Two-way ANOVA differences between GRos and GMetf compared to GC. GC indicates control group; GMetf, metformin group; GRos, rosuvastatin group. Finally, Figure 4 shows the change in oxidative stress markers for each group. The activities of GSH and GPx were both significantly reduced and SOD activity significantly increased by the GRos and GMetf treatments.

Figure 4. Modification of markers of oxidative stress after 12 weeks of treatment. Statins inhibitors of HMG-CoA reductase can induce large reductions in the concentration of plasma lipids; they are therefore the treatment of choice for patients with hypercholesterolemia or high LDL-C concentrations.

In the present work no patient reported any adverse event attributable to rosuvastatin, nor were any changes seen in the liver enzymes that might indicate a modification of hepatic function.

The mechanism of action of this drug and of the statins in general involves the reduction of TC and LDL-C via the inhibition of hepatic cholesterol synthesis, and by increasing the expression of liver LDL-C receptors that favor the capture of this compound.

An interesting finding was the moderate loss of body weight 2. This is thought to be the first report associating statin treatment with such weight loss. It may be that by reducing the serum lipid concentration sensitivity to insulin is improved. In patients with HBP and dyslipidemia it is common that a reduction in insulin resistance be accompanied by weight loss.

Although it has been reported that metformin can reduce plasma lipid values, in the present study no significant differences in serum lipid values were seen in the group treated with this drug. In agreement, Kiayias et al 25 reported metformin to have no effect on plasma lipid levels.

The main metabolic effect of metformin is the improvement in sensitivity to insulin of the liver and peripheral tissues. The beneficial effect of metformin in terms of the reduction of body weight and of pro-insulin-like molecules has been reported.

High blood pressure is reported to promote the endothelial expression of cytokines such as IL-6 and TNFα, which mediate the amplification of proinflammatory signals 33 and participate in the development of atherosclerosis.

In the present work, the administration of rosuvastatin or metformin significantly reduced serum IL-6 and TNFα concentrations. The reduction of these inflammation markers is probably due to a reduction in the activity of nuclear factor kappa B NF-κB and an increase in the activity of the protein Akt as seen in monocyte cultures.

It is known that in patients with HBP, hyperglycemia, and dyslipidemia increase oxidative stress. In the present study, treatment with rosuvastatin or metformin led to a reduction of this stress. This might be explained by a direct effect of these drugs on the suppression of NF-κB, thus reducing inflammation and the production of reactive oxygen species, 41,43,44 or by their regulating the activity of SOD, which would help protect against oxidative stress.

This study has several limitations. For example, body composition was not measured by bioimpedance; therefore while the results indicate that rosuvastatin and metformin have a beneficial effect on body weight, it is not certain that this is due to the loss of fat.

In addition, serum insulin concentrations were not recorded ­ this hormone has a known anti-inflammatory effect. Rosuvastatin and metformin significantly reduce inflammation and oxidative stress, and may therefore offer a protective effect against cardiovascular disease.

Some of their pleiotropic effects are thus made manifest in the present results. Long-term clinical trials are needed to determine whether rosuvastatin and metformin can continue to reduce the cardiovascular risk caused by oxidative stress and inflammation in this type of patient.

This work was funded by the Fondo de Fomento a la Investigación FOFOI, project N o. Correspondence: Dr. Gómez García. Madero Poniente, Centro. CP Morelia. Received April 5, Accepted for publication September 10, Revista Española de Cardiología English Edition follows the Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals.

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ISSN: Call for papers. Translational research Submit an article. Previous article Next article. Issue Pages December Léalo en español. More article options. Rosuvastatin and Metformin Decrease Inflammation and Oxidative Stress in Patients With Hypertension and Dyslipidemia.

Rosuvastatina y metformina reducen la inflamación y el estrés oxidativo en pacientes con hipertensión y dislipemia. Download PDF. Anel Gómez-García a , Gloria Martínez Torres b , Luz E Ortega-Pierres c , Ernesto Rodríguez-Ayala b , Cleto Álvarez-Aguilar d.

a Centro de Investigación Biomédica de Michoacán, Instituto Mexicano del Seguro Social, Morelia, Michoacán, México. b Unidad de Investigación en Epidemiología Clínica, Hospital General Regional No. c Facultad de Ciencias Médicas y Biológicas Dr.

Ignacio Chávez, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, Michoacán, México. d Unidad de Investigación Médica en Enfermedades Nefrológicas, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México DF, México. This item has received.

Article information. Progress of patients through the study process.. TABLE 1. Baseline Clinical and Biochemical Characteristics of the Patients. TABLE 2. Markers of Inflammation and Concentration of Oxidative Stress Enzymes at the Beginning of Treatment.

HDL-C indicates high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides..

GC indicates control group; GMetf, metformin group; GRos, rosuvastatin group.. Show more Show less. Introduction and objectives. Both hypertension and dyslipidemia raise the risk of cardiovascular disease because they have proinflammatory effects and increase oxidative stress.

The aim of this study was to evaluate the effects of rosuvastatin and metformin on inflammation and oxidative stress in patients with hypertension and dyslipidemia. This open parallel-group clinical study involved 48 patients with hypertension and dyslipidemia.

The following variables were recorded during the study: age, weight, body mass index, blood pressure, glucose, total cholesterol, low-density lipoprotein LDL cholesterol, high-density lipoprotein HDL cholesterol, triglycerides, interleukin-6 IL-6 , tumor necrosis factor-alpha TNFα , glutathione reductase GSH , glutathione peroxidase GPx , and superoxide dismutase SOD.

Pharmacological treatment with either rosuvastatin or metformin lead to reductions in IL-6, TNFα, GSH and GPx levels and an increase in the SOD level, and there were significant interactions between the two treatment groups for these variables.

Rosuvastatin improved the lipid profile. Moreover, both rosuvastatin and metformin reduced inflammation and oxidative stress. These results demonstrate the presence of an additional cardioprotective effect, which may result from a direct mechanism of action or be a pleiotropic effect.

Further long-term studies are required to determine whether rosuvastatin or metformin can be used to decrease the cardiovascular risk resulting from oxidative stress and inflammation.. Oxidative stress. Introducción y objetivos. La hipertensión arterial HTA y la dislipemia incrementan el riesgo de enfermedad cardiovascular a través de los efectos proinflamatorios y el estrés oxidativo.

Nuestro objetivo fue estimar el efecto de la rosuvastatina y la metformina en la inflamación y el estrés oxidativo en pacientes con HTA y dislipemia. En un ensayo clínico abierto paralelo, se estudió a 48 pacientes con HTA y dislipemia.

Las variables analizadas durante el estudio fueron edad, peso, índice de masa corporal IMC , presión arterial, glucosa, colesterol total CT , de las lipoproteínas de baja densidad cLDL y de las lipoproteínas de alta densidad cHDL , triglicéridos TG , interleucina 6 IL-6 , factor de necrosis tumoral alfa TNFα , glutatión reductasa GSH , glutatión peroxidasa GPx y superóxido dismutasa SOD.

Después del tratamiento farmacológico con rosuvastatina o metformina, se encontró disminución e interacción entre grupos en la IL-6, el TNFα, la GSH y la GPx e incremento en la SOD.

La rosuvastatina mejoró el perfil de lípidos. Ambos fármacos reducen la inflamación y el estrés oxidativo.

Estos resultados demuestran un efecto adicional cardioprotector, como un mecanismo de acción directo o a través de sus efectos pleiotrópicos. Son necesarios estudios adicionales a largo plazo para determinar si la rosuvastatina o la metformina serán fármacos útiles para disminuir el riesgo cardiovascular causado por el estrés oxidativo y la inflamación..

Palabras clave:. Estrés oxidativo. Full Text. METHODS This open, parallel group study was performed between July and September e, et al.. Hipertensión arterial en México: Resultados de la Encuesta Nacional de Salud ENSA Arch Cardiol Mex, 72 , pp.

To simplify, we grouped the resulting effects into: decreased lipoprotein synthesis, neural reduction of endogenous glucose production, and increased glucagon-like peptide-1 GLP-1 production. Dysregulation of intestinal lipoprotein metabolism is often seen in T2DM patients [ 31 , 32 , 33 ].

The high concentrations of insulin found in T2DM patients may be responsible for this phenomenon [ 34 ]. Lipogenic gene expression, involved in de novo lipogenesis, is regulated by the sterol regulatory element-binding protein-1c SREBP-1c , which is highly expressed in the upper villus of the jejunum and ileum [ 35 ].

SREBP-1c in the intestine is positively regulated by insulin and negatively by AMPK, and is able to upregulate enzymes, such as acetyl-CoA carboxylase ACC1 and fatty acid synthase FAS , which are involved in denovo fatty acid synthesis [ 36 , 37 ]. Figure 1 shows the possible cellular targets of metformin in enterocytes based on the literature discussed here.

Metformin treatment of morbidly obese T2DM patients induced a small decrease in mRNA expression of SREBP-1c, ACC1, and apo A-IV involved in the secretion of chylomicrons , leading to a slightly improved intestinal lipid homeostasis [ 33 ].

Insulin positively regulates synthesis of intestinal apo A-IV as well as secretion [ 38 ], which may cause an increase of this protein at the high insulin levels in the presence of insulin resistance.

Experiments in animal models confirmed the possible interaction of metformin with proteins and enzymes involved in triglyceride and apo B synthesis. Summary of the effects of metformin on intestinal lipoprotein synthesis in different experimental studies.

Key events are the positive regulation of AMPK and GLP-1, from where a spectrum of changes in the fatty acid and TG synthesis, and chylomicron production are observed that effectively result in decreased intestinal lipoprotein synthesis.

Arrows represent stimulation, and T-shaped symbols represent inhibition. Summarizing, metformin treatment impacts importantly on lipoprotein synthesis in the intestine, but the molecular mechanism is not yet fully clear and requires further investigation.

The liver and kidneys are the major organs responsible for gluconeogenesis from amino acids or glycerol. However, pioneering work of the group of Mithieux showed that also the human small intestine expresses considerable activity of the gluconeogenic gene [glucose 6-phosphatase G6Pase ], and may therefore contribute to endogenous glucose production EGP [ 42 ].

Intestinal gluconeogenesis may play a role in the gut-brain axis. In the post absorptive state, amino acids from the meal are used as a substrate for intestinal gluconeogenesis.

This glucose enters the portal vein, where it binds to the sodium-glucose cotransporter 3 SGLT3. This transporter is activated and signals to the hypothalamus in the brain which indicates the liver to decrease hepatic glucose production [ 43 ].

Whether these estimates can be translated to the human situation is not clear yet. The question arises whether metformin interacts with intestinal gluconeogenesis.

Activities of key enzymes [e. Yet, intestinal glucose uptake and intestinal glucose release were increased, and the overall endogenous glucose production was decreased compared to controls Fig.

Another study showed that metformin treatment induces alterations in the gut microbiome in T2DM patients [ 46 ]. This has been reported to increase butyrate and propionate production, possibly via modification of the host lipid absorption [ 46 , 47 ], which may then support intestinal gluconeogenesis [ 46 ].

Summary of the effects of metformin in the intestine small intestine and duodenum that cause glucose-lowering effects by reducing the hepatic EGP. The last few years, the small intestine has come into view as the prime target of metformin.

The protein plays and important regulatory role in cellular energy metabolism [ 49 ]. Several pharmacological compounds e. metformin , natural compounds rooibos, berberine , hormones adiponectin, leptin, IL-6 , and physiological processes exercise, fasting, caloric restriction activate AMPK activity [ 50 ].

Activated AMPK has pleiotropic effects on energy metabolism improving insulin resistance and diabetes type 2 [ 51 ]. In the proposed intestinal-neuronal pathway, metformin activated intestinal AMPK which interacts with the GLPR and PKA, leading to stimulation of a neuronal signal via the nervus vagus to the brain.

According to this hypothetical route in the brain, the N -methyl- d -aspartate NMDA receptors located in the nucleus tractus solitarius contribute to autonomic regulation receive this neuronal signal, and react by sending a signal via the hepatic vagus to the liver where it decreases hepatic EGP.

Additionally, it was hypothesised that metformins glucose lowering effects on short term i. first drop in glucose concentration after a meal might be related to intestinal processes, while long-term effects might be dedicated to hepatic processes [ 48 ].

Production of GLP-1 occurs mainly in the enteroendocrine L cells located mostly in the distal part of the small intestine and in the colon, while it can also be released by α-cells from the pancreas [ 52 ]. The regulation of GLP-1 production is complex and involves a combination of nutrient, hormonal and neural stimuli [ 53 ].

Increased fasting total and active GLP-1 as well as circulating total GLP-1 concentrations have been measured in obese T2DM patients on metformin treatment [ 54 , 55 , 56 ], Different mechanisms have been proposed to explain this increase [ 57 ].

An AMPK-dependent pathway, an AMPK-independent pathway, and a bile acid mediated pathway, have been proposed to explain the effects of metformin on GLP-1 secretion Fig. Summary of the effects of metformin discussed in the text that cause increased intestinal GLP-1 secretion.

Several studies have suggested mechanisms responsible for the increased GLP-1 secretion observed during metformin treatment in which AMPK plays a prominent role [ 48 ]. In the human small intestine, AMPK is present in the apical part of the small intestine, mainly at the lumen villus absorptive cells i.

below brush border and in stromal cells and fulfils important functions in metabolic pathways, leading to favourable effects during metformin treatment [ 41 ]. Instead, [ 58 ] demonstrated that increased expression of precursors of GLP-1 on L-cells is regulated through increased glucose entering in the cell via SGLT1 located in the brush border membrane of the lumen.

Increased glucose uptake by SGLT1 was a consequence of an increased expression of SGLT1. This causes b-catenin, a protein involved in transduction of signals to the nucleus, to move to the nucleus where it merges with transcription factor 7-like 2 TCF4L2 , leading to an increased proglucagon activity a precursor of GLP-1 , and GLP-1 production [ 58 ].

However, in a different study only a slightly increased expression of b-catenin and no effect on the expression of TCF7L2 was observed in the nucleus of NCI-H human intestinal cells during metformin treatment 1 mM [ 59 ].

The precursors of GLP-1, proglucagon and prohormone convertase 3 were also upregulated in this study, causing elevated secretion of GLP-1 [ 59 ]. GLPR on the afferent vagus nerve triggers a gut-brain-liver network, which may decrease the hepatic glucose production [ 48 ].

Metformin might also indirectly act on GLP-1 secretion via the modulation of bile acids in the intestine, for which [ 55 ] summarized two potential mechanisms. Firstly, metformin inhibits the intestinal apical sodium-dependent bile acid transporter ASBT , causing bile acids BA to accumulate in the intestinal lumen.

Therefore, the apical G protein-coupled bile acid receptor 1 TGR5 is stimulated which will cause an increased secretion of GLP Secondly, because of the inhibition of ASBT the concentration of BA in the illeoocyte will decrease, resulting in decreased activation of the nuclear farnesoid X receptor FXR.

Lack of FXR activation results in inhibition of the glycolytic pathway and activates the expression of proglucagon and intracellular ATP, leading to increased GLP-1 production and secretion [ 60 ]. Hepatobiliary transport transport from the sinusoid to the bile of metformin in humans, rats and mice, is negligible indicating that uptake of metformin in the small intestine occurs only by a first pass mechanism [ 22 , 61 , 62 ].

The altered metabolism of bile acids by metformin may also be the reason why metformin influences the composition of the gut microbiome. The gut microbiome composition is associated with dyslipidemia and insulin resistance [ 65 ].

Since the gut bacteria are important in bile acid metabolism and thereby may influence host metabolism via the nuclear hormone receptor FXR and TGR5 signalling pathways [ 66 ] part of the metformin effects on host metabolism may be secondary via this route.

Recently, the effects of metformin on the gut microbiota composition in T2DM patients were investigated [ 67 ]. The composition was changed, including an increased abundance of Akkermansia muciniphila related to metabolic health [ 68 ] and multiple bacteria involved in the short-chain fatty acid i.

butyrate, propionate production. De la Cuesta-Zuluaga et al. suggest that the improved metabolic health is associated with a stronger intestinal mucosal barrier caused by the affected bacteria [ 67 ]. Diversity of the microbiota may also contribute to the different observations seen in T2DM treated with metformin [ 69 ].

The effect of metformin on gut microbiota composition was confirmed in a recent randomised controlled trial in T2DM patients [ 47 ]. Transplantation of fecal microbiota derived from metformin-treated subjects to germ-free mice improved glucose tolerance compared to mice that received fecal microbiota from placebo-treated controls.

This indicates that changes in gut microbiota induced by metformin treatment mediate part of the beneficial effects of this drug on glucose homeostasis [ 47 ].

Alterations in bile acid metabolism may partly explain the effects. Metformin navigates to the liver via the portal vein and is taken up predominantly by OCT1 [ 70 ] as well as by THTR-2 [ 25 ].

The main mechanisms of metformin involved in decreasing the endogenous glucose production and plasma glucose have all been extensively and critically reviewed elsewhere [ 71 , 72 , 73 ].

In this review, the effects of metformin on the lipid metabolism are highlighted, thereby creating a special focus on the effects on lipids related to the activation of AMPK by metformin.

Figure 4 shows the specific interactions of metformin resulting in an improved lipid metabolism. Summary of the effects of metformin in the liver that cause an overall improved lipid metabolism by reducing triglycerides, LDL-C, and total cholesterol. Metformin activated AMPK is able to modulate cholesterol synthesis as well.

Phosphorylation of 3-hydroxymethyl-glutaryl-coenzyme A reductase HMGCR will decrease cholesterol biosynthesis [ 74 ]. Treatment of rat primary hepatocytes with metformin 0.

This indicates that metformin is able to slightly inhibit macrophage HMGCR, even though relatively high concentrations were chosen. This cholesterol lowering effect in the intestine may lead to beneficial effects on cholesterol metabolism, and further supports the hypothesis that the intestine is an important target organ of metformin.

In a nutshell, metformins action on HMGCR is weak in hepatocytes, and it is plausible that other pathways are involved in achieving the lipid lowering effects of metformin.

Metformin shows beneficial effects on the glucose and lipid metabolism [ 81 ], even though the pathways and the corresponding strengths are not fully understood. Part of the variation in metformin efficacy may be due to the presence of responders and non-responders to metformin treatment [ 82 , 83 ], racial and ethnic background [ 84 ], and personal variation in the adaptation of metformin treatment.

In the literature, different pathways are suggested that could contribute to the positive effects of the drug the lipid metabolism Fig.

A pathway inducing reduction of LDL cholesterol has been proposed by Sonne et al. Inhibition of the intestinal absorption of bile acids by metformin causes an increased synthesis of bile acids in the liver, and cholesterol is used for this process [ 86 ], thereby causing a decreased amount of cholesterol in the hepatocytes.

Upregulation of the LDL-C receptor may increase the uptake of lipoproteins, to restore a sufficient level of cholesterol in the liver. Hereby, the LDL-C concentration and plasma total cholesterol concentrations may indirectly decrease by the action of metformin. However, it should be noted that this mechanism could account for only marginal effects.

An interesting hypothesis of anti-atherosclerotic activity by metformin was introduced [ 88 ]. It was found that metformin increased expression of the fibroblast growth factor FGF21 in hepatocytes, likely by the activation of AMPK [ 89 ], thereby stimulating expression of adenosine triphosphate binding cassette ABC transporters A1 and G1.

This may increase cholesterol efflux from macrophages and decrease development of atherosclerotic plaques [ 88 ]. FGF21 is an important metabolic regulator, which may serve as a protection response against glucose-lipid disorders.

The effects of metformin on FGF21 need further investigation, since it was reported that plasma FGF21 levels in humans with T2DM [ 90 ] are decreased after metformin treatment opposite to the description in the hypothesis.

Another alternative pathway via which metformin may influence lipid metabolism in T2DM patients was proposed in [ 91 ].

Metformin induced activation of AMPK in the liver inhibited the SREBP-1c. The SREBP-1c gene was also found to be downregulated by metformin in another study [ 79 ].

This downregulation activated fatty acid desaturase 1 FADS1 and FADS2, which reduced arachidonic acid levels [ 92 ]. This reduction may cause increased membrane fluidity, thereby increasing LDL-C-receptor recycling and a reduction in the LDL-C levels [ 92 ]. Downregulation of SREBP1c affects many lipogenic genes.

The acetyl-CoA carboxylase ACC , catalysing the malonyl-CoA biosynthesis, was inhibited by AMPK during metformin exposure 0.

The gene fatty acid synthase FASN and SREBP-1C were also downregulated [ 75 ]. This indicates that the lipogenesis pathway may also be affected by metformin resulting in decreased fatty acids and triglycerides. Figure 4 Summary of the effects of metformin in the liver that cause an overall improved lipid metabolism by reducing triglycerides, LDL-C, and total cholesterol.

Clearly a decreased β cell mass is an important factor in the development of T2DM. Gluco- and lipotoxicity high glucose and FFA induce damaging effects on β cells e.

decreased insulin secretion and β cell mass [ 94 ]. It is therefore of interest to consider possible beneficial effects of metformin on β cell function. Research in this field is growing. The enzymes lipase and amylase are secreted by the pancreas and are often measured to monitor the condition of the pancreas.

In this study, the product of dynamic, static and total β cell responsiveness and insulin sensitivity, also called the disposition indices DI d , DI s , and DI totOB calculated by an oral minimal model [ 96 ], showed that metformin — mg twice daily for 2 weeks caused a significant increase in DI d , DI s , and DI totOB , a decreased homeostasis model assessment of insulin resistance HOMA-IR , and an increased insulin sensitivity, majorly whole-body insulin sensitivity [ 97 ].

In contrast, another study showed no significant changes, which may perhaps occur because of the different personalized responses to metformin resulting in high standard errors [ 95 ]. The β cell responsivity was not altered in both studies and it was also suggested that metformin gives a more robust response to a high-fat mixed meal.

This is also confirmed when treatment of metformin 1. Summarizing, metformin showed to increase the insulin sensitivity, but not β cell function. Metformin was reported to exert beneficial effects in INS-1E cells cell line which displays characteristics of the β cell.

When these cells were exposed to 0. However, in another study, metformin showed no effects on β cell survival nor β cell death in INS-1 cells, and it was found that GLP-1 through a PKA and PI3K pathway is able to reduce apoptosis [ ].

As discussed previously, metformin treatment showed increased GLP-1 levels from the intestine, and this may explain the finding in the β cells. Metformin treatment may also effect the compound nitric oxide NO and NO synthase NOS system, which play a significant role in β cell functioning and viability [ ].

There is the neuronal constitutive NO synthase ncNOS which is associated with the mitochondria and insulin secretory granules, while inducible NOS iNOS located in the cytoplasm contributes to β cell failure during gluco- and lipotoxicity [ , ].

However, metformin showed significant reduced ncNOS, iNOS, and total NOS activities, and slightly increased insulin secretion when the islets were incubated at 20 mM glucose for 60 min [ ].

Metformin 0. Summarizing, the available literature suggests that metformin ameliorates the damaging effects of high glucose and FFA in β cells, and that the NO-NOS system may play a role in regulating the insulin secretion. Studies to investigate the effects of metformin on β cells in more detail are ongoing [ ].

Statins are a class of drugs that decrease plasma cholesterol levels and are prescribed as first choice to patients suffering from cardiovascular disease [ ]. Recently, it was discovered that the reduction in LDL-C by statins is an important indicator of increased T2DM risk [ ].

In this review, the focus is to investigate the effects of statins on glucose metabolism. We focus on liver and pancreas because of their important role in glucose metabolism. However, statins may also act their worsening effect on glycemic control via other organs intestine and tissues muscle and adipose tissue.

Several mechanisms possibly involved in the effect of statins on glucose metabolism are summarized below and in Fig. A proposed statin signalling pathway that stimulates EGP by activation of gluconeogenic genes was discovered in human liver cells [ ].

Statin activates the pregnane X receptor PXR in the cytoplasm. PXR exerts a number of functions, such as the stimulation of the expression of proteins involved in removal of xenobiotics, and regulation of hepatic glucose and lipid metabolism [ ].

As a result, PXR together with the dephosphorylated SGK2 move to the region where gluconeogenic genes are located in the nucleus. These regions are called the PXR—SGK2 response elements PSRE and an insulin response sequence region IRS.

PXR, SGK2 together with the nuclear retinoid X receptor RXR bind to these regions and thereby activate PEPCK1 and G6Pase [ ].

This may result in an activation of EGP. Additionally, increased expression of PEPCK1 and G6Pase is observed through activation of an autophagic flux. Autophagy is a regulated destructive process of cellular elements and is upregulated for example during starvation, ER stress, or intracellular stress [ ].

Contradictory results were found in a different study, where neither PEPCK1, G6Pase, nor EGP were affected in HepG2 cells treated with atorvastatin 1 and 10 μM [ ]. In vivo experiments investigating the effects of statin treatment on glucose metabolism in T2DM patients showed no remarkable effects on EGP.

However, the EGP measured during clamp isoglycaemic hyperinsulinaemic conditions after 12 weeks of statin treatment was slightly increased compared with the baseline value in [ ], but not in [ ].

Summarizing, an increase of EGP induced by statins is not obvious from the above-mentioned studies performed in statin-treated T2DM patients, while it is observed in in vitro experiments. Therefore, it may be that the effects of statins on EGP are minor.

In the literature, many statin-effected processes are described that may contribute to a decreased insulin secretion in the β cell, possibly contributing to the progress of T2DM Fig.

One of these directly affected processes are the upregulation of LDL-C receptor seen upon inhibition of HMG-CoA reductase, which results in increased uptake of plasma LDL-C into the β cell [ ]. The increased amount of cholesterol within the cell causes interference with translocation of glucokinase, to the mitochondria [ ].

A decreased glucose transporter GLUT2 expression level was observed in simvastatin treated mouse MIN6 cells which resulted in a reduction of ATP levels, inhibition of the K ATP channel closure, membrane depolarization and calcium channel opening all leading to reduced insulin secretion [ ].

The ATP-binding cassette transporter ABCA1 could also play an important role since a relation was discovered between ABCA1 deficiency and an impaired insulin secretion in the β cell [ ].

Inhibition of the ATP-dependent potassium channel, depolarization and the decreased influx of calcium, and intracellular calcium concentrations were observed and were related to a decreased insulin secretion [ ].

However, intracellular calcium levels were not affected in an ex vivo study wherein intact single-islets were treated with simvastatin [ ]. Mouse MIN6 β cells treated with simvastatin Inhibition of this pathway leads to inhibition of promoter activity of the insulin gene and to a decrease of insulin secretion [ ].

Insulin secretion may also be impaired via direct statin induced inhibition of mitochondrial oxidative phosphorylation at complex III [ ]. The resulting decrease in ATP synthesis may induce inhibition of insulin secretion via the cascade described above.

One of the mechanisms of an increased insulin resistance could be the effect on the glucose transporter GLUT-4 located in adipose tissue and muscle. Atorvastatin treatment was shown to reduce the surface expression of GLUT-4 in mice adipocytes by inhibiting isoprenylation via inhibition of the mevalonate pathway [ ].

Mevalonate is an important intermediate in cholesterol synthesis and hence also for the synthesis of isoprenoid intermediates Ras and Rho proteins important in cell proliferation. These are involved in intracellular mobilization and localization of proteins.

Statin treatment may cause inactivation of Ras and Rho molecules so that activation and membrane translocalization of GLUT-4 is inhibited. Experiments in mouse adipocytes confirmed that GLUT-4 located on the plasma membrane moved to the cytosol during atorvastatin treatment [ ].

This may result in an increased insulin resistance. In conclusion, statin treatment may lead to a decreased insulin secretion in the β cell via several mechanisms. However, these effects are up to now mainly seen in animal in vitro studies and so it remains elusive whether these results can be translated to humans.

In addition, it should also be kept in mind that 10 years of statin treatment in patients caused an increased BMI 1. It is not clear whether the patients that developed T2DM on statin treatment increased their BMI excessively. This is in contrast with metformin.

Metformin treated mice showed a decreased weight gain which was related to the increased energy consuming conversion of glucose to lactate in the intestinal wall [ ]. In diabetic rats — g it was shown that after 2 weeks metformin—atorvastatin combination therapy mg metformin and 20 mg atorvastatin per 70 kg body weight , glucose-lowering effects, lipid-lowering effects, reduction of oxidative stress, and positive effects on cardiovascular hypertrophy occurred [ ].

The reduction of oxidative stress and protection of the liver observed by studying the liver histology and blood measurement, e. CRP, TNF-α, IL-6, protein carbonyl levels was also seen in T2DM rats treated with metformin and atorvastatin [ , ].

These positive effects and the fact that a great number of patients are treated with Metformin — statin combination therapy led to the design of a metformin—atorvastatin combination tablet used as a single daily dose [ , ]. There is only a minor chance for toxic drug interactions when metformin and statin are administered together because metformin is not metabolised and most statins are metabolised via the cytochrome P system [ ].

Patients with T2DM are often taking metformin and statins together to control CVD risk as well as glucose metabolism [ 82 ]. Since metformin shows beneficial effects on both dyslipidemia and glycemic control and has been shown to reduce CVD risk while statins may have an added beneficial effect on CVD risk, combined treatment with both drugs seems a good option.

As far as we have been able to discern no randomised clinical trials have been carried out to establish whether combination therapy is superior to monotherapy when focusing on CVD risk. Ethical considerations maybe prohibitive in this respect but perhaps subgroup analysis in ongoing studies such as the DDPOS may provide an answer.

Studies aiming at optimal dosing of both drugs have not been performed. Clinical studies on the effects of metformin and statin combination therapy have been carried out but for different purposes [ 82 , , , , , , , ].

Each of these studies had different objectives and included different patients groups, i. either with T2DM, dyslipidemia, treated different doses , untreated, or newly diagnosed T2DM. This precludes comparing these studies to arrive at overall results of metformin statin combination therapy.

These studies are now discussed briefly to obtain knowledge about the overall effects on glucose and lipid metabolism in T2DM patients with dyslipidemia Table 5. Atorvastatin 20 mg showed to attenuate the glucose- and HbA1c-lowering effect in combination with and mg metformin.

This may complicate analysis of the obtained changes on the glucose and lipid metabolism. However, it could be used for hypothesis-generation rather than making rigid decisions, considering the lack of multiple dose dependent combination studies.

The effects of metformin on lipid homeostasis as discussed in this review article, indicate that lipid metabolism is positively affected in the intestine and liver leading to decreased plasma triglycerides, LDL-C, and total cholesterol.

Metformins effects on lipid metabolism seem to be localized to the intestine. Statins mainly act on plasma cholesterol levels via activation of the LDL-receptor suggesting that combination therapy should show an additional effect on plasma lipids. However, the data in Table 5 give little indication for an added beneficial effect of both drugs on lipid parameters.

Dedicated studies are required to further investigate the effects of both drugs by combination therapy in humans. Metformin has been shown to exert a significant influence on the composition of the gut microbiota.

Interestingly, statins showed such effects as well, particularly in studies with mice and rats [ , ]. Statins were able to decrease the production of butyrate which may relate to the development of new onset T2DM [ ].

Atorvastatin given to hypercholesterolemic patients restored anti-inflammatory bacteria [ ]. In T2DM patients with non-alcoholic fatty liver disease NAFLD beneficial use of combination therapy seems indicated since statin therapy associates negatively with non-alcoholic steatohepatitis and significant fibrosis while a safe use of metformin in patients with T2DM and NAFLD was demonstrated [ ].

Combination therapy consisting of metformin and statin treatment is frequently prescribed to women with an endocrine disorder called polycystic ovary syndrome PCOS.

PCOS increases the risk of T2DM and cardiovascular morbidity as it is associated with abnormal increased lipid levels, insulin resistance, systemic inflammation and endothelial dysfunction [ ]. Meta-analysis showed that combined statin-metformin therapy in women with PCOS resulted in improved lipid and inflammation markers but it did not improve insulin sensitivity [ ].

Additional studies are recommended to confirm these results. Combination therapy could also be considered for T2DM patients with diabetic retinopathy. Diabetic retinopathy DR is a microvascular complication of diabetes caused by hyperglycemia and hyperosmolarity.

Leakage and accumulation of fluid in the macula is known as macular edema and results in severe vision loss in DR patients. The use of statins in T2DM patients and pre-existing DR showed a protective effect against development of diabetic macular edema [ ].

Remarkable is that T2DM patients receiving statin therapy in combination with increased levels of cholesterol remnants and triglycerides were associated with slight decreased in left ventricular systolic function.

Targeting cholesterol remnants in addition to T2DM patients receiving statins might be beneficial on cardiac function [ ]. From a clinical perspective, it was shown that many patients with T2DM and CVD did not receive lipid lowering therapy while their lipid levels were not in the optimal range [ ].

Increased implementation of guideline recommendations for dyslipidemic T2DM patients is therefore recommended [ ]. Metformin is generally thought to exert its beneficial effects on glucose metabolism mainly in the liver. In line with recent literature on the topic we conclude that the drug acts primarily in the intestine.

This is due to the at least one order of magnitude higher concentrations of metformin in the intestine than in the liver. The drug is certainly not absent in the liver hence parts of its effects may be localized to this organ most probably via its effects on gluconeogenesis.

To treat T2DM and its cardiovascular comorbidity combination therapy of metformins with statins seems well placed and may act as a double-sided sword particularly in the case of statins. This drug increases the risk on T2DM particularly in prediabetic subjects, and cotreatment with metformin might reduce this risk.

However, this hypothesis has not yet been systematically verified. In this review, we have investigated possible sites of interaction of metformin and statins and conclude that they act on largely parallel pathways.

Statins reduce plasma cholesterol via activation of LDL-C receptor in the liver and may influence glucose homeostasis primarily by inhibition of insulin secretion in pancreatic β cells.

We propose that combination therapy will ameliorate the risk of statin induced T2DM. Bosi E. Metformin—the gold standard in type 2 diabetes: what does the evidence tell us?

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SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease. Int J Mol Med. Srivastava RA, Pinkosky SL, Filippov S, Hanselman JC, Cramer CT, Newton RS. AMP-activated protein kinase: an emerging drug target to regulate imbalances in lipid and carbohydrate metabolism to treat cardio-metabolic diseases.

Tso P, Sun W, Liu M. Gastrointestinal satiety signals IV. Apolipoprotein A-IV. Am J Physiol Gastrointest Liver Physiol. Lutz TA, Osto E. Glucagon-like peptide-1, glucagon-like peptide-2, and lipid metabolism. Curr Opin Lipidol. Dash S, Xiao C, Morgantini C, Lewis GF. Because the vast majority of research regarding metformin included only people with diabetes or prediabetes, it's unclear whether these potential benefits are limited to people with those conditions, or whether people without diabetes may derive benefit as well.

The safety profile for metformin is quite good. Side effects include nausea, stomach upset, or diarrhea; these tend to be mild. More serious side effects are rare. They include severe allergic reactions and a condition called lactic acidosis , a buildup of lactic acid in the bloodstream.

The risk for this is higher among people with significant kidney disease, so doctors tend to avoid prescribing metformin for them. Metformin is a first-line treatment for type 2 diabetes, according to current diabetes guidelines.

It's relatively inexpensive and its potential side effects are well understood. If you have diabetes and need metformin to help lower your blood sugar, its other potential health benefits are a wonderful — not harmful — side effect.

And if you don't have diabetes? Well, its role in preventing or treating diseases, and possibly even slowing aging and extending life expectancy, is much less clear.

In those BCR-dependent DLBCL cases, the activated BCRs are mobile, aggregated, and polarized via lipid rafts on the cell membrane surface to amplify the signal transduction effect 23 , Lipid rafts-consist of lipids such as cholesterol , which are essential for this BCR function by maintaining the integrity of lipid rafts 25 — BCR is important for the survival of DLBCL, and blocking the BCR signaling pathway may thus inhibit tumor cell proliferation.

There remains a question if BCR signaling, or, the metabolism of cholesterol in BCR-dependent DLBCL cells, is related to the metformin-induced activation of AMPK? We thus explored the effects of metformin on the BCR signaling and cholesterol synthesis in DLBCL cell lines first, and then compared the outcomes of diabetic DLBCL patients on metformin with those on other hypoglycemic agents.

Three BCR-dependent with surface Ig DLBCL cell lines, OCI-LY1 IMDM, GIBCO , OCI-LY8 IMDM, GIBCO , and NU-DUL-1 , GIBCO , were employed.

The status of surface Ig in the cell lines was provided by American Tissue Culture Collection and Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH and was validated by immunophenotyping.

The expression of two BCR signaling-related molecules, phosphorylated SYK pSYK and phosphorylated AKT pAKT , and a key enzyme for cholesterol biosynthesis, 3-hydroxymethylglutaryl-CoA synthase1 HMGCS1 , was evaluated by immunoblotting.

The cells were visualized using a Leica SP5X confocal microscope. Images were captured and analyzed using LAS AF software Leica Microsystems CMS GmbH.

And the BCR and membrane cholesterol levels were evaluated by flow cytometry FACS Canto II, BD Biosciences using cell suspensions 5×10 6 cells each. The studies involving human participants were reviewed and approved by the Medical Ethics Committee of Fudan University Shanghai Cancer Center.

Fifty DLBCL patients with type II diabetes who received metformin throughout their chemotherapeutic treatment course were identified. We extracted important clinicopathological features, including the age, gender, stage of the disease, International Prognostic Index IPI score, cell-of-origin COO subtype of the tumor, and the outcome of treatment.

DLBCL patients with type II diabetes treated with other hypoglycemic agents during the same period, but with other clinicopathological characteristics comparable, served as the control. All of these patients were treated with a regimen containing rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone R-CHOP.

In order to further verify the findings by in vitro experiment, we also evaluated the expression levels of pSYK, pAKT, and HMGCS1 in selected cases of both cohorts by immunohistochemistry using formalin-fixed, paraffin-embedded tumor specimens obtained prior to the immunochemotherapy.

Survival was determined from the time of diagnosis until the time of death or last follow-up or progression. Survival curves were constructed by the Kaplan—Meier method. Survival distributions were compared using the log-rank test. All of the statistical analyses were carried out using GraphPad Prism, version 7.

In vitro , we observed metformin-induced growth inhibition of the tumor cells in all three DLBCL cell lines Figure 1A. The BCR stimulation led to an increased expression of pSYK and pAKT.

These activating effects, however, were remarkably ablated by a metformin pretreatment Figure 1B. BCR stimulation also correlated with an increased expression of HMGCS1, which could be ablated by metformin pretreatment, too Figure 2A.

By immunofluorescence, we noticed the phenomenon of BCR capping, which was caused by BCR stimulation, and represented polymers formed by BCR cross-linking. The colocalization of the cholesterol and BCR signals was observed throughout the experiment, that is, colocalized cholesterol and BCR capping signals appeared at BCR stimulation, whereas the capping signals of both decreased or disappeared following metformin treatment Figure 3A.

In addition, the BCR and membrane cholesterol levels, revealed by flow cytometry assay, were also decreased by the pretreatment with metformin after induction by BCR stimulation Figures 3B, C. Figure 1 Metformin inhibits the growth rates of three DLBCL cell lines A. BCR stimulation upregulates the expression of pSYK and pAKT, which is ablated by a pretreatment with metformin B.

Figure 2 BCR stimulation induces an increased expression of HMGCS1, which is ablated by a pretreatment with metformin A. Figure 3 At BCR stimulation, the BCR capping signals red and cholesterol capping signals green by Filipin appear in three DLBCL lines, and the merged images show the colocalization of these signals.

These capping signals decrease or disappear following a pretreatment of metformin A. The Cy3 BCR levels increase after a BCR stimulation, and decrease following a pretreatment with metformin B. The metformin treatment results in reduced PE membrane cholesterol levels C.

The clinicopathological characteristics of the DLBCL patients on metformin treatment and the control group were summarized in Table 1. In general, there were no significant differences with regard to the distribution of age, gender, stage of the disease, IPI score, and COO subtype of the tumor between the metformin and the control cohort.

Furthermore, there was a trend of improved overall survival OS present in the metformin group, although the difference was not statistically significant Figure 4. Immunohistochemically, the expression levels of pSYK, pAKT and HMGCS1 in the metformin group were significantly lower than those in the control group Figure 5.

Figure 5 The immunohistochemical expression levels of pSYK, pAKT, and HMGCS1 of DLBCL patients from metformin group are significantly lower than that of control group A, B. DLBCL is a group of biologically heterogeneous diseases, comprising a variety of clinicopathologically distinctive entities, which may need different therapeutic strategies.

As aforementioned, Monti et al. demonstrated that DLBCL can be divided into three subgroups, the BCR, OxPhos, and HR, based on their different gene expression profiles Nevertheless, the biological characteristics of these molecular subtypes were poorly understood for a long time, until Caro et al.

They found that mitochondrial oxidative phosphorylation-related proteins are expressed at low levels in BCR-dependent DLBCL 28 , which suggests that the energy supply of BCR-dependent DLBCL may depend on anaerobic metabolism. The lipid rafts, composed mainly of cholesterol and glycosphingolipid, are activated to achieve aggregation and polar distribution, which is essential for the signal transduction effect Thus, restriction of cholesterol synthesis will further affect the integrity of cell membranes and influence the biological function of BCRs, resulting in the blockage of BCR signaling pathway.

We found that metformin can block cholesterol synthesis by inhibiting the key cholesterol synthesis-related enzyme, HMGCS1, which results in a reduced production of the cholesterol contents, especially that of cell membrane.

The decrease of membrane cholesterol leads to an inhibition of cholesterol-dependent BCR and its downstream signaling, that is, BCR signal transduction is blocked at the cell membrane level. However, the mechanism underlying the inhibitory effect of metformin on HMGCS1 in lymphoma cells remains largely unknown.

One possibility lies in the roles played by sterol-regulatory element binding proteins SREBPs , as it has been suggested that SREBPs can be phosphorylated and inhibited by AMPK in liver cells 16 , 17 , Few studies have translated the potential benefit of metformin use in DLBCL into clinical applications.

A retrospective study showed that diabetic DLBCL patients treated with metformin during first-line immunochemotherapy had significantly improved PFS and OS compared to those of nondiabetic or diabetic DLBCL patients treated with other glucose-lowering agents Another study on the effects of combined metformin and R-CHOP treatment on DLBCL patients, however, did not find any impacts on the response rate, event-free survival, or overall survival Of note, the second study did not balance the clinicopathological parameters, such as the age, stage of disease, IPI score, and COO subtype, which may lead to potential bias, in the study and control groups.

To avoid that, we designed the current case-control study to look into the effects of metformin on type II diabetic DLBCL patients by enrolling two cohorts of patients with matched, comparable clinicopathological parameters.

The results demonstrated that metformin use indeed contributes to a significantly improved CR rate and ORR, as well as the PFS. Moreover, a trend of better OS was also observed in the metformin group, although the difference did not reach a statistically significant level, possibly due to the relatively short follow-up time.

To further verify the effects of metformin on cholesterol-dependent BCR signaling, we also conducted a preliminary in vivo study, and obtained the results consistent with that of in vitro experiments. However, other factors that may lead to potential bias cannot be entirely ruled out.

A prospective randomized controlled study is required to further confirm the benefit of metformin on patients with DLBCL. We find that metformin may block the BCR signaling by inhibiting the biosynthesis of cholesterol.

The agent appears to be an effective therapeutic drug against DLBCL, especially in those BCR-dependent cases. Our preliminary work may provide a novel therapeutic strategy for the care of patients with DLBCL. Clinical trials are essential to evaluate the safety, efficacy, and optimal dosing schedule of metformin combined with immunochemotherapy, especially in nondiabetic DLBCL patients.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Medical ethics committee of Fudan University Shanghai Cancer Center.

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Factors associated with diabetes onset during metformin versus placebo therapy in the Diabetes Prevention Program.

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Materials and Methods. Journal Article. Lifestyle and Metformin Treatment Favorably Influence Lipoprotein Subfraction Distribution in the Diabetes Prevention Program. Goldberg , R. Miller School of Medicine R. Oxford Academic.

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Figure 2. Table 3. Baseline Covariate. HOMA IR 0. Table 4. Δ Large VLDL-P. Δ Small LDL-P. Δ Large LDL-P. Abbreviation: APN, adiponectin; CI, confidence interval. a The effects were estimated in regression models in which baseline and changes in metabolic parameters BMI, log HOMA-IR, and APN were standardized.

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