METFORMIN

First synthesized and found to reduce blood sugar in the 1920s, metformin was forgotten for the next two decades as research shifted to insulin and other antidiabetic drugs. Interest in metformin was rekindled in the late 1940s after several reports that it could reduce blood sugar levels in people, and in 1957, French physician Jean Sterne published the first clinical trial of metformin as a treatment for diabetes. It was introduced to the United Kingdom in 1958, Canada in 1972, and the United States in 1995.

  • Metformin is now believed to be the most widely prescribed antidiabetic drug in the world; in the United States alone, more than 48 million prescriptions were filled in 2010 for its generic formulations.[12][13

 

Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis

Full pdf

This systematic review investigated whether the insulin sensitiser metformin has a geroprotective effect in humans. Pubmed and Embase were searched along with databases of unpublished studies. Eligible research investigated the effect of metformin on all-cause mortality or diseases of ageing relative to non-diabetic populations or diabetics receiving other therapies with adjustment for disease control achieved. Overall, 260 full-texts were reviewed and 53 met the inclusion criteria.

Diabetics taking metformin had significantly lower all-cause mortality than non-diabetics (hazard ratio (HR)= 0.93, 95%CI 0.88-0.99), as did diabetics taking metformin compared to diabetics receiving non-metformin therapies (HR= 0.72, 95%CI 0.65-0.80), insulin (HR=0.68, 95%CI 0.63-0.75) or sulphonylurea (HR= 0.80, 95%CI 0.66-0.97). Metformin users also had reduced cancer compared to non-diabetics (rate ratio= 0.94, 95%CI 0.92-0.97) and cardiovascular disease (CVD) compared to diabetics receiving non-metformin therapies (HR= 0.76, 95%CI 0.66-0.87) or insulin (HR= 0.78, 95%CI 0.73-0.83). Differences in baseline characteristics were observed which had the potential to bias findings, although statistical adjustments were made.

The apparent reductions in all cause mortality and diseases of ageing associated with metformin use suggest that metformin could be extending life and healthspans by acting as a geroprotective agent.

Cancer Lett. 2019 Sep 4;465:94-104. doi: 10.1016/j.canlet.2019.08.020. [Epub ahead of print]

Cancer stem cells in prostate cancer radioresistance.

Tsao T1, Beretov J2, Ni J1, Bai X1, Bucci J1, Graham P1, Li Y3.

Abstract

Cancer stem cells (CSCs) in prostate cancer (CaP) are regarded as major contributors to radioresistance due to complex mechanisms including enhanced DNA repair, increased intracellular reactive oxygen species scavenging, activation of anti-apoptotic pathways, microenvironment hypoxia, epithelial-to-mesenchymal transition (EMT) and autophagy. They are also believed to cause tumour recurrence and metastasis due to their unique capability to survive and replicate the heterogeneity of the original tumour. Finding markers of prostate CSCs (PCSC) for identification, prognostication and targeting is key in enhancing therapeutic and clinical outcomes. Markers such as aldehyde dehydrogenase, CD44, integrins and EMT markers have been proved to show great potential in being sensitive and specific to the presence of PCSCs. Novel therapies such as Hedgehog and Wnt pathway inhibitors, angiogenesis inhibitors and metformin show potential in eliminating PCSCs to improve therapeutic outcomes. Here, we review the current state of the literature regarding mechanisms of PCSC radioresistance, promising PCSC markers and novel PCSC-specific therapeutic approaches and their implications in CaP treatment and prognosis.

Anim Cells Syst (Seoul). 2019 May 14;23(4):302-309. doi: 10.1080/19768354.2019.1614092. eCollection 2019.

Metformin inhibits cervical cancer cell proliferation via decreased AMPK O-GlcNAcylation.

Abstract

Metformin is a widely used drug for the treatment of type 2 diabetes. Antidiabetic drugs are also known to influence cancer progression, as high glucose levels affect both cancer and diabetes. Metformin induces cell cycle arrest in cancer cells, but the underlying mechanism remains unclear in cervical cancer system. Here, we examined how metformin affects cell cycle arrest and apoptosis in cervical cancer cells. Western blot analysis showed that levels of O-linked N-acetylglucosamine (O-GlcNAc) and O-GlcNAc transferase (OGT) were increased in cervical cancer cells; these effects were reversed by metformin treatment. Immunoprecipitation analysis was used to examine the interplay between O-GlcNAcylation and phosphorylation in HeLa cells, revealing that metformin decreased O-GlcNAcylated AMP-activated protein kinase (AMPK) and increased levels of phospho-AMPK compared to untreated cells. These results were associated with decreased cell cycle arrest and apoptotic cell death in HeLa cells, as shown by flow cytometry. Moreover, 6-diazo-5-oxo-L-norleucine (a glutamine fructose-6-phosphate aminotransferase inhibitor) or thiamet G (an O-GlcNAcase inhibitor) decreased or increased levels of O-GlcNAcylated AMPK, and increased or decreased levels of phosphorylated AMPK, respectively, suggesting that O-GlcNAc modification affects AMPK activation. Of note, we found that metformin treatment of HeLa cells increased the levels of p21 and p27 (which are AMPK-dependent cell cycle inhibitors), leading to increased cell cycle arrest and apoptosis in HeLa cells compared to untreated cells.

 * These findings suggest that metformin may serve as a useful antiproliferative drug in cervical cancer cells, with potential therapeutic benefit.

Anti-inflammatory mechanism of metformin and its effects in intestinal inflammation and colitis-associated colon cancer

The aim of this study is to evaluate the effect of metformin on intestinal inflammation.

METHODS:

COLO205 cells were pretreated with metformin and stimulated with tumor necrosis factor (TNF)-α. Expression of interleukin (IL)-8 was determined by luciferase assay and real-time PCR. Inhibitor of kappaB (IκB) phosphorylation/degradation and adenosine monohosphate-activated protein kinase (AMPK) activity were evaluated by Western blotting. DNA-binding activity of transcription factor nuclear factor-kappaB (NF-κB) was assessed by electrophoretic mobility shift assay. In an acute colitis model, mice were given 4% dextran sulfate sodium (DSS) for 5 days. IL-10−/− mice were used to evaluate the effect of metformin on chronic colitis. In an inflammation-associated tumor model, mice were given a single intraperitoneal injection of azoxymethane followed by three cycles of 2% DSS for 5 days and 2 weeks of free water consumption.

RESULTS:

Metformin significantly inhibited IL-8 induction in COLO 205 cells stimulated with TNF-α. Metformin attenuated IκBα phosphorylation and NF-κB DNA-binding activity. Administration of metformin significantly reduced the severity of DSS-induced colitis. In addition, DSS-induced IκB kinase (IKK) activation was significantly reduced in mice treated with metformin. Metformin significantly attenuated the severity of colitis in IL-10−/− mice, induced AMPK activity in intestinal epithelial cells, and inhibited the development of colitic cancer in mice.

CONCLUSIONS:

These results indicate that metformin suppresses NF-κB activation in intestinal epithelial cells and ameliorates murine colitis and colitis-associated tumorigenesis in mice, suggesting that metformin could be a potential therapeutic agent for the treatment of inflammatory bowel disease.

J Clin Endocrinol Metab. 2015 Mar;100(3):E427-32. doi: 10.1210/jc.2014-3045. Epub 2015 Jan 15.

Metformin reverts the secretion of CXCL8 induced by TNF-α in primary cultures of human thyroid cells: an additional indirect anti-tumor effect of the drug.

Rotondi M1, Coperchini F, Pignatti P, Magri F, Chiovato L.

Author information

Abstract

CONTEXT:

Metformin displays both direct and indirect anti-tumor effects. CXCL8 is a crucial downstream mediator of Nuclear-Factor-κB signaling related to the growth and progression of thyroid cancers. Targeting CXCL8 results in prolonged survival and reduced metastatic spread in in-vivo animal models of thyroid tumors.

OBJECTIVE:

This study aimed to evaluate whether metformin inhibits the secretion of CXCL8 induced by Tumor-Necrosis-Factor-α (TNF-α) in primary cultures of normal and tumor human thyroid cells as well as in thyroid cancer cell lines.

METHODS:

Normal human thyrocytes, papillary thyroid cancer cells, and thyroid cancer cell lines (TPC-1 and BCPAP) were stimulated with TNF-α (10 ng/mL) alone or in combination with metformin (0.01, 0.1, 1, 2.5, 5, and 10mM). CXCL8 levels were measured in the cell supernatants after 24 hours.

RESULTS:

Metformin significantly and dose-dependently inhibited the TNF-α-induced CXCL8 secretion in both normal thyrocytes (ANOVA: F = 42.04; P < .0001) and papillary thyroid cancer cells (ANOVA: F = 21.691; P < .0001) but not in TPC-1 and BCPAP cell lines.

CONCLUSION:

Metformin inhibits the TNF-α-induced CXCL8 secretion in primary cultures of normal thyroid cells and differentiated thyroid cancer cells at least of the most frequent poorly aggressive phenotype. The recruitment of neutrophils within the thyroid gland is a crucial metastasis-promoting factor, and it depends on the amount of CXCL8 produced by both tumor cells and by the more abundant normal thyroid cells exposed to TNF-α. Thus, the here-reported inhibiting effect of metformin on TNF-α-induced CXCL8 secretion could be considered as a further indirect anticancer property of the drug.

  • 1Unit of Internal Medicine and Endocrinology, Laboratory for Endocrine Disruptors (M.R., F.C., F.M., L.C.), and Allergy and Immunology Unit (P.P.), Fondazione Salvatore Maugeri I.R.C.C.S., 27100 Pavia, Italy.

Combination of Metformin and Hyperbaric oxygen Therapy increases NOS concentrations

Source: Folia Medica Indonesiana . oct2010, Vol. 46 Issue 4, p241-246. 6p.

Author(s): Dewi, Bernadette Dian Novita; Guritno, Endang Isbandiati1

Abstract: Metformin is the first line drug of type 2 diabetes patients. Its improves Insulin sensitivity as mechanism of action via activation of cyclic-adenomonophosphat dependent protein kinase (AMPK), reduces hepatic glucose product by reducing gluconeogenesis, and increases endothelial Nitric Oxide Synthase (eNOS).

Chronic hyperglycemia induces Nitric Oxide (NO) dysfunction, where as, NO is important vasodilator in human body. Due to of NO dysfunction, cells become hypoxia to ischemic then cell apoptotic, included cells beta pancreatic.

The aim of this study to find new management in optimalisation of Metformin therapy in patients with type 2 diabetes, especially in the improvement of blood glucose into 'normoglycemia' and eNOS, the important indicator for vascular condition. Hyperbaric oxygen (HBO) therapy, 2.4 ATA oxygen, which is given 3x30 minutes with 5 minutes intervals with air for 10 times within 10 days continually, reduces directly blood glucose, improves NO function and inhibits cytokines released. Therefore, HBO therapy is considered as an adjuvant treatment in type 2 DM beside Metformin. This study was conducted by a clinical pre and post experiment without control. The ten men's correspondents in the study were chosen randomly. Blood glucose and eNOS concentration are used as the parameters in this study. They were examined before, during and after the combination treatment of Metformin and HBO therapy were given.

The concentration of eNOS were increased significantly and also with the blood glucose condition, it reduced significantly after the combination treatment of Metformin and HBO therapy.

  • In conclusion, HBO therapy works synergism with Metformin in diabetes type2 therapy, especially by improving Metformin therapy in reduced blood glucose and raised eNOS. It is a new hope to prevent micro and macro angiopathy's complication in patient with chronic hyperglycemia caused by type 2 diabetes.

J Gastroenterol Hepatol. 2014 Mar;29(3):502-10.

Anti-inflammatory mechanism of metformin and its effects in intestinal inflammation and colitis-associated colon cancer

Koh SJ, Kim JM, Kim IK, Ko SH, Kim JS.

Abstract

BACKGROUND AND AIM:

The aim of this study is to evaluate the effect of metformin on intestinal inflammation.

METHODS:

COLO205 cells were pretreated with metformin and stimulated with tumor necrosis factor (TNF)-α. Expression of interleukin (IL)-8 was determined by luciferase assay and real-time PCR. Inhibitor of kappaB (IκB) phosphorylation/degradation and adenosine monohosphate-activated protein kinase (AMPK) activity were evaluated by Western blotting. DNA-binding activity of transcription factor nuclear factor-kappaB (NF-κB) was assessed by electrophoretic mobility shift assay. In an acute colitis model, mice were given 4% dextran sulfate sodium (DSS) for 5 days. IL-10−/− mice were used to evaluate the effect of metformin on chronic colitis. In an inflamation-associated tumor model, mice were given a single intraperitoneal injection of azoxymethane followed by three cycles of 2% DSS for 5 days and 2 weeks of free water consumption.

RESULTS:

Metformin significantly inhibited IL-8 induction in COLO 205 cells stimulated with TNF-α. Metformin attenuated IκBα phosphorylation and NF-κB DNA-binding activity. Administration of metformin significantly reduced the severity of DSS-induced colitis. In addition, DSS-induced IκB kinase (IKK) activation was significantly reduced in mice treated with metformin. Metformin significantly attenuated the severity of colitis in IL-10−/− mice, induced AMPK activity in intestinal epithelial cells, and inhibited the development of colitic cancer in mice.

CONCLUSIONS:

These results indicate that metformin suppresses NF-κB activation in intestinal epithelial cells and ameliorates murine colitis and colitis-associated tumorigenesis in mice, suggesting that metformin could be a potential therapeutic agent for the treatment of inflammatory bowel disease.

 

Diabet Med. 2015 May 13. doi: 10.1111/dme.12800. [Epub ahead of print]

Cardiovascular risks associated with second-line oral antidiabetic agents added to metformin in patients with Type 2 diabetes: a nationwide cohort study

Chang YC1,2,3,4, Chuang LM2,3,5, Lin JW2,3,6, Chen ST5, Lai MS5, Chang CH2,3,5.

AIM:

To compare the cardiovascular risks associated with second-line oral antidiabetic agents added to initial metformin therapy in a large nationwide observational study.

METHODS:

We conducted a nationwide retrospective cohort study using the Taiwan National Health Insurance database. A total of 36 118 users of different add-on oral antidiabetic agents (sulphonylureas, glinides, pioglitazone, α-glucosidase inhibitors and dipeptidyl peptidase-4 inhibitors) after initial metformin therapy were included in the analysis. The reference group was sulphonylureas added to metformin, the most commonly used combination regimen. The main outcomes of interest were hospitalizations for any cardiovascular event including acute myocardial infarction, congestive heart failure and ischaemic stroke. In the main analysis, all patients were followed within their initiation groups until the study end, disregarding any changes in treatment status over time.

RESULTS:

In intention-to-treat analyses, there was no difference in the risk of any cardiovascular event among the add-on combination treatment groups, but significantly lower risks of acute myocardial infarction were found for the glinides plus metformin treatment group (crude hazard ratio 0.52, adjusted hazard ratio 0.39; 95% CI 0.20-0.75) and for the α-glucosidase inhibitors plus metformin treatment group (crude hazard ratio 0.63, adjusted hazard ratio 0.54; 95% CI 0.31-0.95). No difference in risk of congestive heart failure or ischaemic stroke risk was found among the combination treatment groups. In secondary as-treated analyses, similar but less significant associations were found as compared with the primary intention-to-treat analyses for all treatment groups.

CONCLUSION:

There were no differences in overall cardiovascular risks among several add-on second-line oral antidiabetic agents; however, glinide plus metformin and α-glucosidase inhibitors plus metformin combination therapies might be associated with lower risks of acute myocardial infarction. This article is protected by copyright. All rights reserved.

Biochem J. 2014 Sep 15;462(3):475-87. doi: 10.1042/BJ20140620.

Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria.

Bridges HR1, Jones AJ1, Pollak MN2, Hirst J1.

Author information

Abstract

The biguanide metformin is widely prescribed for Type II diabetes and has anti-neoplastic activity in laboratory models. Despite evidence that inhibition of mitochondrial respiratory complex I by metformin is the primary cause of its cell-lineage-specific actions and therapeutic effects, the molecular interaction(s) between metformin and complex I remain uncharacterized. In the present paper, we describe the effects of five pharmacologically relevant biguanides on oxidative phosphorylation in mammalian mitochondria. We report that biguanides inhibit complex I by inhibiting ubiquinone reduction (but not competitively) and, independently, stimulate reactive oxygen species production by the complex I flavin. Biguanides also inhibit mitochondrial ATP synthase, and two of them inhibit only ATP hydrolysis, not synthesis. Thus we identify biguanides as a new class of complex I and ATP synthase inhibitor. By comparing biguanide effects on isolated complex I and cultured cells, we distinguish three anti-diabetic and potentially anti-neoplastic biguanides (metformin, buformin and phenformin) from two anti-malarial biguanides (cycloguanil and proguanil): the former are accumulated into mammalian mitochondria and affect oxidative phosphorylation, whereas the latter are excluded so act only on the parasite. Our mechanistic and pharmacokinetic insights are relevant to understanding and developing the role of biguanides in new and existing therapeutic applications, including cancer, diabetes and malaria.