Actions of metformin and statins on lipid and glucose metabolism and possible benefit of combination therapy.

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hyperglycemia 4 endocrinologydiseases
metformin 168 endocrinologydiseasesdrugs
polycystic ovary syndrome 1 endocrinologydiseases
simvastatin 8 endocrinologydiseasesdrugs
Insulin 3 endocrinologydiseasesdrugs
atorvastatin 13 endocrinologydiseasesdrugs
diabetes mellitus 1 endocrinologydiseases
diabetic retinopathy 1 endocrinologydiseases

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Select Drug Character Offset Drug Term Instance
Insulin 1244 concentration (hyperglycemia) caused by persistent insulin resistance, and progressive β cell failure. Insulin resistance is a normal reaction of the body to cope with an excess of circulating triglycerides. Normally,
Insulin 16310 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
Insulin 45277 inhibition of promoter activity of the insulin gene and to a decrease of insulin secretion [[124]]. Insulin secretion may also be impaired via direct statin induced inhibition of mitochondrial oxidative phosphorylation
atorvastatin 39302 prescribed as first choice to patients suffering from cardiovascular disease [[107]]. Simvastatin and atorvastatin are often given as a first choice to patients with cardiovascular risk factors/cardiovascular disease.
atorvastatin 39440 first choice to patients with cardiovascular risk factors/cardiovascular disease. Low dose (20 mg/day) atorvastatin therapy given to patients with myocardial infarction showed improved lipid, adipokine, and pro-inflammatory
atorvastatin 39636 adipokine, and pro-inflammatory markers and decreased insulin resistance while higher dose (40 mg/day) of atorvastatin showed hyperglycemia, increased leptin levels and ghrelin deficiency [[108], [109]]. A meta-analysis
atorvastatin 42275 a different study, where neither PEPCK1, G6Pase, nor EGP were affected in HepG2 cells treated with atorvastatin (1 and 10 μM) [[115]].In vivo experiments investigating the effects of statin treatment on glucose
atorvastatin 42494 metabolism in T2DM patients showed no remarkable effects on EGP. Basal EGP in T2DM patients treated with atorvastatin (10 mg; 12 weeks) [[116]] or simvastatin (80 mg/day; 8 weeks) [[117]] showed no changes. However,
atorvastatin 46565 in mouse adipocytes confirmed that GLUT-4 located on the plasma membrane moved to the cytosol during atorvastatin treatment [[128]]. This may result in an increased insulin resistance.In conclusion, statin treatment
atorvastatin 47600 [[130]].Metformin–statin combination therapyIn diabetic rats (200–220 g) it was shown that after 2 weeks metformin– atorvastatin combination therapy (500 mg metformin and 20 mg atorvastatin per 70 kg body weight), glucose-lowering
atorvastatin 47663 shown that after 2 weeks metformin–atorvastatin combination therapy (500 mg metformin and 20 mg atorvastatin per 70 kg body weight), glucose-lowering effects, lipid-lowering effects, reduction of oxidative stress,
atorvastatin 48081 e.g. CRP, TNF-α, IL-6, protein carbonyl levels) was also seen in T2DM rats treated with metformin and atorvastatin [[132], [133]]. These positive effects and the fact that a great number of patients are treated with
atorvastatin 48269 patients are treated with Metformin–statin combination therapy led to the design of a metformin– atorvastatin combination tablet used as a single daily dose [[134], [135]]. There is only a minor chance for toxic
atorvastatin 50168 T2DM patients with dyslipidemia (Table 5). Surprisingly, the lowest dose of metformin (500 mg) and atorvastatin (10 mg) once daily resulted in the highest reduction of fasting plasma glucose (− 35%). Atorvastatin
atorvastatin 51249 changes of glucose and lipid variables of patients during combination therapy of metformin (M) and atorvastatin (A)/simvastatin (S)Nr.Study ref.Treatment before the studyCombination treatmentDaily dosesTime (months)NDifferences:
atorvastatin 53173 (10.2)− 23.1− 24− 31− 359T2DM patients receiving metformin slow release and newly diagnosed with dyslipidemia or on atorvastatin with newly diagnosed diabetes or patients with newly diagnosed diabetic dyslipidemia. BMI ≥ 25,
metformin 44 Title: Cardiovascular DiabetologyActions of metformin and statins on lipid and glucose metabolism and possible benefit of combination therapyMariël F. van
metformin 460 for cardiovascular disease and commonly use combination therapy consisting of the anti-diabetic drug metformin and a cholesterol-lowering statin. However, both drugs act on glucose and lipid metabolism which could
metformin 724 compared to monotherapy. In this review, the proposed molecular mechanisms of action of statin and metformin therapy in patients with diabetes and dyslipidemia are critically assessed, and a hypothesis for mechanisms
metformin 3180 monotherapy to dyslipidemic patients is associated with increased incidence of T2DM [[6], [7]]. Both metformin and statins thus act on glucose—as well as lipid metabolism which is why metformin–statin combination
metformin 3265 [[6], [7]]. Both metformin and statins thus act on glucose—as well as lipid metabolism which is why metformin –statin combination therapy is prescribed to many T2DM patients. However, the therapeutic effects of
metformin 3407 prescribed to many T2DM patients. However, the therapeutic effects of different doses of statin and metformin given in combination have not been thoroughly and systematically investigated. Since both drugs act
metformin 3622 glucose as well as lipid metabolism, it is important to understand in detail the interactions between metformin and statin action on metabolism to be able to design treatments with optimal safety/efficacy profilesTable 1Overview
metformin 5010 [[179]]The aim of this article is therefore to provide insight in the molecular mechanism of statin/ metformin interaction which can help to determine an optimal dosing strategy of both drugs.Antidiabetic drug metformin
metformin 5119 interaction which can help to determine an optimal dosing strategy of both drugs.Antidiabetic drug metformin and the potential mechanisms by which it may affect lipid metabolismMetformin, discovered in 1922, came
metformin 5455 in Galega officinalis. Metformin is available in different formulations including immediate-release metformin , extended-release metformin [[9]], and delayed-release metformin [[10]]. The latter two forms were developed
metformin 5483 Metformin is available in different formulations including immediate-release metformin, extended-release metformin [[9]], and delayed-release metformin [[10]]. The latter two forms were developed to expand the absorption
metformin 5520 formulations including immediate-release metformin, extended-release metformin [[9]], and delayed-release metformin [[10]]. The latter two forms were developed to expand the absorption of metformin along the gut (Table 2).
metformin 5602 and delayed-release metformin [[10]]. The latter two forms were developed to expand the absorption of metformin along the gut (Table 2). Administration of metformin 30 min before a meal showed highest therapeutic
metformin 5656 forms were developed to expand the absorption of metformin along the gut (Table 2). Administration of metformin 30 min before a meal showed highest therapeutic efficacy in lowering postprandial hyperglycemia [[11]].Table 2Different
metformin 5865 [[11]].Table 2Different formulations and the corresponding relevant characteristics of the oral drug metformin (information from [[180]])Metformin formulationDoseCmax (ng/ml)tmax (h)AUCmean (ng*h/ml)PropertiesRefsImmediate
metformin 6437 (DR) [[183]]500 mg bid/1000 mg bid905/6079/99010/6160Enteric coated (polymers) core tabletRelease of metformin by pH of 6.5 (distal small intestine)Late gut absorption (ileum)Increased GLP-1 secretionLess systemic
metformin 6822 hydrogen bond acceptor. There is only a limited understanding of the physicochemical properties of metformin in solvent [[12]]. Metformin hydrochloride shows two distinct pKa values referring to different protonated
metformin 6948 [[12]]. Metformin hydrochloride shows two distinct pKa values referring to different protonated forms of metformin (Table 3). The pKa values were reported as 2.8 and 11.6 [[13]], but using a more accurate pH determination
metformin 7136 more accurate pH determination as 3.1 and 13.8 [[14]].Table 3Percentage of fractional ionization of metformin after oral administration in different organs/tissues calculated using the Henderson–Hasselbalch equationHuman
metformin 7514 cavity7099.990.01–Stomach207.3692.6410%Jejunum + ileum80100060%Duodenum6.25099.930.0720%Plasma/liver7.4099.990.01–The pH in the different organs/tissues/plasma leads to different forms of metformin . Neutral metformin, which is a base, will only be dominant at very high pH. The monoprotonated conversion
metformin 7533 cavity7099.990.01–Stomach207.3692.6410%Jejunum + ileum80100060%Duodenum6.25099.930.0720%Plasma/liver7.4099.990.01–The pH in the different organs/tissues/plasma leads to different forms of metformin. Neutral metformin , which is a base, will only be dominant at very high pH. The monoprotonated conversion of metformin
metformin 7633 metformin, which is a base, will only be dominant at very high pH. The monoprotonated conversion of metformin with a stabilized cation (equally distribution between the nitrogen atoms) occurs in a neutral environment
metformin 7783 distribution between the nitrogen atoms) occurs in a neutral environment (pH ≈ 7). Biprotonation of metformin appears by a decreasing pH valueIntracellular localizationAs is evident from Table 3, metformin is
metformin 7880 of metformin appears by a decreasing pH valueIntracellular localizationAs is evident from Table 3, metformin is present for over 99% in the monoprotonated form in all tissues of the body except the stomach. The
metformin 8108 molecule precludes passive diffusion across lipid bilayers. To be able to evaluate the interaction of metformin with its putative targets it is important to know the intracellular and intraorganellar concentration.
metformin 8437 different compartments (cytoplasm, mitochondria, nucleus, etc.). The sparse data reported, indicate that metformin is mostly distributed in the cytosolic fraction (~ 70%) of rat hepatocytes compared to mixed membranes
metformin 8658 nucleus (~ 5%), and mitochondrial and lysosomal fractions (8%) [[15]]. A low binding affinity of metformin to mitochondrial membranes was seen, perhaps because of the two methyl groups of metformin [[15]], but
metformin 8749 affinity of metformin to mitochondrial membranes was seen, perhaps because of the two methyl groups of metformin [[15]], but perhaps also due to the used fractionation technique [[16]]. However, the mitochondrial
metformin 8922 technique [[16]]. However, the mitochondrial membrane potential may promote entry to the positively charged metformin [[17]], which will then concentrate inside the negatively charged mitochondria [[18]]. Modelling of
metformin 9036 [[17]], which will then concentrate inside the negatively charged mitochondria [[18]]. Modelling of the metformin distribution and validation confirmed the presence of high concentrations of the drug in the mitochondria
metformin 9247 mitochondria and the endoplasmic reticulum (ER), dependent on the membrane potential [[19]].Distribution of metformin concentrations over organs, tissues, and plasmaMetformin is able to (in)directly interact with many
metformin 9568 (mGPD)], which lead to a large diversity of possible effects of the drug. When scrutinizing literature on metformin effects, one needs to consider that in many studies supraphysiological concentrations of metformin were
metformin 9667 metformin effects, one needs to consider that in many studies supraphysiological concentrations of metformin were used [[20]]. The reported cellular sites of actions and effects thus may not reflect the in vivo
metformin 9794 The reported cellular sites of actions and effects thus may not reflect the in vivo situation when metformin is given to T2DM patients. Normally, the therapeutic window of metformin in plasma is between 1 and
metformin 9867 the in vivo situation when metformin is given to T2DM patients. Normally, the therapeutic window of metformin in plasma is between 1 and 50 μM [[21]]. Table 4 presents an overview of metformin concentrations
metformin 9953 therapeutic window of metformin in plasma is between 1 and 50 μM [[21]]. Table 4 presents an overview of metformin concentrations as observed in vivo in organs/tissues of humans, mice, and rats upon administration of
metformin 10148 administration of doses that lie in the range of therapeutic applications in humans. Accumulation of metformin occurs majorly in the intestine, but also in the stomach, liver, kidney and to a lesser extent in muscle.
metformin 10284 intestine, but also in the stomach, liver, kidney and to a lesser extent in muscle. The accumulation of metformin in intestine and stomach is not surprising in view of the fact that these organs are most exposed to
metformin 10418 is not surprising in view of the fact that these organs are most exposed to high concentrations of metformin . A recent radiotracer study confirmed the high metformin levels in these organs [[22]]. These concentrations
metformin 10475 are most exposed to high concentrations of metformin. A recent radiotracer study confirmed the high metformin levels in these organs [[22]]. These concentrations are at least tenfold higher than metformin concentrations
metformin 10570 high metformin levels in these organs [[22]]. These concentrations are at least tenfold higher than metformin concentrations in the liver, indicating that the intestine is probably an important site of action.
metformin 10704 liver, indicating that the intestine is probably an important site of action. In fact, the effects of metformin in the intestine may be rather different than the effects in the liver.Table 4Metformin concentrations
metformin 11964 of this review, we will concentrate on the organs considered to be most relevant for interaction of metformin with glucose and lipid metabolism, i.e. the intestine because of the high metformin concentrations,
metformin 12048 interaction of metformin with glucose and lipid metabolism, i.e. the intestine because of the high metformin concentrations, the liver because of the organ’s central role in linking glucose and lipid metabolism,
metformin 12280 pancreatic β cells which secrete insulin and play a key role in the regulation of glucose metabolism. Since metformin concentrations differ between intestine, liver and β cells, different organ-specific effects may be
metformin 12448 cells, different organ-specific effects may be expected.Intestinal absorptionAfter oral administration, metformin is transported in the small intestine across the apical membrane into the enterocytes via several transporter
metformin 12969 Km value of 1.15 mM [[25]]. This binding affinity is comparable with the Km of PMAT (1.32 mM) for metformin [[26]]. THTR-2 is highly expressed in the intestine, and primarily transports vitamin B1. Polymorphism
metformin 13162 vitamin B1. Polymorphism in the human OCT1 gene has been reported and could cause a reduced transport of metformin leading to the development of metformin intolerance [[27]]. In Caco-2 cells there is no evidence for
metformin 13202 gene has been reported and could cause a reduced transport of metformin leading to the development of metformin intolerance [[27]]. In Caco-2 cells there is no evidence for a role of apical organic cation transporter
metformin 13352 there is no evidence for a role of apical organic cation transporter 3 (OCT3; SLC22A3) in the uptake of metformin [[23]]. Transporters mediating metformin efflux from the enterocytes have not been unequivocally identified.
metformin 13393 organic cation transporter 3 (OCT3; SLC22A3) in the uptake of metformin [[23]]. Transporters mediating metformin efflux from the enterocytes have not been unequivocally identified. The OCT1 has been suggested, but
metformin 13820 experiments on caco-2 cells, suggests that there is no carrier mediated transport to the bloodstream. Rather, metformin accumulates in the cell until the luminal concentration is less than the concentration in the enterocytes,
metformin 14165 up again by cells [[29]]. This hypothesis has been partly confirmed in experiments with C11-labeled metformin followed by positron emission tomography. These experiments revealed a low capacity of basolateral membrane
metformin 14398 activity in humans resulting indeed in accumulation in the cell when there was a higher concentration of metformin in the lumen compared to in the cell [[22]].Mechanisms of metformin action in the intestineThe concentration
metformin 14466 there was a higher concentration of metformin in the lumen compared to in the cell [[22]].Mechanisms of metformin action in the intestineThe concentration of metformin in human jejunum has been shown to be 30- to 300-fold
metformin 14520 compared to in the cell [[22]].Mechanisms of metformin action in the intestineThe concentration of metformin in human jejunum has been shown to be 30- to 300-fold greater than in plasma (Table 4), again demonstrating
metformin 14655 shown to be 30- to 300-fold greater than in plasma (Table 4), again demonstrating accumulation of metformin in the intestinal mucosa [[30]]. Because of this remarkably high concentration it seems logical to assume
metformin 14786 mucosa [[30]]. Because of this remarkably high concentration it seems logical to assume that all known metformin targets present in enterocytes are addressed.To simplify, we grouped the resulting effects into: decreased
metformin 16004 remnant lipoprotein fractions) in T2DM patients [[34]]. Figure 1 shows the possible cellular targets of metformin in enterocytes based on the literature discussed here. Metformin treatment of morbidly obese T2DM patients
metformin 16578 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.Fig. 1Summary of the effects
metformin 16692 proteins and enzymes involved in triglyceride and apo B synthesis.Fig. 1Summary of the effects of metformin on intestinal lipoprotein synthesis in different experimental studies. Key events are the positive regulation
metformin 17249 concentration could also be caused by an elevated GLP-1 concentration in the intestine (induced by metformin ; see “Increased GLP-1 production”) by reducing apo B-48, the triglyceride availability, and chylomicron
metformin 17459 chylomicron secretion [[39], [40]], although this is not considered in [[33]–[35], [41]].Summarizing, metformin treatment impacts importantly on lipoprotein synthesis in the intestine, but the molecular mechanism
metformin 18690 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.g. phosphoenolpyruvate carboxykinase
metformin 18915 (PEPCK), hexokinase] contributing to small intestine glucose metabolism were not affected during one-week metformin treatment (50 mg/kg/day) in high-fat fed rats [[45]]. Yet, intestinal glucose uptake and intestinal
metformin 19176 endogenous glucose production was decreased compared to controls (Fig. 2). Another study showed that metformin treatment induces alterations in the gut microbiome in T2DM patients [[46]]. This has been reported
metformin 19493 [[46], [47]], which may then support intestinal gluconeogenesis [[46]].Fig. 2Summary of the effects of metformin in the intestine (small intestine and duodenum) that cause glucose-lowering effects by reducing the
metformin 19696 reducing the hepatic EGPThe last few years, the small intestine has come into view as the prime target of metformin . Experiments with infusion of the drug in the proximal small intestine (50 or 200 mg/kg; 50 min),
metformin 20232 important regulatory role in cellular energy metabolism [[49]]. Several pharmacological compounds (e.g. metformin ), natural compounds (rooibos, berberine), hormones (adiponectin, leptin, IL-6), and physiological processes
metformin 20584 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
metformin 21076 the hepatic vagus to the liver where it decreases hepatic EGP. Additionally, it was hypothesised that metformin s glucose lowering effects on short term (i.e. first drop in glucose concentration after a meal) might
metformin 21789 GLP-1 as well as circulating total GLP-1 concentrations have been measured in obese (T2DM) patients on metformin treatment [[54]–[56]], Different mechanisms have been proposed to explain this increase [[57]]. An
metformin 22032 AMPK-independent pathway, and a bile acid mediated pathway, have been proposed to explain the effects of metformin on GLP-1 secretion (Fig. 3) as discussed below.Fig. 3Summary of the effects of metformin discussed
metformin 22123 effects of metformin on GLP-1 secretion (Fig. 3) as discussed below.Fig. 3Summary of the effects of metformin discussed in the text that cause increased intestinal GLP-1 secretionSeveral studies have suggested
metformin 22306 secretionSeveral 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
metformin 22643 cells) and fulfils important functions in metabolic pathways, leading to favourable effects during metformin treatment [[41]]. Whereas in rats on metformin treatment (50 or 200 mg/kg) the need of duodenal AMPK
metformin 22690 metabolic pathways, leading to favourable effects during metformin treatment [[41]]. Whereas in rats on metformin treatment (50 or 200 mg/kg) the need of duodenal AMPK in order to activate GLPR was confirmed [[48]].Non-AMPK
metformin 22943 dependent pathways exist, for instance, it is argued in [[58]] that effects on GLP-1 production by metformin (1 mM in NCI-H716 human intestinal cells and/or 12.5 mg/kg body weight in mice) were not mediated
metformin 24326 effect on the expression of TCF7L2 was observed in the nucleus of NCI-H716 human intestinal cells during metformin treatment (1 mM) [[59]]. The precursors of GLP-1, proglucagon and prohormone convertase 3 were also
metformin 24803 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)
metformin 26139 and the re-uptake by hepatocytes.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
metformin 26215 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]]. Metformin (> 1000 mg/day)
metformin 26562 increased faecal bile acid excretion in T2DM patients [[63]]. The altered metabolism of bile acids by metformin may also be the reason why metformin influences the composition of the gut microbiome. This has developed
metformin 26599 T2DM patients [[63]]. The altered metabolism of bile acids by metformin may also be the reason why metformin influences the composition of the gut microbiome. This has developed into an important subject of research
metformin 27170 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
metformin 27265 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,
metformin 27851 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
metformin 27883 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
metformin 28051 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
metformin 28259 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
metformin 28443 homeostasis [[47]]. Alterations in bile acid metabolism may partly explain the effects.Mechanisms of metformin s action in the liverMetformin navigates to the liver via the portal vein and is taken up predominantly
metformin 28623 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
metformin 28815 all been extensively and critically reviewed elsewhere [[71]–[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
metformin 28961 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.Fig. 4Summary
metformin 29017 lipids related to the activation of AMPK by metformin. Figure 4 shows the specific interactions of metformin resulting in an improved lipid metabolism.Fig. 4Summary of the effects of metformin in the liver that
metformin 29102 interactions of metformin resulting in an improved lipid metabolism.Fig. 4Summary of the effects of metformin in the liver that cause an overall improved lipid metabolism by reducing triglycerides, LDL-C, and total
metformin 29243 overall improved lipid metabolism by reducing triglycerides, LDL-C, and total cholesterolAMPK-dependent metformin effects on HMG-CoA reductaseMetformin activated AMPK is able to modulate cholesterol synthesis as well.
metformin 29676 HMG-CoA synthase (HMGCS) were detected in rat FaO hepatoma cells treated with 2*10−3 and 5*10−3 M metformin [[75]]. This drastic decrease was, however, not observed when metformin was administered in a lower
metformin 29748 with 2*10−3 and 5*10−3 M metformin [[75]]. This drastic decrease was, however, not observed when metformin was administered in a lower more physiological relevant concentration (1*10−3 M). Treatment of rat
metformin 29884 lower more physiological relevant concentration (1*10−3 M). Treatment of rat primary hepatocytes with metformin (0.5–5*10−4 M) induced inhibition of HMGCR and HMGCS mRNA expression [[76]]. A not significant decrease
metformin 30067 [[76]]. A not significant decrease of HMGCR activity of human cultured fibroblast was observed with metformin treatment (4226 ± 413, no metformin vs. 4082 ± 396 pmol/h per mg, 5*10−5 M metformin) [[77]].
metformin 30108 HMGCR activity of human cultured fibroblast was observed with metformin treatment (4226 ± 413, no metformin vs. 4082 ± 396 pmol/h per mg, 5*10−5 M metformin) [[77]]. In another study, the cholesterol
metformin 30165 with metformin treatment (4226 ± 413, no metformin vs. 4082 ± 396 pmol/h per mg, 5*10−5 M metformin ) [[77]]. In another study, the cholesterol biosynthesis rate from [3H] acetate, but not from [14C] mevalonate,
metformin 30369 [14C] mevalonate, was suppressed by 11% following murine macrophage cell incubation with 2*10−3 M metformin , respectively [[78]]. This indicates that metformin is able to slightly inhibit macrophage HMGCR, even
metformin 30421 murine macrophage cell incubation with 2*10−3 M metformin, respectively [[78]]. This indicates that metformin is able to slightly inhibit macrophage HMGCR, even though relatively high concentrations were chosen.
metformin 30799 showed the differences of HMGCR in the liver and intestine of diabetic rats before and after 250 mg/kg metformin treatment [[80]]. Hepatic HMGCR was not affected by metformin treatment, while intestinal HMGCR showed
metformin 30861 diabetic rats before and after 250 mg/kg metformin treatment [[80]]. Hepatic HMGCR was not affected by metformin treatment, while intestinal HMGCR showed a decrease in activity of ~ 62%. The Acyl-CoA cholesterol
metformin 31291 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
metformin 31317 supports the hypothesis that the intestine is an important target organ of metformin. In a nutshell, metformin s action on HMGCR is weak in hepatocytes, and it is plausible that other pathways are involved in achieving
metformin 31464 hepatocytes, and it is plausible that other pathways are involved in achieving the lipid lowering effects of metformin .Other mechanisms of metformin effecting the lipid metabolismMetformin shows beneficial effects on the
metformin 31494 other pathways are involved in achieving the lipid lowering effects of metformin.Other mechanisms of metformin effecting the lipid metabolismMetformin shows beneficial effects on the glucose and lipid metabolism
metformin 31721 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]],
metformin 31803 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
metformin 31918 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
metformin 32245 by Sonne et al. [[85]] and is as follows. 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]],
metformin 32684 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. Major increases
metformin 33078 total cholesterol and LDL-C levels [[87]].An interesting hypothesis of anti-atherosclerotic activity by metformin was introduced [[88]]. It was found that metformin increased expression of the fibroblast growth factor
metformin 33129 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
metformin 33607 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
metformin 33748 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
metformin 33854 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
metformin 34066 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
metformin 34520 acetyl-CoA carboxylase (ACC), catalysing the malonyl-CoA biosynthesis, was inhibited by AMPK during metformin exposure (0.5, 1, 2 mM; 27 h) in human hepatoma HepG2 cells [[93]], leading to a reduced amount of
metformin 34795 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
metformin 34894 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
metformin 35044 improved lipid metabolism by reducing triglycerides, LDL-C, and total cholesterol.(In)-direct effects of metformin on β cellsClearly a decreased β cell mass is an important factor in the development of T2DM. Gluco-
metformin 35363 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
metformin 35633 condition of the pancreas. There were no changes observed in lipase, amylase, and the pancreas volume when metformin (1950 mg/day) was given to T2DM patients for 24 weeks [[95]] suggesting that metformin does not repair
metformin 35722 volume when metformin (1950 mg/day) was given to T2DM patients for 24 weeks [[95]] suggesting that metformin does not repair damaged β cells. In this study, the product of dynamic, static and total β cell responsiveness
metformin 35986 disposition indices (DId, DIs, and DItotOB) calculated by an oral minimal model [[96]], showed that metformin (1000–1500 mg twice daily) for 2 weeks caused a significant increase in DId, DIs, and DItotOB, a
metformin 36387 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
metformin 36527 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
metformin 36633 metformin gives a more robust response to a high-fat mixed meal. This is also confirmed when treatment of metformin (1.45*10−5 M) showed to prevent damaging effects when human pancreatic islets were incubated with
metformin 36814 pancreatic islets were incubated with FFAs by restoring the insulin secretion dynamics [[98]]. Summarizing, metformin showed to increase the insulin sensitivity, but not β cell function.Metformin was reported to exert
metformin 37060 (cell line which displays characteristics of the β cell). When these cells were exposed to 0.5 mM metformin for 24 h an increase in AMPK phosphorylation, a 30% reduction of SREBP-1C protein expression, a 80%
metformin 37434 suppress c-jun N-terminal kinase (JNK) and p38 MAPK, resulting in reduced β cell apoptosis (2*10−3 M metformin INS-1E cells) [[100]]. However, in another study, metformin showed no effects on β cell survival nor
metformin 37494 in reduced β cell apoptosis (2*10−3 M metformin INS-1E cells) [[100]]. 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
metformin 37699 GLP-1 (through a PKA and PI3K pathway) is able to reduce apoptosis [[101]]. As discussed previously, metformin treatment showed increased GLP-1 levels from the intestine, and this may explain the finding in the
metformin 38425 insulin secretion in human and murine islets incubated at 7 mM glucose for 60 min [[104]]. However, metformin showed significant reduced ncNOS, iNOS, and total NOS activities, and slightly increased insulin secretion
metformin 38774 INS-1 cells incubated with 25 mM glucose [[105]].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
metformin 38972 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 [[106]].Potential mechanisms by which lipid lowering statins
metformin 47304 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
metformin 47588 [[130]].Metformin–statin combination therapyIn diabetic rats (200–220 g) it was shown that after 2 weeks metformin –atorvastatin combination therapy (500 mg metformin and 20 mg atorvastatin per 70 kg body weight),
metformin 47642 (200–220 g) it was shown that after 2 weeks metformin–atorvastatin combination therapy (500 mg metformin and 20 mg atorvastatin per 70 kg body weight), glucose-lowering effects, lipid-lowering effects, reduction
metformin 48067 measurement, e.g. CRP, TNF-α, IL-6, protein carbonyl levels) was also seen in T2DM rats treated with metformin and atorvastatin [[132], [133]]. These positive effects and the fact that a great number of patients
metformin 48257 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 [[134], [135]]. There is only a minor
metformin 48407 as a single daily dose [[134], [135]]. 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
metformin 48462 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 P450 system [[136]].Patients
metformin 48599 statins are metabolised via the cytochrome P450 system [[136]].Patients with T2DM are often taking metformin and statins together to control CVD risk as well as glucose metabolism [[82]]. Since metformin shows
metformin 48694 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
metformin 49368 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], [137]–[143]].
metformin 49739 untreated, or newly diagnosed T2DM. This precludes comparing these studies to arrive at overall results of metformin statin combination therapy.Table 5 shows the glucose and lipid parameters after different doses combination
metformin 50144 and lipid metabolism in T2DM patients with dyslipidemia (Table 5). Surprisingly, the lowest dose of metformin (500 mg) and atorvastatin (10 mg) once daily resulted in the highest reduction of fasting plasma glucose
metformin 50391 20 mg showed to attenuate the glucose- and HbA1c-lowering effect in combination with 1000 and 2000 mg metformin . A high daily dose of simvastatin (40 mg) and metformin (3000 mg) resulted in an improved insulin
metformin 50448 effect in combination with 1000 and 2000 mg metformin. A high daily dose of simvastatin (40 mg) and metformin (3000 mg) resulted in an improved insulin resistance, but fasting plasma glucose decreased only by
metformin 50669 minor changes were observed on lipid metabolism parameters, but this was probably due to the fact that metformin was given on top of simvastatin treatment. The patients in these studies had different diseased states,
metformin 51231 studies.Table 5Observed percentage changes of glucose and lipid variables of patients during combination therapy of metformin (M) and atorvastatin (A)/simvastatin (S)Nr.Study ref.Treatment before the studyCombination treatmentDaily
metformin 53106 (15/15)6[[137]]Metformin/statin/−M + A500 mg M + 10 mg A3213− 7− 35 (10.2)− 23.1− 24− 31− 359T2DM patients receiving metformin slow release and newly diagnosed with dyslipidemia or on atorvastatin with newly diagnosed diabetes
metformin 53570 A3109− 2− 8 (7.8)− 1− 12 (2.1)− 9− 173Patients with a diagnosis of T2DM and treated with metformin 8[[143]]–A20 mg A265− 7− 3 (5.9)2− 10 (1.9)− 7− 160Non-diabetic overweight/obese
metformin 54310 between 5.6 and 7 mmol/l and a plasma glucose 2 h after a 75 g OGTT below 7.8 mmol/lThe effects of metformin on lipid homeostasis as discussed in this review article, indicate that lipid metabolism is positively
metformin 55477 hypercholesterolemic patients restored anti-inflammatory bacteria [[146]].Combination therapy with statins and metformin demonstrated beneficial effects in patients with other disease(s)/disorder(s) than T2DM and dyslipidemia.
metformin 55834 associates negatively with non-alcoholic steatohepatitis and significant fibrosis while a safe use of metformin in patients with T2DM and NAFLD was demonstrated [[147]]. Combination therapy consisting of metformin
metformin 55936 metformin in patients with T2DM and NAFLD was demonstrated [[147]]. Combination therapy consisting of metformin and statin treatment is frequently prescribed to women with an endocrine disorder called polycystic
metformin 56309 systemic inflammation and endothelial dysfunction [[148]]. Meta-analysis showed that combined statin- metformin therapy in women with PCOS resulted in improved lipid and inflammation markers but it did not improve
metformin 57913 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
metformin 58185 effects on gluconeogenesis. To treat T2DM and its cardiovascular comorbidity combination therapy of metformin s with statins seems well placed and may act as a double-sided sword particularly in the case of statins.
metformin 58396 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,
metformin 58567 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
simvastatin 42538 effects on EGP. Basal EGP in T2DM patients treated with atorvastatin (10 mg; 12 weeks) [[116]] or simvastatin (80 mg/day; 8 weeks) [[117]] showed no changes. However, the EGP measured during clamp (isoglycaemic
simvastatin 43691 the mitochondria [[119]]. 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 KATP channel
simvastatin 44447 calcium levels were not affected in an ex vivo study wherein intact single-islets were treated with simvastatin [[123]].Fig. 6Hypothetical mechanisms related to a decreased insulin secretion in β cells induced
simvastatin 44602 related to a decreased insulin secretion in β cells induced by statinsMouse MIN6 β cells treated with simvastatin (14.3 μM) showed inhibition of GPR40 (fatty acid receptor), and minor inhibition of GLP-1 resulting
simvastatin 45570 inhibition of insulin secretion via the cascade described above.An interesting observation is that simvastatin treatment (40 mg/day; 6 weeks) in 148 patients resulted in a decreased β cell function (53%) and
simvastatin 50423 glucose- and HbA1c-lowering effect in combination with 1000 and 2000 mg metformin. A high daily dose of simvastatin (40 mg) and metformin (3000 mg) resulted in an improved insulin resistance, but fasting plasma glucose
simvastatin 50699 lipid metabolism parameters, but this was probably due to the fact that metformin was given on top of simvastatin treatment. The patients in these studies had different diseased states, such as an impaired fasting
simvastatin 51266 glucose and lipid variables of patients during combination therapy of metformin (M) and atorvastatin (A)/ simvastatin (S)Nr.Study ref.Treatment before the studyCombination treatmentDaily dosesTime (months)NDifferences:
Select Disease Character Offset Disease Term Instance
diabetes mellitus 939 mechanisms underlying interactions between these drugs in combination therapy is developed.BackgroundType 2 diabetes mellitus (T2DM) and cardiovascular diseases are common medical conditions that are often found comorbid with
diabetic retinopathy 56579 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.
hyperglycemia 1155 with each other. T2DM is a metabolic disorder characterized by increased plasma glucose concentration ( hyperglycemia ) caused by persistent insulin resistance, and progressive β cell failure. Insulin resistance is a normal
hyperglycemia 5749 Administration of metformin 30 min before a meal showed highest therapeutic efficacy in lowering postprandial hyperglycemia [[11]].Table 2Different formulations and the corresponding relevant characteristics of the oral drug
hyperglycemia 39656 pro-inflammatory markers and decreased insulin resistance while higher dose (40 mg/day) of atorvastatin showed hyperglycemia , increased leptin levels and ghrelin deficiency [[108], [109]]. A meta-analysis observed that both intensive
hyperglycemia 56681 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
polycystic ovary syndrome 56035 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

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