucose transport into hepatocytes [[31]].In the liver, metformin also affects lipid synthesis and catabolism. By activating AMPK, metformin down-regulates SREBP-1 (sterol
metformin 9257 hepatocytes [[31]].In the liver, metformin also affects lipid synthesis and catabolism. By activating AMPK, metformin down-regulates SREBP-1 (sterol regulatory element binding protein 1) gene expression. SREBP-1 regulates
metformin 10127 (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase) inhibition [[34]].In the skeletal muscle cells, metformin increases insulin-dependent glucose uptake and its utilization in anaerobic glycolysis [[35],[36]].
metformin 10250 insulin-dependent glucose uptake and its utilization in anaerobic glycolysis [[35],[36]]. Furthermore, metformin enhances anaerobic glycolysis in other tissues [[11],[37]].In adipocytes metformin regulates adipogenesis,
metformin 10333 [[35],[36]]. Furthermore, metformin enhances anaerobic glycolysis in other tissues [[11],[37]].In adipocytes metformin regulates adipogenesis, lipolysis, and FFA oxidation, thus reduces the release of FFA from the adipose
metformin 10602 with more efficient glucose uptake by the cells of peripheral tissues [[38],[39]].In the intestines metformin inhibits absorption of glucose and other simple carbohydrates [[40]]. In addition, it has been proved
metformin 10719 inhibits absorption of glucose and other simple carbohydrates [[40]]. In addition, it has been proved that metformin is able to improve the action of intestine-pancreas axis (incretin effect). The drug is considered to
metformin 11023 through inhibiting dipeptidyl peptidase-4 (DPP-4), an enzyme responsible for incretin degradation, metformin may prolong the duration and activity of endogenous incretins [[37],[41]]. Metformin may also exert
metformin 11623 that may contribute to the gastrointestinal-associated side effects [[45]]. Intestinal absorption of metformin is probably facilitated by plasma membrane monoamine transporter (PMAT) as well as OCT1 and OCT3 (organic
metformin 11812 as OCT1 and OCT3 (organic cation transporters) [[46]]. OCTs play important role in distribution of metformin over body tissues, such as intestine, kidney, and liver [[46],[47]]. Steady-state plasma concentrations
metformin 11929 body tissues, such as intestine, kidney, and liver [[46],[47]]. Steady-state plasma concentrations of metformin may vary from one to 10 μM [[45]]. The drug is not metabolized in the liver and is excreted unchanged
metformin 12557 associated with wide variations in pharmacokinetics profile and a large inter-individual variability in metformin response [[47],[48]].3. Diabetic CardiomyopathyDiabetes mellitus is an independent risk factor of congestive
metformin 25867 cardiomyocytes, in spite of comparable ATP generation and oxygen utilization [[103]].In vitro study showed that metformin added to the incubation medium significantly increased glucose uptake by stimulating the phosphoinositide
metformin 26819 people, even without symptoms of left ventricular dysfunction [[50]]. Hence a question arises, will metformin treatment not worsen lipotoxicity resulting from accumulation of fatty acids and triglycerides? No unequivocal
metformin 27028 unequivocal answer has been found so far. Nevertheless, in vitro studies showed that small doses of metformin did not worsen, but even protected heart muscle from fat-induced apoptosis. It has been observed that
metformin 27391 caspase 3, is involved in myocytes apoptosis [[93]].On the other hand, there are studies showing that metformin at high doses may increase the number of cells undergoing apoptosis as a result of FFA accumulation
metformin 27532 number of cells undergoing apoptosis as a result of FFA accumulation [[106]]. As already mentioned, metformin -induced AMPK phosphorylation enhances not only glucose transport and glycolysis, but also fatty acid
metformin 28143 from the incubation medium. Lactate synthesis and pH reduction are also observed when lower doses of metformin are used, but metformin at low concentrations has no influence on cardiomyocytes survival [[106]].In
metformin 28167 medium. Lactate synthesis and pH reduction are also observed when lower doses of metformin are used, but metformin at low concentrations has no influence on cardiomyocytes survival [[106]].In addition, in vivo studies
metformin 28318 cardiomyocytes survival [[106]].In addition, in vivo studies showed that chronic administration of metformin declined FFA level in the plasma and increased their oxidation in non-diabetic cardiomyocytes. At the
metformin 28549 inhibition of glucose oxidation was observed, probably as a result of the glycolysis-blocking effect of metformin , directly or indirectly, by acetyl-CoA synthesized during FFA oxidation. Increased β-oxidation and
metformin 29320 kinase phosphorylases eEF-2 kinase [[111]] and ribosomal protein S6 [[112]]. It has been proven that metformin -induced AMPK activation inhibits protein synthesis by increasing the level of phosphorylated, (inactive)
metformin 29693 activity [[108]].5.3. Mitochondrial FunctionThe other mechanism explaining the beneficial effect of metformin on metabolism of failing heart is improvement of mitochondria function in cardiomyocytes. In experimental
metformin 29906 experimental heart failure induced by myocardial ischemia in mice, four-week administration of small doses of metformin significantly improved left ventricular function and structure and increased animal survival almost
metformin 30608 performed in transgenic animals with inactive AMPKα2 and eNOS genes, this cardioprotective effect of metformin was not observed [[113]].5.4. iNOS Activity and Calcium Ions TransportIn the heart tissue, there are
metformin 32795 lipopolysaccharide-induced elevation of iNOS mRNA (messenger ribonucleic acid) expression in macrophages. Therefore, metformin via blocking the excessive NO generation can reduce formation of cardiotoxic peroxynitrite. This effect
metformin 33189 cytokines, such as IL-1β (interleukin-1β) [[122]]. In vitro studies proved that, through AMPK activation, metformin inhibited synthesis of IL-1β in activated macrophages [[121]]. It is also noteworthy, that metformin,
metformin 33291 metformin inhibited synthesis of IL-1β in activated macrophages [[121]]. It is also noteworthy, that metformin , by activating AMPK, facilitates eNOS phosphorylation/activity [[123]] and reduces the activity of TGF-β1,
metformin 33848 preclinical study conducted in normoglycemic mice with left ventricular pressure overload showed that metformin can inhibit collagen synthesis in myocardium, which contributes to left ventricular dimension reduction
metformin 34061 and significantly decreases diastolic pressure in the LV. This effect resulted from the ability of metformin to inhibit the synthesis of TGF-β1 in myocardium and was independent of its glucose and insulin-lowering
metformin 34242 of its glucose and insulin-lowering effects [[126]]. The same authors, in another study, showed that metformin in cultured fibroblasts may inhibit phosphorylation of Smad3 factor and its translocation to the nucleus
metformin 34556 regulation of the expression of extracellular matrix protein genes [[127]]. Thus, its inhibition by metformin explains the reduction of collagen synthesis. This effect of metformin was not related to AMPK activation
metformin 34627 [[127]]. Thus, its inhibition by metformin explains the reduction of collagen synthesis. This effect of metformin was not related to AMPK activation [[126]].Non-enzymatic protein glycation (NEG) plays an important
metformin 36147 dicarbonyls, through binding the guanidine group of drug to α-dicarbonyl group of methylglyoxal. Furthermore, metformin activates the glyoxolase, an enzyme that converts methylglyoxal to D-lactate. This beneficial effect
metformin 36355 effect was confirmed in numerous preclinical studies [[135],[136]]. For example, it was documented that metformin is able to protect apolipoprotein A-I of HDL (high density lipoprotein) fraction from glycation induced
metformin 36805 glyoxal [[139]]. In the rats with streptozotocin-induced diabetes, as a result of administration of metformin , smaller amounts of AGEs in the kidney cortex, lens and sciatic nerve were observed [[140]]. Moreover,
metformin 36996 observed [[140]]. Moreover, lower levels of circulating AGEs were found in diabetic patients treated with metformin [[141]]. In addition, a study performed on diabetic dogs revealed that metformin could also prevent
metformin 37077 patients treated with metformin [[141]]. In addition, a study performed on diabetic dogs revealed that metformin could also prevent glycation of collagen in the heart muscle and thereby could reduce heart stiffness.
metformin 37220 collagen in the heart muscle and thereby could reduce heart stiffness. It has been demonstrated that metformin can restore diastolic myocardial function in these animals, reflected by the normalization of end-diastolic
metformin 37403 the normalization of end-diastolic pressure and end-diastolic volume. In the heart of animals given metformin , there was observed reduced AGEs binding to collagen fibers. It is interesting that although the total
metformin 37585 interesting that although the total amount of collagen in the heart of these animals remained unchanged, metformin significantly improved heart function [[125]].5.6. ApoptosisProtective effect of metformin on heart
metformin 37676 unchanged, metformin significantly improved heart function [[125]].5.6. ApoptosisProtective effect of metformin on heart muscle is also mediated by the inhibition of cardiomyocyte apoptosis. It has been demonstrated
metformin 37795 muscle is also mediated by the inhibition of cardiomyocyte apoptosis. It has been demonstrated that metformin , through AMPK activation, prevents apoptosis of cardiomyocytes during their incubation with H2O2 [[104]].
metformin 37951 of cardiomyocytes during their incubation with H2O2 [[104]]. Similarly, an in vivo study showed that metformin reduced the number of dead cardiomyocytes in the hearts of dogs with experimental heart failure. After
metformin 38090 cardiomyocytes in the hearts of dogs with experimental heart failure. After four weeks treatment with metformin , improvement of LV function and hemodynamic parameters was observed. These cardioprotective, antiapoptotic
metformin 38404 phosphorylation/activation, resulting in the increase in NO synthesis [[104]].The evidence of cardioprotective effect of metformin was also found in a study on rats with heart damage caused by subcutaneous injection of isoproterenol
metformin 39431 and clinical observations supply a growing number of arguments that confirm safety and benefits of metformin in patients with heart failure. For example, in study involving patients with heart failure and type
metformin 39605 patients with heart failure and type 2 diabetes, at the first stage of antihyperglycemic treatment, metformin , in monotherapy or in combination with sulfonylureas, reduced the total mortality and risk of death
metformin 40072 mortality in comparison with traditional treatment based only on diet and life style changes. The effect of metformin was independent of glycemic control and the BMI (body mass index) value, and has not been observed after
metformin 40319 administration [[146]]. In another non-randomized study, during two years observation, treatment with metformin reduced mortality of ambulatory patients with diabetes and heart failure [[147]]. There is also evidence
metformin 40439 mortality of ambulatory patients with diabetes and heart failure [[147]]. There is also evidence that metformin monotherapy is associated with a lower risk of heart failure development in patients with recent diabetes
metformin 40651 diabetes than sulfonylurea monotherapy, even at high doses [[148]]. In addition, it has been proven that metformin use in monotherapy or in combination with other antihyperglycemic drugs such as sulfonylurea derivatives,
metformin 41165 (death or urgent heart transplant) risk and to increase in left ventricular ejection fraction after metformin therapy in comparison to other oral antihyperglycemic drugs or insulin [[149]].According to the recommendations
metformin 41320 antihyperglycemic drugs or insulin [[149]].According to the recommendations of the international guidelines, metformin should not be used in patients with diabetes and heart failure because of a risk of lactic acidosis.
metformin 41463 with diabetes and heart failure because of a risk of lactic acidosis. However, the connection between metformin blood level and lactate blood level during lactic acidosis is not observed in clinical practice. Lactic
metformin 41679 acidosis is rather the result of comorbid diseases and the risk of lactic acidosis is similar whether metformin is used or not [[150],[151]]. Metanalysis of nine observational studies demonstrated that metformin
metformin 41779 metformin is used or not [[150],[151]]. Metanalysis of nine observational studies demonstrated that metformin can be safely used in heart failure. In none of the trials metformin increased mortality of patients
metformin 41848 observational studies demonstrated that metformin can be safely used in heart failure. In none of the trials metformin increased mortality of patients with decreased left ventricular ejection fraction, even in those with
metformin 42071 NYHA class of heart failure and patients with chronic kidney failure. The analysis also showed that metformin reduced the risk of all-cause hospitalization and the risk of hospitalization due to heart failure.
metformin 42220 hospitalization and the risk of hospitalization due to heart failure. There was no trial to demonstrate that metformin treatment was associated with a higher risk of lactic acidosis than other antihyperglycemic drugs [[151]].In
metformin 42392 than other antihyperglycemic drugs [[151]].In conclusion, based on experimental and clinical data, metformin therapy in diabetes and concomitant heart failure is not associated with higher risk and the benefits
metformin 42590 the benefits of its usage exceed the potential danger. Moreover, it is increasingly suggested that metformin should be a first choice of treatment in this group of patients [[152],[153]]. Therefore, the revising
metformin 42727 treatment in this group of patients [[152],[153]]. Therefore, the revising of contraindications of metformin use seems to be reasonable.As the cardioprotective properties of metformin are not associated with an
metformin 42802 of contraindications of metformin use seems to be reasonable.As the cardioprotective properties of metformin are not associated with an antihyperglycemic effect, the drug could be also beneficial for patients
metformin 42983 also beneficial for patients with heart failure without concomitant diabetes. Figure 1The impact of metformin on gluconeogenesis. ADP, adenosine diphosphate; ATP, adenosine triphosphate; NADH, nicotinamide adenine
metformin 44365 increase and decrease in the concentration of specific compound, respectively.Figure 4The effect of metformin on apoptosis. Acetyl-CoA, acetyl coenzyme A; acyl-CoA, acyl coenzyme A; AMPK, AMP-activated protein
pioglitazone 3169 events. For example, saxagliptin and alogliptin should be avoided in patients with diabetes and HF and pioglitazone is contraindicated in this population [[6],[7]]. On the other hand, it is suggested that some antihyperglycemic
Select Disease Character Offset Disease Term Instance
diabetes mellitus 644 shows that metformin is an insulin-sensitizing antidiabetic drug widely used in the treatment of type 2 diabetes mellitus (T2DM), which can exert favorable effects on cardiovascular risk and may be safely used in patients
diabetes mellitus 1734 a primary endpoints are necessary.1. IntroductionAs first reported in the Framingham study, type 2 diabetes mellitus (T2DM) is not only an independent risk factor for cardiovascular diseases (CVD), but is also associated
diabetes mellitus 3846 antihyperglycemic drugs and insulin [[9],[10],[11]]. The biguanide derivatives have been implemented to diabetes mellitus treatment in the 1950’s [[12]]. Phenformin and buformin have been withdrawn two decades later due
diabetes mellitus 5313 metformin does not enhance the risk of lactic acidosis, and can be safety used in patients with type 2 diabetes mellitus and early heart failure [[19]]. This review presents the molecular basis of antihyperglycemic mechanism
diabetes mellitus 12918 development of HF in diabetes. The risk of heart failure in T2DM remains higher compared to non-DM ( diabetes mellitus ) individuals after adjustment for other risk factors such as serum cholesterol levels, hypertension,
hyperglycemia 2406 significantly worsens a prognosis in this group of patients. There is a tight positive correlation between hyperglycemia and heart failure development and progression. Diabetic patients have an 8% increase in the risk of
hyperglycemia 15493 attributed to metabolic derangements that accompany T2DM like insulin resistance, hyperinsulinemia, hyperglycemia and dyslipidemia. These perturbations disturb myocardial metabolism and impair endothelial function
hyperglycemia 19594 cardiomyocytes in patients with diabetes arise from toxic action of both high levels of FFA (lipotoxicity) and hyperglycemia (glucotoxicity). Physiologically, at normal work loads in aerobic conditions, the energy is acquired
hyperglycemia 23104 palmitoyltransferase I, that is responsible for transport of FFA into mitochondria [[90],[99]]. In addition, hyperglycemia blocks FFA oxidation at the level of gene expression via inhibiting PPARα (peroxisome proliferator-activated
hyperglycemia 23649 transporters GLUT-1 and GLUT-4 [[83],[100]].Moreover, advanced glycation end products generated during hyperglycemia induces the synthesis of reactive oxygen species that impair the function of ion transporters and mitochondria,
hyperglycemia 24092 disturb conduction of impulses thus results in arrhythmias [[61],[101]]. Oxidative stress caused by hyperglycemia and AGEs contributes to damage of autonomic neurons that regulate contractility of heart and coronary
hyperglycemia 35093 nucleic acids or phospholipids (Figure 5) [[128],[129],[130]]. In diabetes, in addition to sustained hyperglycemia , inflammation, oxidative stress and polyol pathway are also the important processes that can exacerbate
hyperinsulinemia 15475 but can largely be attributed to metabolic derangements that accompany T2DM like insulin resistance, hyperinsulinemia , hyperglycemia and dyslipidemia. These perturbations disturb myocardial metabolism and impair endothelial
hypoglycemia 4794 the risk of death due to diabetes by 42% and the risk of myocardial infarction by 39%. The risk of hypoglycemia was lower for intensive metformin treatment than for intensive treatment with sulfonyloureas or insulin
hypoglycemia 7721 activation of AMPK induced by processes that decrease ATP levels in the cell, such as physical effort, hypoglycemia , ischemia, and hypoxia. AMPK activity can also be stimulated by hormones that regulate energy balance,
lactic acidosis 4002 Phenformin and buformin have been withdrawn two decades later due to frequent cases of life-threatening lactic acidosis [[13],[14],[15]]. Metformin, as a safer, less lipophilic derivative, after 20 years of its use in Europe
lactic acidosis 5249 metformin in this setting. The recent trials demonstrated that metformin does not enhance the risk of lactic acidosis , and can be safety used in patients with type 2 diabetes mellitus and early heart failure [[19]]. This
lactic acidosis 41414 guidelines, metformin should not be used in patients with diabetes and heart failure because of a risk of lactic acidosis . However, the connection between metformin blood level and lactate blood level during lactic acidosis
lactic acidosis 41516 lactic acidosis. However, the connection between metformin blood level and lactate blood level during lactic acidosis is not observed in clinical practice. Lactic acidosis is rather the result of comorbid diseases and
lactic acidosis 41644 observed in clinical practice. Lactic acidosis is rather the result of comorbid diseases and the risk of lactic acidosis is similar whether metformin is used or not [[150],[151]]. Metanalysis of nine observational studies
lactic acidosis 42277 failure. There was no trial to demonstrate that metformin treatment was associated with a higher risk of lactic acidosis than other antihyperglycemic drugs [[151]].In conclusion, based on experimental and clinical data, metformin
obesity 4518 ability of metformin to reduce the risk of macroangiopathy in patients with newly diagnosed diabetes and obesity or overweight, more than sulfonylureas or insulin. In comparison with conventional diet therapy, metformin
type 2 diabetes mellitus 637 evidence shows that metformin is an insulin-sensitizing antidiabetic drug widely used in the treatment of type 2 diabetes mellitus (T2DM), which can exert favorable effects on cardiovascular risk and may be safely used in patients
type 2 diabetes mellitus 1727 patients as a primary endpoints are necessary.1. IntroductionAs first reported in the Framingham study, type 2 diabetes mellitus (T2DM) is not only an independent risk factor for cardiovascular diseases (CVD), but is also associated
type 2 diabetes mellitus 5306 that metformin does not enhance the risk of lactic acidosis, and can be safety used in patients with type 2 diabetes mellitus and early heart failure [[19]]. This review presents the molecular basis of antihyperglycemic mechanism

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