Metformin and glucose metabolism -
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Glucose transport into everted sacs of the small intestine of mice. Article PubMed Google Scholar. Download references. This work was supported by the grant from the Czech Science Foundation No. We wish to thank B. Viollet Institut Cochin, Paris, France for providing the AMPKα2-KO mice.
We wish to thank Sona Hornova and Daniela Salkova for excellent technical assistance. Department of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Videnska , 20, Prague 4, Czech Republic. You can also search for this author in PubMed Google Scholar.
and J. made substantial contributions to conception and design. and P. performed the experiments. performed indirect calorimetry measurement and analysis.
made substantial contributions to analysis and interpretation of data. and M. wrote the manuscript. provided conceptual advice and supervised the manuscript. All authors have approved the final version of the article.
is the guarantor of this work. Correspondence to Olga Horakova. Open Access This article is licensed under a Creative Commons Attribution 4. Reprints and permissions. Horakova, O. 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.
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Thank you for visiting nature. You glucosee Metformin and glucose metabolism a browser version with metanolism support for CSS. To wnd the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Metformin is currently the most prescribed drug for treatment of type 2 diabetes mellitus in humans. Thank you for Metformin and glucose metabolism nature. You are using Kid-friendly healthy recipes browser version with limited Metformin and glucose metabolism for CSS. To obtain the Mftformin experience, we metabilism you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Even though metformin is widely used to treat type2 diabetes, reducing glycaemia and body weight, the mechanisms of action are still elusive.
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