Ampk metformin non

Do you use metformin? Then it might be useful to make an effort to maintain normal homocysteine levels. Metformin is a drug that is mainly prescribed to diabetics, to improve insulin resistance. This effect occurs by stimulating the protein AMPK, which plays an important role in cellular energy regulation 1. One of the risks of metformin is the increased formation of homocysteine. This effect not only applies to diabetics taking metformin 2, 3 but also applies to patients taking metformin to reduce cardiovascular risk 4.

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• Metformin activates AMPK, but increases homocysteine
• Will Metformin Become the First Anti-Aging Drug?
• Metformin as an anti-inflammatory agent: a short review
• An AMPK-dependent, non-canonical p53 pathway plays a key role in adipocyte metabolic reprogramming
• Molecular Mechanisms of Metformin for Diabetes and Cancer Treatment
• microRNAs and cancer metabolism reprogramming: the paradigm of metformin

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The design was conceived using isosteric replacement, chain-ring transformation, and lower and higher homologation strategies. All compounds were obtained as crystals and their structure was confirmed on the basis of their spectral data NMR and mass spectra , and their purity was ascertained by microanalysis. The results indicated that compounds 4 , 5 , and 6 showed similar or even better effect compared to metformin. Compound 6 was selected for an oral glucose tolerance test, showing an antihyperglycemic effect similar to metformin.

The in vivo results indicated that compounds 4 — 6 may be effective in treating experimental T2DM. Type 2 diabetes mellitus T2DM is a long-lasting and progressive metabolic disease characterized by insulin resistance in several peripheral tissues such as liver, muscle, and adipose, as well as impaired insulin secretion by the pancreas [ 1 ].

Metformin a biguanide, Figure 1 is the most extensively prescribed oral antidiabetic drug for the treatment of T2DM [ 2 ]. The main effect of metformin is to decrease hepatic glucose production, being a perfect agent for controlling fasting hyperglycemia. Due to the central role played by AMPK in cellular energy homeostasis, it has emerged as an attractive drug target for the treatment of a number of metabolic diseases such as type 2 diabetes mellitus T2DM [ 2 ]. Another biguanide, phenformin Figure 1 , also activates AMPK, but in it was retired from the market due to its toxicity, producing lactic acidosis as a major side effect that prompted the withdrawal of phenformin as a treatment for diabetes [ 5 ].

In our ongoing research on molecules with antidiabetic activity [ 6 , 7 ], we report in this manuscript the preparation of ten alicyclic and aromatic biguanides Table 1 , as well as the in vitro activation of AMPK.

Starting materials and solvents were purchased from Sigma-Aldrich and were used without any further purification. Reactions were monitored by thin layer chromatography on 0. The following abbreviations are used: s, singlet; d, doublet; q, quartet; dd, doublet of doublet; t, triplet; m, multiplet; bs, broad signal.

To a solution of dicyandiamide 21 0. After that, the obtained residue was neutralized with a diluted solution of NH 4 OH. Solvent was removed under vacuum, and the residues were washed with water. The crude solid products were then recrystallized from ethanol affording title compounds Figure 2 , Table 1. White crystals obtained from ethanol. Found: C, Mp Primary rat hepatocytes were obtained by collagenase digestion as described by Berry and Friend [ 8 ].

The cultured dishes were then washed three times with PBS to remove unattached dead cells. After this time, the plated cells were washed three times with cold PBS.

All antibodies were purchased from Cell Signaling. Streptozotocin STZ was dissolved in citrate buffer pH 4. Hyperglycemia was confirmed by elevated glucose concentration in plasma, determined after 2 weeks by strip-glucometer. The diabetic animals were divided into three groups of five animals each. Blood glucose concentration was estimated by enzymatic glucose oxidase method using a commercial glucometer [ 13 ]. Normoglycemic rats were divided into groups of five animals each.

Blood samples were collected from the tail tip at 0 before oral administration , 1, 1. Discovery Studio version 3. Docking calculations were conducted with AutoDock Vina. The program performs several runs in each docking experiment. Each run provides one predicted binding mode. The AutoDock Vina plugin through Pymol program was used, where we generated the grid maps. Each grid was centered at the crystallographic coordinates of the cocrystal ligand.

Also, the protein file was selected as the rigid part, and the ligand file as the flexible one, allowing all its torsions to rotate during docking. AutoDock Vina uses default algorithms of searching and automatically prepares the files for use as it adds charges and polar hydrogens to the protein necessary to perform scoring calculations; it clusters showing only the main results. The number of docking runs was After finishing, the poses were visualized on Pymol and compared against the cocrystalized ligand over the protein.

The root mean square deviation between the cocrystal ligand and the docked structure was less than 2. This value indicates that the parameters for docking simulations are good in reproducing orientation and conformation in the X-ray crystal structure of enzyme and receptors. Compounds 1 — 10 were designed on the basis of the structure of metformin and phenformin Figure 1 , Table 1 , maintaining the biguanide group, removing both dimethyl and phenylethyl side chains, and substituting the proximal amino group with diethyl or cycloalkyl groups using a straightforward approach called chain-ring transformation, attaining conformational constraint connecting alkyl substituents to give the corresponding cyclic analogues.

The homologation criteria were employed to pass from pyrrolidine to piperidine. A homologous series is a group of compounds that differ by a constant unit, generally a methylene group [ 14 ]. Morpholine and 4-methylpiperazine derivatives were selected as isosteric replacements of piperidine.

Benzyl or 4-substituted phenyl groups were designed as lower homologues, with one or two methylene groups less than those presented by phenformin. Some physicochemical properties of compounds 1 — 10 are described in Table 1. Compounds 1 — 10 were prepared in a single step starting from cyanoguanidine 21 , which was condensed with several alkylamines 11 — 15 or aryl amines 16 — 20 under reflux conditions Figure 2.

Their chemical structures were confirmed by spectral data NMR and mass spectra , and their purity was ascertained by elemental analysis. To test the ability of each derivative to activate AMPK, an in vitro assay was performed on a primary culture of hepatocytes. Aliquots of stock solutions of the analogues dissolved in DMSO were diluted with the assay buffer, using metformin as positive control. The phosphorylation of AMPK and its target ACC were assessed by immunoblot analysis, where it is observed that aliphatic or alicyclic compounds 1 — 3 were not able to activate the enzyme data not shown.

Conversely, we found that AMPK phosphorylation activation was increased in a concentration-dependent manner with compounds 4 , 5 , and 6 , being more pronounced with compound 6 ; in fact, the concentrations of three of the compounds required for activation of AMPK were significantly lower than those of metformin Figure 3. On the other hand, aromatic biguanides 7 — 10 were unable to activate the AMPK. These results are in accordance with those reported in a parallel work performed with closely related biguanides [ 15 ].

This enzyme is one of the targets of AMPK. The phosphorylation of this enzyme causes its inactivation, and this leads to an increase in the oxidation of free fatty acids [ 16 ]. The phosphorylation of ACC indicates that analogues induce the phosphorylation activation of AMPK, which leads to modification of the different metabolic pathways. Based on the in vitro biological assay of AMPK activation, the most active compounds were selected to explain the experimental activities.

Figure 4 shows the binding mode of compounds 4 — 6 found by AutoDock showing an extensive hydrogen bonds network. These results contribute to explaining at the molecular level the relevant activities of compounds 4 — 6 in the in vitro test.

With the aim of anticipating potential toxicity issues of compounds 4 — 6 , a computational prediction of safety profiles was performed. Several basic nitrogen compounds are associated with cardiovascular risks due to human ether-a-go-go related gene hERG channel blockade [ 18 — 20 ].

In the calculation of acute toxicity, compounds 4 — 6 demonstrated similar predicted LD 50 than metformin and phenformin by two different administration routes. Compounds 4 — 6 were the most potent AMPK activators of the series, and they were selected in order to evaluate their in vivo antidiabetic activity using an STZ-nicotinamide non-insulin-dependent diabetes mellitus rat model.

The antidiabetic assay shows that analogue 4 significantly reduced glucose levels compared to the vehicle and is as good as to the control group metformin , having at 7 hours after administration a percentage of glucose decrease of Analogue 5 also decreased glucose levels compared to vehicle.

In addition, its effect was similar to that presented by metformin at the same dose. The activity was retained during the 7 hours of experimentation.

Analogue 6 , which was the compound that showed the best activity on AMPK activation, was also active in the in vivo assay, and its antihyperglycemic effect was retained throughout the assay. In order to verify the plausible antihyperglycemic effect of compound 6 , glucose tolerance test curves in normoglycemic rats were obtained.

As shown in Figure 6 , compound 6 displayed a significant reduction of hyperglycemic peak which was attained at 0. In Figure 6 , it can be seen that the animals treated with analogue 6 reached a lower hyperglycemic value than the animals treated with metformin and compared to the vehicle, 0. During the experiment, glucose levels did not decrease beyond baseline, indicating that the antidiabetic effect of compound 6 is due to an antihyperglycemic action rather than a hypoglycemic effect.

Also, compounds 4 — 6 did not increase the lactic acid concentrations in plasma of rats tested less than 1. With these results, it can be concluded that the mechanism of action of the analogues 4 — 6 that confer their antidiabetic activity is similar to metformin, through the activation of AMPK and of some of the pathways that are regulated by this enzyme.

Previously in vitro reports agree with the AMPK results obtained with compound 6 [ 15 ]. However, in our current study, we have demonstrated the robust in vivo effect produced by this compound after an oral administration.

Further studies are being conducted by us in order to demonstrate the cardiovascular action of compound 6 in a murine model of fructose-induced insulin resistance [ 21 ]. In summary, ten alkarylbiguanides have been developed as promising compounds for the treatment of type 2 diabetes mellitus. Compounds 4 — 6 a exhibited AMPK activation similar to or greater than metformin, b demonstrated a robust reduction of glucose levels with marked in vivo antihyperglycemic efficacy, and c showed predicted low toxicity profiles and any experimental evidence of lactic acidosis.

These compounds could be an alternative to metformin, the only biguanide currently available. The authors declare that there are no conflicts of interest regarding the publication of this paper. The authors are in debt with Abraham Gutierrez-Hernandez, M. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors.

Read the winning articles. Journal overview. Special Issues. Academic Editor: Teodorico C. Received 16 Aug Accepted 22 Oct Published 15 Nov Introduction Type 2 diabetes mellitus T2DM is a long-lasting and progressive metabolic disease characterized by insulin resistance in several peripheral tissues such as liver, muscle, and adipose, as well as impaired insulin secretion by the pancreas [ 1 ].

Figure 1. Table 1. Physicochemical properties of biguanides 1 —

Metformin activates AMPK, but increases homocysteine

This is an open access article distributed under the terms of Creative Commons Attribution License. Gastric cancer is a leading cause of mortality worldwide according to the World Health Organization, accounting for , mortalities in 1. According to the annual report by the Ministry of Health and Welfare in Taiwan, gastric cancer is the 7th leading cause of cancer-associated mortality. The mortality rate of gastric cancer was 9. The major risk factors of gastric cancer are Helicobacter pylori infection, and dietary and environmental factors 3 , 4. Paclitaxel, carboplatin, cisplatin, 5-fluorouracil, capecitabine and leucovorin are recognized as the most effective agents against gastric cancer 6 , 7. Apart from surgery, no satisfactory chemotherapeutic strategies are currently available for gastric cancer, and novel effective therapies are required to improve gastric anticancer treatment.

Will Metformin Become the First Anti-Aging Drug?

Despite being the frontline therapy for type 2 diabetes, the mechanisms of action of the biguanide drug metformin are still being discovered. Transcriptionally, AMPK and mTORC1 were both important for regulation of anabolic metabolism and inflammatory programs triggered by metformin treatment. The hepatic transcriptional response in mice on high-fat diet treated with metformin was largely ablated by AMPK deficiency under the conditions examined, indicating the essential role of this kinase and its targets in metformin action in vivo. Article published online ahead of print. View all Shokhirev 3 , Yelena Dayn 4 , Gene W. Yeo 2 and Reuben J. Abstract Despite being the frontline therapy for type 2 diabetes, the mechanisms of action of the biguanide drug metformin are still being discovered. Footnotes Supplemental material is available for this article.

Metformin as an anti-inflammatory agent: a short review

Metformin , sold under the brand name Glucophage among others, is the first-line medication for the treatment of type 2 diabetes , [6] [7] [8] particularly in people who are overweight. Metformin is generally well tolerated. Metformin is a biguanide antihyperglycemic agent. Metformin was discovered in Metformin is used to lower the blood sugar in those with type 2 diabetes.

An AMPK-dependent, non-canonical p53 pathway plays a key role in adipocyte metabolic reprogramming

Metformin is a first-line therapy for the treatment of type 2 diabetes, due to its robust glucose-lowering effects, well-established safety profile, and relatively low cost. While metformin has been shown to have pleotropic effects on glucose metabolism, there is a general consensus that the major glucose-lowering effect in patients with type 2 diabetes is mostly mediated through inhibition of hepatic gluconeogenesis. However, despite decades of research, the mechanism by which metformin inhibits this process is still highly debated. A key reason for these discrepant effects is likely due to the inconsistency in dosage of metformin across studies. Thus, these mechanisms have been challenged in recent years and new mechanisms have been proposed.

Molecular Mechanisms of Metformin for Diabetes and Cancer Treatment

Cardiovascular Diabetology volume 15 , Article number: 88 Cite this article. Metrics details. Endothelial dysfunction has been suggested as a possible causal link between hyperglycemia and microvascular complications in diabetes mellitus. The effect of metformin on endothelial progenitor cells EPCs is still unclear. This study was designed to test the hypothesis that metformin could accelerate wound healing by improving the impaired EPC functions in streptozotocin-induced diabetic mice. Wound closure was evaluated by wound area and number of CD31 stained capillaries. Metformin accelerated wound closure and stimulated angiogenesis in diabetic mice.

microRNAs and cancer metabolism reprogramming: the paradigm of metformin

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RELATED VIDEO: METFORMIN or BERBERINE? The Same? 1 HUGE Difference! [2021]

The design was conceived using isosteric replacement, chain-ring transformation, and lower and higher homologation strategies. All compounds were obtained as crystals and their structure was confirmed on the basis of their spectral data NMR and mass spectra , and their purity was ascertained by microanalysis. The results indicated that compounds 4 , 5 , and 6 showed similar or even better effect compared to metformin. Compound 6 was selected for an oral glucose tolerance test, showing an antihyperglycemic effect similar to metformin.

Purpose : Inflammation has been recognized as a key component in the pathogenesis of diabetic retinopathy DR. We have previously reported substantially reduced severity of DR in metformin-treated type 2 diabetes patients, and a significant anti-inflammatory effect of metformin in the retinal vasculature. Metformin-treated proliferative diabetic retinopathy PDR patients had reduced levels of human intravitreal inflammatory cytokines than non-metformin-treated PDR patients. This study was to explore potential mechanisms of the anti-inflammatory effect of metformin. Methods : Undiluted core vitreous biopsies were collected for analysis of a panel of inflammatory and immune cytokines using a Human Cytokine Array. Results : Among 36 inflammatory cytokines on the array, 24 were detected in the vitreous of PDR patients. The anti-inflammatory action of metformin may play a key role in its vascular protective effect.

Metformin is a commonly used drug for treating patients with Type 2 diabetes. Extensive research has shown that metformin can also be used as an anti-aging therapy. For this reason, many people without diabetes, including Silicon Valley techies , take the inexpensive drug in the hopes it will keep them healthy longer.