Metformin: An Old Drug with New Applications

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diabetes mellitus 1 endocrinologydiseases
hyperglycemia 6 endocrinologydiseases
hyperinsulinemia 1 endocrinologydiseases
metabolic syndrome 6 endocrinologydiseases
obesity 9 endocrinologydiseases
atorvastatin 1 endocrinologydiseasesdrugs
metformin 136 endocrinologydiseasesdrugs
polycystic ovary syndrome 2 endocrinologydiseases
type 2 diabetes mellitus 1 endocrinologydiseases

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atorvastatin 10508 interleukine-6 (IL-6) were also seen in T2D rats treated for two weeks with a combination of metformin and atorvastatin when compared to metformin monotherapy [[10]]. Taken together, these combination therapies were able
metformin 727 diabetes mellitus for more than 60 years. The United Kingdom Prospective Diabetic Study (UKPDS) has shown metformin to improve mortality rates in diabetes patients, and recent studies suggest metformin has additional
metformin 813 (UKPDS) has shown metformin to improve mortality rates in diabetes patients, and recent studies suggest metformin has additional effects in treating cancer, obesity, nonalcoholic fatty liver disease (NAFLD), polycystic
metformin 1151 antipsychotic medication. Metformin has recently been extensively studied and emerging evidence suggests metformin decreases hepatocyte triglyceride accumulation in NAFLD and prevents liver tumorigenesis. Interestingly,
metformin 1290 triglyceride accumulation in NAFLD and prevents liver tumorigenesis. Interestingly, studies have also shown metformin reduces visceral fat, suppresses white-adipose-tissue (WAT) extracellular matrix remodeling, and inhibits
metformin 1473 matrix remodeling, and inhibits obesity-induced inflammation. However, clinical evidence for using metformin to treat NAFLD, cancer, metabolic syndrome, or to prevent hepatocellular carcinoma in NAFLD patients
metformin 1664 carcinoma in NAFLD patients is lacking. This review therefore addresses the potential beneficial effects of metformin on NAFLD, its role in protecting against cardiac ischemia–reperfusion (I/R) injury, atherosclerosis,
metformin 2270 be safe and is highly cost-effective. Unlike other antidiabetic drugs, when used as a monotherapy, metformin does not have hypoglycemic side effects and has a favorable effect on body weight [[2]]. According to
metformin 2471 According to the American Diabetes Association (ADA) guidelines, of all the antidiabetic medications, metformin is now the recommended first-line treatment for type 2 diabetes (T2D) [[3]]. A reduction in hepatic
metformin 2683 glucose production has been established as the primary contribution to the glucose-reducing effect of metformin ; however, the mechanism of action of this old drug is still not fully understood [[1],[4]]. The United
metformin 2890 United Kingdom Prospective Diabetic Study (UKPDS) observed reduced mortality rates in patients using metformin [[5]]. Furthermore, metformin is one of the few drugs that significantly reduce macrovascular events
metformin 2920 Diabetic Study (UKPDS) observed reduced mortality rates in patients using metformin [[5]]. Furthermore, metformin is one of the few drugs that significantly reduce macrovascular events in diabetes patients when compared
metformin 3479 rheumatic arthritis (RA), have also been shown very recently [[6],[7]]. Emerging evidence suggests metformin may have many other benefits, including reducing endoplasmic reticulum (ER) and oxidative stress, as
metformin 3661 (ER) and oxidative stress, as well as anti-inflammatory properties [[8],[9]]. The diverse effects of metformin could be the result of the interaction of metformin with numerous enzymes, including mitochondrial electron
metformin 3713 anti-inflammatory properties [[8],[9]]. The diverse effects of metformin could be the result of the interaction of metformin with numerous enzymes, including mitochondrial electron transport chain complex I and AMP-activated
metformin 3929 protein kinase (AMPK) [[10]]. This review will address the currently available evidence on the effects of metformin on NAFLD, inflammation, and cardiovascular and pancreatic β-cell dysfunction.2. Metformin Improves
metformin 4718 interventions that have proven to be effective are weight loss and physical activity [[14]]. The benefits of metformin in inhibiting hepatic gluconeogenesis, modifying hepatic fatty acid metabolism (including inhibition
metformin 5022 lipogenesis and enhancing insulin sensitivity are well-established [[4],[15]]. These favorable effects of metformin on liver histology in patients with NAFLD/NASH have been reported in several recent studies [[16],[17],[18]].
metformin 5271 serum Alanine transaminase (ALT) has also been reported [[19]]. However, clinical evidence for using metformin to treat NAFLD is still lacking.2.1 Metformin Decreases Hepatocyte Triglyceride Accumulation and Plasma
metformin 5682 Furthermore, TG accumulation in HepG2 cells induced by hyperglycemia and hyperinsulinemia were attenuated by metformin (3 mM) treatment [[20]]. Finally, hepatic and plasma TG in obese mice were also reduced by metformin
metformin 5783 metformin (3 mM) treatment [[20]]. Finally, hepatic and plasma TG in obese mice were also reduced by metformin treatment in a dose-dependent manner [[21],[22]].The underlying mechanism of hepatic and plasma TG reduction
metformin 5912 dose-dependent manner [[21],[22]].The underlying mechanism of hepatic and plasma TG reduction following metformin treatment has been reported by several studies. Apolipoprotein A5 (ApoA5) plays a key role in regulating
metformin 6259 has been positively correlated with hepatocyte TG in obese mice [[22]]. Four weeks of treatment with metformin (50 or 100 mg/kg) also reduces hepatocyte ApoA5 expression in obese mice [[21],[22]]. Interestingly,
metformin 6440 mice [[21],[22]]. Interestingly, hepatic TG reduction induced by ApoA5 knockdown is further reduced by metformin treatment [[22]], suggesting the involvement of ApoA5 in metformin’s effect. Liver X receptor α (LXRα)
metformin 6507 knockdown is further reduced by metformin treatment [[22]], suggesting the involvement of ApoA5 in metformin ’s effect. Liver X receptor α (LXRα) is a transcription factor that plays an important role in the
metformin 7031 LXRα through siRNA significantly diminished the downregulation of cellular ApoA5 expression induced by metformin treatment [[22]]. Taken together, metformin reduces hepatic TG accumulation through the inhibition of
metformin 7075 downregulation of cellular ApoA5 expression induced by metformin treatment [[22]]. Taken together, metformin reduces hepatic TG accumulation through the inhibition of hepatic ApoA5 synthesis, which is partially
metformin 7304 the AMPK/LXRα signaling pathway (Table 1 and Figure 1).Inhibition of hepatocyte lipid synthesis by metformin may contribute to the reduction of TG accumulation [[20],[23]]. Stearyl-coenzyme A desaturase 1 (SCD1)
metformin 7707 [[20]]. Metformin has been observed to decrease the expression of SCD1; furthermore, the effect of metformin on decreasing TG accumulation is reduced when SCD1 is overexpressed in HepG2 cells [[20]]. Thus, inhibition
metformin 7872 overexpressed in HepG2 cells [[20]]. Thus, inhibition of SCD1 partially contributes to the effect of metformin in reducing hepatic lipid synthesis.The underlying mechanisms of metformin in lowering plasma triglycerides
metformin 7947 contributes to the effect of metformin in reducing hepatic lipid synthesis.The underlying mechanisms of metformin in lowering plasma triglycerides were studied in APOE*3-Leiden CETP mice, which offer a well-established
metformin 8331 very-low-density lipoprotein (VLDL)-TG, and lowered hepatic lipid composition [[24]]. Interestingly, metformin selectively elevated glycerol tri[(3)H]oleate-labeled VLDL-like emulsion-particle clearance by brown
metformin 8521 emulsion-particle clearance by brown adipose tissue (BAT), suggesting elevation of BAT VLDL-TG clearance induced by metformin significantly contributed to the reduced plasma TG levels in mice [[24]] (Table 1).2.2. Combination
metformin 9020 the AMPK signal pathway [[29]]. L-leucine, an allosteric Sirt1 activator, combined with low doses of metformin or sildenafil were able to reverse mild NAFLD in mouse models via the AMPK-eNOS-Sirt1 pathway [[26]].
metformin 9162 reverse mild NAFLD in mouse models via the AMPK-eNOS-Sirt1 pathway [[26]]. A combination of sildenafil– metformin –leucine has been shown to reduce inflammatory markers in vitro, increase hepatic fatty acid oxidation,
metformin 9721 ballooning and triglyceride accumulation were completely reversed after the combination of sildenafil– metformin –leucin therapy [[26]].The combination of L-cysteine and metformin have also been shown to suppress
metformin 9789 the combination of sildenafil–metformin–leucin therapy [[26]].The combination of L-cysteine and metformin have also been shown to suppress HFD-induced insulin resistance in streptozotocin-induced T2D rats [[30]].
metformin 10060 (FFAs), oxidative stress and inflammatory markers, caspase-3, and cytochrome c levels were detected with metformin monotherapy in T2D rats compared to controls, and a combination of L-cysteine and metformin therapy
metformin 10152 detected with metformin monotherapy in T2D rats compared to controls, and a combination of L-cysteine and metformin therapy led to even greater improvements in these domains [[30]].Greater improvements of liver histology,
metformin 10494 TNF-α, and interleukine-6 (IL-6) were also seen in T2D rats treated for two weeks with a combination of metformin and atorvastatin when compared to metformin monotherapy [[10]]. Taken together, these combination therapies
metformin 10538 in T2D rats treated for two weeks with a combination of metformin and atorvastatin when compared to metformin monotherapy [[10]]. Taken together, these combination therapies were able to increase the therapeutic
metformin 10662 [[10]]. Taken together, these combination therapies were able to increase the therapeutic efficacy of metformin in the treatment of NAFLD and NASH better than monotherapy in animal models. However, clinical studies
metformin 11182 mechanism is likely associated with the suppression of adipose-tissue inflammation [[12]]. However, metformin (250 mg/kg/d) failed to protect against HFD-induced liver tumorigenesis in mice following the development
metformin 11353 tumorigenesis in mice following the development of NAFLD [[12]]. This suggests early intervention with metformin to suppress liver-fat accumulation prior to the onset of NAFLD, thus delaying adipose inflammation,
metformin 11561 inflammation, may help to prevent HFD-induced liver tumorigenesis [[12]]. However, clinical evidence supporting metformin ’s ability to modify the risk of HCC in NAFLD/NASH patients has not been reported. The effects of metformin
metformin 11670 metformin’s ability to modify the risk of HCC in NAFLD/NASH patients has not been reported. The effects of metformin on NAFLD and potential mechanisms involved are summarized in Table 1.3. Metformin Has a Beneficial Effect
metformin 12021 Visceral fat mass is an important factor that contributes to the development of metabolic syndrome, and metformin has been shown to significantly reduce visceral fat mass in mice [[31]]. Furthermore, a clinical study
metformin 12188 in mice [[31]]. Furthermore, a clinical study conducted on the Chinese population demonstrated that metformin monotherapy for 24 weeks resulted in significant weight loss, reductions in body fat mass, and better
metformin 12677 alanine-aminotransferase concentrations and serum aspartate-aminotransferase concentrations [[32]]. It is recognized that metformin -induced intracellular TG lipolysis and fatty acid oxidation contribute to its beneficial effect on energy
metformin 13449 protein-1 (UCP-1) in BAT and uncoupling protein-3 (UCP-3) in skeletal muscle were upregulated after metformin treatment (1500 mg/day) [[31]]. Furthermore, uptake of the murine interscapular BAT depot was detected
metformin 13591 Furthermore, uptake of the murine interscapular BAT depot was detected following injection of [11C]- metformin , confirming metformin’s ability to target BAT in vivo [[24],[34]].Metformin has also been shown to
metformin 13613 the murine interscapular BAT depot was detected following injection of [11C]-metformin, confirming metformin ’s ability to target BAT in vivo [[24],[34]].Metformin has also been shown to attenuate weight gain
metformin 13911 olanzapine, a first-line treatment for schizophrenia. One study has shown that, after two weeks of metformin treatment, WAT accumulation and weight gain induced by olanzapine were significantly attenuated in patients
metformin 14051 and weight gain induced by olanzapine were significantly attenuated in patients [[35]]. Additionally, metformin salvaged BAT that would have been lost due to olanzapine treatment [[35]]. This evidence further indicates
metformin 14236 This evidence further indicates that upregulation of adaptive thermogenesis is a mechanism by which metformin reduces visceral fat. Additionally, gene-expression analysis showed metformin was able to modify the
metformin 14314 a mechanism by which metformin reduces visceral fat. Additionally, gene-expression analysis showed metformin was able to modify the expression of multiple key energy expenditures [[35]]. Hence, metformin may reduce
metformin 14409 showed metformin was able to modify the expression of multiple key energy expenditures [[35]]. Hence, metformin may reduce visceral fat and improve energy metabolism by upregulating adaptive thermogenesis [[31]]
metformin 15485 was expressed in primary cells of the stromal vascular fraction [[36]]. This evidence suggests that metformin reduces ECM remodeling in WAT through the inhibition of TGF-β1 signaling, which is AMPK-dependent [[36]].
metformin 15628 through the inhibition of TGF-β1 signaling, which is AMPK-dependent [[36]]. The beneficial effects of metformin on energy metabolism and WAT remodeling are summarized in Table 2.4. Metformin Suppresses Inflammation4.1.
metformin 15869 Adipocyte InflammationReduction of adipose inflammation has been shown to contribute to the ability of metformin to improve obesity-associated metabolic dysregulation [[37]]. However, the underlying mechanism is still
metformin 16406 (proinflammatory), which is associated with the development of metabolic syndrome [[40]]. One recent study indicates metformin reduces proinflammatory-cytokine production through inhibition of M1 macrophages and an elevation of
metformin 16603 elevation of the M2 (anti-inflammatory) macrophages [[41]]. Hence, the anti-inflammatory effect of metformin may be related to activation of anti-inflammatory macrophage polarization.Suppression of lipopolysaccharide
metformin 16873 Kinase (JNK) p46 and reduction of cytokine release, including interleukin-1β (IL-1β) and TNFα, after metformin (50 µM) treatment has also been reported in differentiated 3T3-L1 in vitro [[37]]. Metformin also increased
metformin 17245 when PFKFB3/iPFK2 was knocked down [[37]], thus suggesting LPS-induced inflammation is inhibited by metformin through PFKFB3/iPFK2 signaling.4.2. Metformin Suppresses Obesity Induced Inflammation in Liver and MacrophagesFindings
metformin 17439 Inflammation in Liver and MacrophagesFindings have been inconsistent regarding the anti-inflammatory effect of metformin on the liver during obesity. Short-term treatment (10 days) with metformin suppressed accumulation of
metformin 17514 anti-inflammatory effect of metformin on the liver during obesity. Short-term treatment (10 days) with metformin suppressed accumulation of lipids in the livers of obese mice, but induced inflammatory markers. Elevation
metformin 17828 the concentration of IL-1β and IL-6 in a hepatocyte culture medium, was detected after short-term metformin treatment [[31]]. In contrast, long-term (four-week) treatment with metformin (150 mg/kg/d) was found
metformin 17906 detected after short-term metformin treatment [[31]]. In contrast, long-term (four-week) treatment with metformin (150 mg/kg/d) was found to reduce inflammation in the liver of HFD-fed obese mice [[15],[32]]. Similar
metformin 18056 inflammation in the liver of HFD-fed obese mice [[15],[32]]. Similar to the findings in adipocyte tissue, metformin decreased the phosphorylation of c-JNK-1, reduced fat deposition as well as hepatocyte-proinflammatory
metformin 18290 association with enhanced AMPK phosphorylation, and decreased fat deposition after long-term treatment with metformin [[15],[32]]. Hence, the anti-inflammatory effect of metformin in the liver may require longer duration
metformin 18352 deposition after long-term treatment with metformin [[15],[32]]. Hence, the anti-inflammatory effect of metformin in the liver may require longer duration of treatment to achieve positive results.Bone marrow-derived
metformin 18505 treatment to achieve positive results.Bone marrow-derived macrophages have also been assessed, and metformin partially suppressed LPS-induced phosphorylation of JNK1 and nuclear factor kappa B (NF-κB) p65, along
metformin 18906 macrophage-culture medium [[31]].In summary, reduction of the obesity-induced inflammatory response following metformin treatment may act through different mechanisms in different tissues. Multiple pathways are involved
metformin 19051 mechanisms in different tissues. Multiple pathways are involved in the anti-inflammatory effect of metformin in adipose tissue, including modification of macrophage polarization towards an M2 phenotype, inhibition
metformin 19266 of the c-Junk pathway, and upregulation of PFKFB3/iPFK2 (Table 3). The anti-inflammatory effects of metformin in hepatocytes and macrophages may act through inhibition of the JNK pathway, but longer duration of
metformin 20087 in Clinical TrialsResults of several clinical trials suggest a cardiovascular protective effect of metformin in individuals with CVD [[45],[46],[47]]. UKPDS revealed reduced macrovascular complications that were
metformin 20248 revealed reduced macrovascular complications that were independent from the glucose-lowering effect of metformin [[5]]. The risk of developing nonfatal MI in diabetes patients treated with metformin was reduced by
metformin 20334 glucose-lowering effect of metformin [[5]]. The risk of developing nonfatal MI in diabetes patients treated with metformin was reduced by 39% [[5]]. Importantly, the protective effects of metformin were observed even in the
metformin 20409 diabetes patients treated with metformin was reduced by 39% [[5]]. Importantly, the protective effects of metformin were observed even in the 10-year post-trial monitoring in patients who survived to the end of the UKPDS
metformin 20624 [[48]]. Another recent large double-blind randomized trial evaluated the cardiometabolic effects of metformin in overweight or obese type 1 diabetes adult patients who had high CVD risk. Reductions in body weight,
metformin 20965 observed in that population [[49]]. A recent cohort study of older U.S. veterans with T2D also showed that metformin reduced CVD events among individuals with T2D [[50]]. These findings indicate the potential role of
metformin 21075 reduced CVD events among individuals with T2D [[50]]. These findings indicate the potential role of metformin for decreasing CVD risk, and evidence suggests that a combination therapy of metformin with statins
metformin 21162 potential role of metformin for decreasing CVD risk, and evidence suggests that a combination therapy of metformin with statins has an even more favorable effect on CVD comorbidity in T2D patients [[10]].5.2. Metformin
metformin 21827 size and improved survival rates following MI in human subjects and animal models were observed after metformin treatment [[52]]. Even a single low-dose (125 µg/kg) therapy in nondiabetic and diabetic mice has demonstrated
metformin 22022 diabetic mice has demonstrated a protective effect after MI [[52]]. Several studies have suggested that metformin protects against cardiac IRI through the activation of AMPK [[52],[53],[54]]. Activation of AMPK promotes
metformin 22437 increased phosphorylation of eNOS, resulting in nitric oxide (NO) production. This evidence suggests metformin protects the heart against IRI through AMPK–eNOS signaling [[52],[53]]. Finally, metformin has been
metformin 22530 suggests metformin protects the heart against IRI through AMPK–eNOS signaling [[52],[53]]. Finally, metformin has been observed to reduce myocardial injury after ischemia through restoration of depleted PGC-1α
metformin 22720 of depleted PGC-1α levels and increased mitochondrial biogenesis [[53]].The beneficial effects of metformin on the heart have been observed in patients with and without heart failure [[54]]. Decreased left-ventricular
metformin 22956 improvement of left-ventricular ejection fraction were detected in MI patients after twelve weeks of metformin treatment in subjects without diabetes, and is associated with decreased atrial natriuretic peptide
metformin 23080 subjects without diabetes, and is associated with decreased atrial natriuretic peptide [[54]]. Thus, metformin may attenuate cardiac remodeling and slow heart-failure development post-MI [[54]].5.3. Metformin Attenuates
metformin 23751 protein (CHOP) content in the cytosol and nucleus of myocardial cells [[55]]. The concentration of metformin in the mitochondria and the ER was found to be dependent on membrane potential [[56]]. In summary, metformin
metformin 23860 in the mitochondria and the ER was found to be dependent on membrane potential [[56]]. In summary, metformin reduced cardiac injury during ER stress through the protection of cardiac mitochondria and attenuation
metformin 24379 correlated even with recently and newly diagnosed T2D patients [[57]]. An antiatherogenic effect of metformin has been shown in previous studies [[59],[60]], and, importantly, improvement of endothelial dysfunction
metformin 24499 shown in previous studies [[59],[60]], and, importantly, improvement of endothelial dysfunction with metformin treatment in newly diagnosed T2D patients has been detected [[57]]. However, the underlying mechanisms
metformin 24907 cells [[61]]. Superoxide production and fragmentation of mitochondria were markedly suppressed after metformin therapy. Furthermore, suppression of atherosclerotic lesions was detected in streptozotocin (STZ)-induced
metformin 25059 atherosclerotic lesions was detected in streptozotocin (STZ)-induced diabetic ApoE−/− mice following metformin treatment [[61]]. In contrast, the protective effects of metformin on Drp1 expression, oxidative stress,
metformin 25126 diabetic ApoE−/− mice following metformin treatment [[61]]. In contrast, the protective effects of metformin on Drp1 expression, oxidative stress, and atherosclerosis were ablated when AMPK-α2 was knocked out
metformin 25294 were ablated when AMPK-α2 was knocked out in diabetic ApoE−/−/AMPK-α2−/− mice, suggesting metformin exerts antiatherosclerotic action in vivo via the AMPK-mediated blockage of Drp1-mediated mitochondrial
metformin 26085 essential role in mitochondrial respiration and oxidative phosphorylation [[64]]. One study has shown that metformin directly inhibits both isolated complex I in intact cells and purifiedcomplex I [[64]]. Inhibition of
metformin 26236 in intact cells and purifiedcomplex I [[64]]. Inhibition of mitochondrial respiratory complex I by metformin is therefore suggested as one of the therapeutic targets as well as inhibition of mitochondrial ATP
metformin 26407 well as inhibition of mitochondrial ATP synthase [[64]].Inhibition of atherosclerosis progression by metformin has also been demonstrated recently in an atherogenic diet-induced rabbit atherosclerotic model [[65]].
metformin 27341 and FOXO1 [[66]]. However, inhibition of AMPK partially diminished these protective effects. Hence, metformin protects against high glucose-induced endothelial cell dysfunction and exerts vascular protective effects
metformin 27589 FOXO1, a mechanism that is partially dependent on AMPK activation [[66]].In conclusion, the role of metformin in treating macrovascular complications in patients with T2D is well-established. Emerging evidence
metformin 27709 treating macrovascular complications in patients with T2D is well-established. Emerging evidence indicates metformin inhibits atherosclerosis progression and improves endothelial dysfunction through multiple pathways,
metformin 28002 ChREBP and FOXO1 in an AMPK-dependent manner. Endothelial mitochondria are likely a major target of metformin , and through its inhibition of respiratory complex I, PKC-NAD (P) H oxidase, and ATP synthase, metformin
metformin 28107 metformin, and through its inhibition of respiratory complex I, PKC-NAD (P) H oxidase, and ATP synthase, metformin is able to exert vascular protective effects. These cardiovascular protective effects of metformin,
metformin 28206 metformin is able to exert vascular protective effects. These cardiovascular protective effects of metformin , and the potential mechanisms involved, are summarized in Table 4.5.5. Metformin Suppresses Angiotensin
metformin 28429 II-Induced ER Stress and HypertensionAntihypertensive effects have been observed in diabetic patients taking metformin [[67]]; however, the underlying mechanism is unclear. One possible mechanism is the inhibition of Angiotensin
metformin 28713 of ER stress markers in Angiotensin II-infused wild-type (WT) mice were significantly suppressed by metformin (300 mg/kg) treatment; however, metformin lost its protective effect in reducing ER stress makers in
metformin 28755 II-infused wild-type (WT) mice were significantly suppressed by metformin (300 mg/kg) treatment; however, metformin lost its protective effect in reducing ER stress makers in AMPKα2-deficient mice [[67]]. It is therefore
metformin 28883 protective effect in reducing ER stress makers in AMPKα2-deficient mice [[67]]. It is therefore likely that metformin inhibits angiotensin II-induced ER stress in vascular smooth muscle cells and suppresses angiotensin
metformin 29052 smooth muscle cells and suppresses angiotensin II-induced hypertension by activating AMPKα2.In summary, metformin has demonstrated cardiovascular protective effects via reduction of cardiac IRI, attenuation of cardiac
metformin 30064 plasma chylomicrons by 50%, and chylomicron-remnant lipoprotein fractions by 20% [[70]], suggesting metformin is able to improve intestinal lipoprotein metabolism. Metformin has been found to affect both intestinal
metformin 30281 and liver tissues resulting in decreased plasma triglycerides, LDL-C, and total cholesterol. However, metformin ’s effects on lipid metabolism seems to be localized to the intestine [[10]].A slight improvement of
metformin 30470 slight improvement of intestinal lipid homeostasis was observed in obese T2D patients treated with metformin in association with a decrease in mRNA expression of sterol regulatory element-binding protein 1 (SREBP-1c),
metformin 30918 insulin upregulates the expression of SREBP-1c, though it can be inhibited by AMPK. In conclusion, metformin , which improves intestinal lipoprotein metabolism and inhibition of SREBP-1C, which reduces fatty acid
metformin 31872 diabetes [[72],[73]].7.1. Metformin Reduces Compensatory Pancreatic β-Cell HyperplasiaThe effect of metformin on high-glucose-induced pancreatic β-cell hyperplasia remains controversial. HFD-triggered adaptive
metformin 32047 controversial. HFD-triggered adaptive pancreatic β-cell replication was suppressed by eight weeks of metformin treatment [[73]]. However, after sixty weeks of HFD feeding, increased β-cell mass was not suppressed
metformin 32233 β-cell mass was not suppressed [[73]]. High-glucose-induced β-cell proliferation was also inhibited by metformin in both islets and INS-1 cells [[73]]. However, the underlying mechanism of metformin on reducing pancreatic
metformin 32319 inhibited by metformin in both islets and INS-1 cells [[73]]. However, the underlying mechanism of metformin on reducing pancreatic β-cell hyperplasia is still unknown. In summary, metformin can directly suppress
metformin 32402 underlying mechanism of metformin on reducing pancreatic β-cell hyperplasia is still unknown. In summary, metformin can directly suppress β-cell proliferation induced by HFD and high glucose.7.2. Metformin Protects
metformin 33085 Intracellular ROS production and CD36 expression, induced by high glucose, were significantly inhibited after metformin (0.5 mM) treatment. In addition, CD36 activation by sulfa-N-succinimidyl oleate (SSO) significantly
metformin 33287 significantly decreased the apoptotic response in high glucose-treated INS-1 cells [[74]]. In conclusion, metformin is able to protect against glucotoxicity-induced ROS production and inhibits the CD36-mediated free
metformin 33911 (p-EIF2α), CHOP, and cleaved caspase 3, but their levels were normalized in the presence of 25 µM metformin [[75]]. This suggests metformin is able to improve chronic fatty acid exposure-induced pancreatic β-cell
metformin 33943 caspase 3, but their levels were normalized in the presence of 25 µM metformin [[75]]. This suggests metformin is able to improve chronic fatty acid exposure-induced pancreatic β-cell dysfunction. This suggests
metformin 34054 is able to improve chronic fatty acid exposure-induced pancreatic β-cell dysfunction. This suggests metformin is able to improve pancreatic β-cell function following chronic fatty acid exposure, as well as protect
metformin 34589 Forty-six gut microbes have been found to be significantly changed after 30 days of treatment with metformin (200 mg/kg body weight) in healthy mice [[77]]. Particularly, the diversity of gut microbiota was
metformin 34960 modulation of the gut microbiota may be one of the mechanisms contributing to the antidiabetic effects of metformin [[76]].9. ConclusionsMetformin, an old drug with magical roles, has drawn much attention in recent years
metformin 35387 vascular, pancreas, and bones (as shown in Figure 1). These diverse effects may due to the action of metformin on several enzymes located in the mitochondria and ER, as AMPK is one of the primary therapeutic targets
metformin 35798 adaptive thermogenesis, inhibiting lipid synthesis, and promoting fatty acid oxidation. Furthermore, metformin prevents glucotoxicity-induced pancreatic β-cell dysfunction via reduction of ROS and CD36-mediated
metformin 36655 are unclear. Future large-scale clinical trials with longer durations to assess the effectiveness of metformin in reducing HCC risks are needed. Liver biopsy is still the current gold standard for diagnosis of NASH
metformin 36942 are lacking. Although combination therapies have shown more favorable effects in treating NAFLD than metformin monotherapy in animal models, more clinical studies are needed to address therapeutic efficacy before
metformin 37219 therapy would reverse mild NAFLD is still unclear.Hence, although there are many putative applications of metformin in an enormous spectrum of diseases, many mechanisms remain to be elucidated. More clinical evidence
metformin 37378 mechanisms remain to be elucidated. More clinical evidence is needed before the therapeutic application of metformin can be extended to treat those diseases outside of diabetes.Figure 1Potential underlying molecular mechanisms
metformin 37511 treat those diseases outside of diabetes.Figure 1Potential underlying molecular mechanisms of action of metformin on NAFLD, atherosclerosis, oxidative stress, and pancreatic β-cell dysfunction (dotted arrows: inhibition,
metformin 38321 production reducedBAT VLDL-TG clearance increasedijms-19-02863-t002_Table 2Table 2Beneficial effects of metformin on energy metabolism and white-adipose-tissue (WAT) remodeling.TissuesMetformin Effects and MechanismsSubjectsReferenceBATUCP-1
metformin 39126 macrophage polarizationMice[[41]]ijms-19-02863-t004_Table 4Table 4Cardiovascular protective effect of metformin .TissueMetformin Effects and MechanismSubjectsReferencesVascular smooth muscle cellsInfarct size smallerSprague–Dawley
Select Disease Character Offset Disease Term Instance
diabetes mellitus 621 date (collection): 10/2018AbstractMetformin is a biguanide drug that has been used to treat type 2 diabetes mellitus for more than 60 years. The United Kingdom Prospective Diabetic Study (UKPDS) has shown metformin to
hyperglycemia 5628 high-fat diet (HFD) in vivo and in vitro [[20]]. Furthermore, TG accumulation in HepG2 cells induced by hyperglycemia and hyperinsulinemia were attenuated by metformin (3 mM) treatment [[20]]. Finally, hepatic and plasma
hyperglycemia 19731 subjects without diabetes [[33]]. Although current antidiabetic medication is highly effective in treating hyperglycemia , T2D remains a high risk factor for cardiovascular disease (CVD). Furthermore, CVD-related morbidity
hyperglycemia 25486 Drp1-mediated mitochondrial fission [[61]].Several biochemical pathways have been found to be involved in hyperglycemia -induced reactive oxygen species (ROS) production in endothelial cells [[62]]. Among these, PKC-dependent
hyperglycemia 25721 NAD (P) H oxidase is one of the major sources [[63]]. Metformin (10 µM) has been observed to prevent hyperglycemia -induced oxidative stress through inhibition of the PKC-NAD(P)H oxidase pathway in cultured human endothelial
hyperglycemia 27158 human aortic endothelial cells [[66]]. Metformin (final dose of 150 mg/kg/day) was able to attenuate hyperglycemia -induced TXNIP expression and reduce the nuclear entry rate of ChREBP and FOXO1 [[66]]. However, inhibition
hyperglycemia 31296 resistance are characteristics of T2D. It is known that oxidative stress and inflammation result from hyperglycemia and eventually lead to impaired insulin secretion and increased apoptosis in β-cells [[71]]. In addition,
hyperinsulinemia 5646 vivo and in vitro [[20]]. Furthermore, TG accumulation in HepG2 cells induced by hyperglycemia and hyperinsulinemia were attenuated by metformin (3 mM) treatment [[20]]. Finally, hepatic and plasma TG in obese mice were
metabolic syndrome 955 treating cancer, obesity, nonalcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and metabolic syndrome . Metformin has also been shown to alleviate weight gain associated with antipsychotic medication. Metformin
metabolic syndrome 1507 obesity-induced inflammation. However, clinical evidence for using metformin to treat NAFLD, cancer, metabolic syndrome , or to prevent hepatocellular carcinoma in NAFLD patients is lacking. This review therefore addresses
metabolic syndrome 3268 treating cancer, obesity, nonalcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and metabolic syndrome [[4]]. Furthermore, antiaging and bone-protective effects, especially in the first stages of rheumatic
metabolic syndrome 11997 metabolism [[31]]. Visceral fat mass is an important factor that contributes to the development of metabolic syndrome , and metformin has been shown to significantly reduce visceral fat mass in mice [[31]]. Furthermore,
metabolic syndrome 16352 polarization toward the M1 phenotype (proinflammatory), which is associated with the development of metabolic syndrome [[40]]. One recent study indicates metformin reduces proinflammatory-cytokine production through inhibition
metabolic syndrome 34450 emerging evidence suggests that gut microbiota are an important factor in mediating the development of metabolic syndrome and T2D [[76],[77]]. Forty-six gut microbes have been found to be significantly changed after 30 days
obesity 866 diabetes patients, and recent studies suggest metformin has additional effects in treating cancer, obesity , nonalcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and metabolic syndrome.
obesity 1406 reduces visceral fat, suppresses white-adipose-tissue (WAT) extracellular matrix remodeling, and inhibits obesity -induced inflammation. However, clinical evidence for using metformin to treat NAFLD, cancer, metabolic
obesity 3179 [[2],[5]]. In addition, it may also be effective in a number of other applications, such as treating cancer, obesity , nonalcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and metabolic syndrome
obesity 4520 hepatopathy” [[13]]. Unfortunately, the prevalence of NAFLD and NASH are increasing due to the epidemics of obesity and diabetes. There is currently no established therapy for NAFLD/NASH. The only interventions that
obesity 14801 extracellular-matrix (ECM) remodeling, which has been recognized as an indicator of metabolic dysregulation in obesity [[36]]. In obese human subjects, WAT fibrosis is associated with AMPK inactivation, adipocyte apoptosis,
obesity 15890 InflammationReduction of adipose inflammation has been shown to contribute to the ability of metformin to improve obesity -associated metabolic dysregulation [[37]]. However, the underlying mechanism is still not well-understood.
obesity 16218 in removing dead adipocytes [[38]]. ATMs are significantly increased in both humans and mice during obesity [[39]] with a concomitant polarization toward the M1 phenotype (proinflammatory), which is associated
obesity 17469 MacrophagesFindings have been inconsistent regarding the anti-inflammatory effect of metformin on the liver during obesity . Short-term treatment (10 days) with metformin suppressed accumulation of lipids in the livers of obese
obesity 18858 IL-6, and TNF-α stimulated by LPS in a macrophage-culture medium [[31]].In summary, reduction of the obesity -induced inflammatory response following metformin treatment may act through different mechanisms in
polycystic ovary syndrome 917 metformin has additional effects in treating cancer, obesity, nonalcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and metabolic syndrome. Metformin has also been shown to alleviate weight gain associated with
polycystic ovary syndrome 3230 of other applications, such as treating cancer, obesity, nonalcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and metabolic syndrome [[4]]. Furthermore, antiaging and bone-protective effects, especially
type 2 diabetes mellitus 614 9/2018Publication date (collection): 10/2018AbstractMetformin is a biguanide drug that has been used to treat type 2 diabetes mellitus for more than 60 years. The United Kingdom Prospective Diabetic Study (UKPDS) has shown metformin to

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