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Metformin and cholesterol management

Metformin and cholesterol management

Abbreviation: APN, adiponectin; CI, confidence interval. Therefore, Metformin and cholesterol management may play chopesterol anti-atherosclerotic role through AMPK-mediated VSMCs regulation. Download PDF. Effects of metformin on the body composition in subjects with risk factors for type 2 diabetes.

Metformin and cholesterol management -

The findings pointed to metformin working via the AMP-activated protein kinase pathway, and will help to learn more about the drug. Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes.

Diabetes Care doi: Implications of the United Kingdom prospective diabetes study. Diabetes Care ;26 1 :S The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review.

As a result, malonyl CoA levels are reduced leading to a reduction in fatty acid synthesis need for TG production and an enhancement of fatty acid oxidation. Therefore, metformin improves the lipid profile beyond its glucose lowering effects by reducing triglyceride and cholesterol synthesis.

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The Mechanism for Metformin's Glucophage Improvement in the Lipid Profile Beyond its Glucose Lowering Effects in Diabetes Mellitus Summary : It is well known that type 2 diabetics may have uncontrolled glucose levels but are known to have dyslipidemia that has been characterized as being an "atherogenic" lipid profile.

Treating uncontrolled glucose levels can indirectly improve lipids, in particular TG. Metformin has been shown to decrease the activity and expression of several products involved in lipid synthesis, such as: acetyl CoA carboxylase, SREBP-1, fatty acid synthase, and HMG CoA reductase.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA Reviewers: Jon D. Herrington, PharmD, BCPS, BCOP and Donald S. Nuzum, PharmD, BCACP, CDE Last Reviewed: August Explanation It is well known that patients with type 2 diabetes mellitus T2DM are characterized as having central obesity or increased abdominal visceral fat , hepatic insulin resistance, decreased peripheral insulin mediated glucose uptake despite elevated insulin levels , excessive or accelerated "basal rates" of hepatic glucose production or hepatic gluconeogenesis , and abnormal lipid profiles that are considered to be more "atherogenic".

References: Monnier L, Colette C, Owens DR. Type 2 diabetes: a well-characterised but suboptimally controlled disease. Metformin improves cholesterol efflux and ATP-binding cassette transporters expression in vitro.

Cholesterol efflux was expressed as the percentage of radioactivity in the medium relative to the total quantity of radioactivity detected in the cells and medium A. It is well known that ATP-binding cassette transporters A1 ABCA1 and G1 ABCG1 , and scavenger receptor class B type I SR-BI are key factors involved in macrophage cholesterol efflux We then examined the involvement of upstream regulators of ABCA1 and ABCG1 expression, such as nuclear factor κB NF-κB , liver X receptor α LXRα , and AKT 17 , 18 , 19 , Our results showed that metformin did not affect LXRα expression or phosphorylation of AKT Fig.

ABCA1 siRNA and ABCG1 siRNA were transfected into cells, respectively, before the combined treatment with metformin and atorvastatin. Neither atorvastatin nor metformin affected the expression of SR-BI Fig. Co-treatment of metformin and atorvastatin promotes cholesterol efflux and expression of ABCA1 and ABCG1 in acLDL loaded THP-1 macrophages.

Examples of cholesterol trafficking regulators tested by Western blot C. In the current study, we used a high cholesterol diet-induced atherosclerotic model to evaluate effects of the combined use of atorvastatin and metformin.

Our results suggest that atorvastatin and metformin combination therapy is superior to atorvastatin monotherapy for the treatment of atherosclerosis and the underlying mechanisms might be associated with cholesterol efflux in macrophages.

It is well known that statins attenuate atherosclerosis mainly through reducing LDL-C levels, but it is unclear how metformin exerts its anti-atherosclerotic effects. The CAMERA study revealed that metformin did not affect the lipid profile in statin-treated patients Forouzandeh et al.

These data strongly suggest an additional anti-atherosclerotic mechanism for metformin when added to atorvastatin, which is independent of the lipid-lowering effect. Goldberg et al. Previous research has suggested an inverse association of large HDL subfraction with coronary artery disease 24 , 25 , which may involve reverse cholesterol transport RCT.

Notably, initiation and progression of atherosclerosis are known to involve multiple factors including dysfunction of RCT, dyslipidemia, microRNAs, and so on ref.

Cholesterol efflux from macrophages in aortic walls in response into HDL is an initial and important step of RCT. Small HDL accepts the transfer of cellular cholesterol and is then converted to large HDL Thus, an increase in large HDL possibly indicates its increased conversion, and large HDL may serve as a measure of the capacity for RCT.

Cholesterol efflux from macrophages is mainly mediated by the ABCA1 and ABCG1 More specifically, metformin combined with atorvastatin promoted cholesterol efflux and the expression of ABCA1 and ABCG1 in acLDL-loaded THP-1 macrophages.

In addition, we observed that atorvastatin decreased the expression of ABCA1 without affecting ABCG1 expression in acLDL-loaded THP-1 macrophages, keeping consistent with previous studies 21 , Li et al. Increased cholesterol efflux into HDL may promote the conversion of small HDL to large HDL.

Therefore, we conclude that the supplementary anti-atherosclerotic effect of metformin, when combined with atorvastatin, may be at least partially mediated by improving cholesterol efflux. Our conclusion is further supported by the intracellular signaling mechanism.

Our results showed that co-treatment with atorvastatin and metformin could inhibit phosphorylation of NF-κB p65 without altering phosphorylation of AKT and the expression of LXRα. Although the effect of co-administration of metformin and atorvastatin on NF-κB p65 was not reported before, metformin was reported to inhibit activation of NF-κB p65 in vascular wall in vivo 14 and inhibit phosphorylation of NF-κB p65 in smooth muscle cells in vitro Cheng et al.

It was previously reported that statin-associated diabetes is both dose- and time-dependent 32 , Importantly, our studies have shown that the delay in glucose clearance induced by atorvastatin was completely reversed by metformin. Supportively, Krysiak et al.

Therefore, the addition of metformin to atorvastatin therapy may counteract the adverse effect of atorvastatin on glucose metabolism. In this study, we demonstrated that addition of metformin to atorvastatin therapy enhances the anti-atherosclerotic effects in a rabbit model with a high-cholesterol diet.

However, there are several limitations to our study. Although we demonstrated that metformin alone or combined with atorvastatin could improve cholesterol efflux by up-regulating ABCA1 and ABCG1 expression in vitro , we did not investigate whether such a phenomenon was replicated in v i vo.

Besides, it is well known that endothelial cell function plays a pivotal role in atherosclerosis Santulli et al. In our study, we did not evaluate the endothelial functions and related miRNAs. Further studies are required to explore the potential signaling pathways in vivo and in vitro in order to provide robust evidence for this novel approach to anti-atherosclerotic therapy.

The protocol was approved by the Animal Research Committee, Central South University, Hunan, China and carried out in accordance with the Guidelines for Animal Experimentation of Central South University and the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health NIH Publication NO.

Forty male New Zealand white rabbits 2. Rabbits were housed in individual cages and standard environmental conditions. Rabbits were fed a high-cholesterol diet 0. Metformin hydrochloride tablets were purchased from Bristol—Myers Squibb New York, NY, USA and atorvastatin calcium was purchased from Pfizer New York, NY, USA.

Both of these were dissolved in normal saline and administrated by gastric gavage orally at a fixed time. The doses of the drugs were determined based on body surface area calculations of therapeutic human dosing metformin of 2. The rational to use a high cholesterol-fed rabbit model was that the lipid metabolism and pathologic characteristics of atherosclerosis in these animals more closely resemble those of humans compared with murine models At the end of the experiment, all rabbits were sacrificed by injection of an overdose of sodium pentobarbital solution.

Between the aortic arch and the junctions of the iliac arteries, the aortas were separated from the surrounding tissues. From the initiation of the aortic arch, 0. The concentrations of serum TC, LDL-C, HDL-C, TG, ALT, aspartate transaminase AST , creatinine, and glucose were determined using enzymatic methods bioMerieux, Lyon, France.

Rabbits were fasted overnight, and then a bolus of glucose 0. Human THP-1 cells were obtained from the American Type Culture Collection ATCC, Rockville, USA and cultured as previously described THP-1 macrophages were plated in 6-well plates and loaded with acLDL and 3 H-cholesterol.

The proteins from THP-1 macrophages were extracted with RIPA lysis buffer Beyotime, Beijing, China and separated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis SDS-PAGE before transferring onto polyvinylidene difluoride PVDF membranes.

Blots were washed, incubated with the secondary antibody, and visualized by chemiluminescence. Comparison of lipid and glucose levels between two independent groups was performed using the non-parametric Wilcoxon rank sum test.

Comparisons between multiple groups were conducted using one-way analysis of variance ANOVA followed by least significant difference post hoc tests.

AUC was calculated according to the trapezium rule. Baigent, C. et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90, participants in 14 randomised trials of statins. Lancet , —, doi: Article CAS PubMed Google Scholar. Cholesterol Treatment Trialists, C.

Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from , participants in 26 randomised trials. Stone, N. Circulation , S1—45, doi: Article PubMed Google Scholar.

Kataoka, Y. Atheroma progression in hyporesponders to statin therapy. Arteriosclerosis, thrombosis, and vascular biology 35 , —, doi: Waters, D.

Lipid treatment assessment project 2: a multinational survey to evaluate the proportion of patients achieving low-density lipoprotein cholesterol goals. Circulation , 28—34, doi: Sattar, N. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.

Preiss, D. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. Jama , —, doi: Cannon, C. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 25 , —, doi: Article Google Scholar.

Krysiak, R. The effect of metformin on monocyte secretory function in simvastatin-treated patients with impaired fasting glucose. Metabolism: clinical and experimental 62 , 39—43, doi: Article CAS Google Scholar.

Metformin for non-diabetic patients with coronary heart disease the CAMERA study : a randomised controlled trial. The lancet. Luo, F. Metformin promotes cholesterol efflux in macrophages by up-regulating FGF21 expression: a novel anti-atherosclerotic mechanism. Lipids in health and disease 15 , , doi: Article PubMed PubMed Central Google Scholar.

Hong, J. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes care 36 , —, doi: Article CAS PubMed PubMed Central Google Scholar. Forouzandeh, F. Metformin beyond diabetes: pleiotropic benefits of metformin in attenuation of atherosclerosis.

Journal of the American Heart Association 3 , e—e, doi: Li, S. Metformin inhibits nuclear factor kappaB activation and decreases serum high-sensitivity C-reactive protein level in experimental atherogenesis of rabbits. Heart and vessels 24 , —, doi: Article ADS PubMed Google Scholar.

Mora, S. Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women. Circulation , —, doi: Rosenson, R. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport.

Zhao, G. International journal of cardiology , e93—95, doi:

Goldberg, M. Temprosa, J. Otvos, J. Brunzell, S. Marcovina, K. Janine J. Dairy-free optionsMariëtte R. BoonMetformin and cholesterol management Anc. van der ZonSjoerd A. van den BergAnita M. van den HoekMarc LombèsHans M. Metformin and cholesterol management

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