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Akimoto H, Nagashima T, Minagawa K, Hayakawa T, Takahashi Y, Asai S. Non-Linear Dose-Response Relationship for Metformin in Japanese Patients With Type 2 Diabetes: Analysis of Irregular Longitudinal Data by Interpretable Machine Learning Models. Pharmacol Res Perspect 2025; 13:e70055. [PMID: 39908147 PMCID: PMC11797302 DOI: 10.1002/prp2.70055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 11/11/2024] [Accepted: 12/10/2024] [Indexed: 02/07/2025] Open
Abstract
The dose-response relationship between metformin and change in hemoglobin A1c (HbA1c) shows a maximum at 1500-2000 mg/day in patients with type 2 diabetes (T2D) in the U.S. In Japan, there is little evidence on the HbA1c-lowering effect of high-dose metformin because the maintenance and maximum doses of metformin were raised in 2010. The aim of this study was to investigate whether there is saturation of the dose-response relationship for metformin in Japanese T2D patients. Longitudinal clinical information of T2D patients was extracted from electronic medical records. Supervised machine learning models with random effect were constructed to predict change in HbA1c: generalized linear mixed-effects models (GLMM) with/without a feature selection and combining tree-boosting with Gaussian process and mixed-effects models (GPBoost). GPBoost was interpreted by SHapley Additive exPlanations (SHAP) and partial dependence. GPBoost had better predictive performance than GLMM with/without feature selection: root mean square error was 0.602 (95%CI 0.523-0.684), 0.698 (0.629-0.774) and 0.678 (0.609-0.753), respectively. Interpretation of GPBoost by SHAP and partial dependence suggested that the relationship between the daily dose of metformin and change in HbA1c is non-linear rather than linear, and the HbA1c-lowering effect of metformin reaches a maximum at 1500 mg/day. Interpretation of GPBoost, a non-linear supervised machine-learning algorithm, suggests that there is saturation of the dose-response relationship of metformin in Japanese patients with T2D. This finding may be useful for decision-making in pharmacotherapy for T2D.
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Affiliation(s)
- Hayato Akimoto
- Division of Pharmacology, Department of Biomedical SciencesNihon University School of Medicine; Oyaguchi‐Kamicho 30‐1Itabashi‐kuTokyoJapan
- Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research CenterNihon University School of MedicineItabashi‐kuTokyoJapan
| | - Takuya Nagashima
- Division of Pharmacology, Department of Biomedical SciencesNihon University School of Medicine; Oyaguchi‐Kamicho 30‐1Itabashi‐kuTokyoJapan
- Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research CenterNihon University School of MedicineItabashi‐kuTokyoJapan
| | - Kimino Minagawa
- Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research CenterNihon University School of MedicineItabashi‐kuTokyoJapan
| | - Takashi Hayakawa
- Division of Pharmacology, Department of Biomedical SciencesNihon University School of Medicine; Oyaguchi‐Kamicho 30‐1Itabashi‐kuTokyoJapan
- Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research CenterNihon University School of MedicineItabashi‐kuTokyoJapan
| | - Yasuo Takahashi
- Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research CenterNihon University School of MedicineItabashi‐kuTokyoJapan
| | - Satoshi Asai
- Division of Pharmacology, Department of Biomedical SciencesNihon University School of Medicine; Oyaguchi‐Kamicho 30‐1Itabashi‐kuTokyoJapan
- Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research CenterNihon University School of MedicineItabashi‐kuTokyoJapan
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Anwardeen NR, Naja K, Elrayess MA. Advancements in precision medicine: multi-omics approach for tailored metformin treatment in type 2 diabetes. Front Pharmacol 2024; 15:1506767. [PMID: 39669200 PMCID: PMC11634602 DOI: 10.3389/fphar.2024.1506767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Accepted: 11/20/2024] [Indexed: 12/14/2024] Open
Abstract
Metformin has become the frontline treatment in addressing the significant global health challenge of type 2 diabetes due to its proven effectiveness in lowering blood glucose levels. However, the reality is that many patients struggle to achieve their glycemic targets with the medication and the cause behind this variability has not been investigated thoroughly. While genetic factors account for only about a third of this response variability, the potential influence of metabolomics and the gut microbiome on drug efficacy opens new avenues for investigation. This review explores the different molecular signatures to uncover how the complex interplay between genetics, metabolic profiles, and gut microbiota can shape individual responses to metformin. By highlighting the insights from recent studies and identifying knowledge gaps regarding metformin-microbiota interplay, we aim to highlight the path toward more personalized and effective diabetes management strategies and moving beyond the one-size-fits-all approach.
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Affiliation(s)
| | - Khaled Naja
- Biomedical Research Center, Qatar University, Doha, Qatar
| | - Mohamed A. Elrayess
- Biomedical Research Center, Qatar University, Doha, Qatar
- College of Medicine, QU Health, Qatar University, Doha, Qatar
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Peng CY, Xie QY, Xie X, Tang LY, Ma TX, Ke DW, Tu ZC, Zhang L. Extraction, phytochemicals characterization, in vivo and in vitro anti-diabetic ability of non-extractable polyphenols from Undaria pinnatifida. Food Res Int 2024; 196:115021. [PMID: 39614473 DOI: 10.1016/j.foodres.2024.115021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 08/11/2024] [Accepted: 09/01/2024] [Indexed: 12/01/2024]
Abstract
Undaria pinnatifida (Up) is an edible seaweed known for its abundant nutrients and active compounds. In this research, six different methods, including acid hydrolysis extraction (AHE), alkaline hydrolysis extraction (LHE), enzymatic hydrolysis extraction (EHE), as well as their combinations with ultrasonic assisted extraction (AHE-U, LHE-U, EHE-U), were applied to extract non-extractable polyphenols from Up (UNEPPs). Results revealed that LHE-U was the most effective way to extract UNEPPs, it gave the highest yield (1.26 %) and total phenolics content (29.88 μg GAE/mg E), as well as considerable antioxidant and in vitro hypoglycemic effects. HPLC-Q-TOF-MS/MS analysis revealed the identification of 36 compounds from ULNEPPs, ferulic acid, p-coumaric acid and ferulic acid 4-O-glucuronide were the major compounds. In vivo study found that ULNEPPs could reduce fasting blood glucose (FBG) level, ameliorate abnormal glucose metabolism and dyslipidemia, repair insulin resistance and pancreas islet damage in type 2 diabetes (T2D) mice. Additionally, RT-qPCR analysis revealed that ULNEPPs improved glucose metabolism through the up-regulation of gene expression levels of Pi3k, Glut4, Akt, Ampk and the down-regulation of gene expression levels of Foxo1, Pgc-1α, Gsk-3β, Glut4, and G6pc. These results evidence that has the potential as dietary ingredients for preventing and treating T2D.
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Affiliation(s)
- Chun-Yan Peng
- National R&D Center of Freshwater Fish Processing, College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
| | - Quan-Yuan Xie
- College of Life Science, Nanchang University, Nanchang, Jiangxi 330047, China
| | - Xing Xie
- National R&D Center of Freshwater Fish Processing, College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi 330022, China.
| | - Lin-Yi Tang
- College of Health, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
| | - Tian-Xin Ma
- National R&D Center of Freshwater Fish Processing, College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
| | - Dai-Wei Ke
- National R&D Center of Freshwater Fish Processing, College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
| | - Zong-Cai Tu
- College of Health, Jiangxi Normal University, Nanchang, Jiangxi 330022, China; National R&D Center of Freshwater Fish Processing, College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi 330022, China; State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang, Jiangxi 330047, China
| | - Lu Zhang
- College of Health, Jiangxi Normal University, Nanchang, Jiangxi 330022, China; National R&D Center of Freshwater Fish Processing, College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi 330022, China.
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Naidoo K, Khathi A. Effects of Gossypetin on Glucose Homeostasis in Diet-Induced Pre-Diabetic Rats. Molecules 2024; 29:4410. [PMID: 39339405 PMCID: PMC11434540 DOI: 10.3390/molecules29184410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 09/12/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
Natural flavonoids exert many potential health benefits, including anti-hyperglycaemic effects. However, the effects of gossypetin (GTIN) on glucose homeostasis in pre-diabetes have not yet been investigated. This study examined the effects of GTIN on key markers of glucose homeostasis in a diet-induced pre-diabetic rat model. Pre-diabetes was induced by allowing the animals to feed on a high-fat high-carbohydrate (HFHC) diet supplemented with 15% fructose water for 20 weeks. Following pre-diabetes induction, the pre-diabetic animals were sub-divided into five groups (n = 6), where they were either orally treated with GTIN (15 mg/kg) or metformin (MET) (500 mg/kg), both with and without dietary intervention, over a 12-week period. The results demonstrated that animals in the untreated pre-diabetic (PD) control group exhibited significantly higher fasting and postprandial blood glucose levels, as well as elevated plasma insulin concentrations and increased homeostatic model assessment for insulin resistance (HOMA2-IR) index, relative to the non-pre-diabetic (NPD) group. Similarly, increased caloric intake, body weight and plasma ghrelin levels were observed in the PD control group. Notably, these parameters were significantly reduced in the PD animals receiving GTIN treatment. Additionally, glycogen levels in the liver and skeletal muscle, which were disturbed in the PD control group, showed significant improvement in both GTIN-treated groups. These findings may suggest that GTIN administration, with or without dietary modifications, may offer therapeutic benefits in ameliorating glucose homeostasis disturbances associated with the PD state.
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Affiliation(s)
- Karishma Naidoo
- Department of Human Physiology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa
| | - Andile Khathi
- Department of Human Physiology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa
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Wen Y, Juhasz A, Cui X. Regulating the absorption and excretion of perfluorooctane sulfonate and its alternatives through influencing enterohepatic circulation. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 933:173161. [PMID: 38735313 DOI: 10.1016/j.scitotenv.2024.173161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 05/09/2024] [Accepted: 05/09/2024] [Indexed: 05/14/2024]
Abstract
Enterohepatic circulation has been reported to play a significant role in the bioaccumulation of PFASs. In this study, the tissue distribution and excretion of PFOS and its alternatives, namely 6:2 and 8:2 fluorotelomer sulfonic acid (FTSA) was investigated using a mouse assay with a focus on role of enterohepatic circulation. Liver was the primarily accumulating organ for PFOS and 8:2 FTSA (33.4 % and 25.8 % of total doses absorbed after 14 days), whereas 65 % of 6:2 FTSA was excreted via urine within 24 h. Peak levels of 8:2 FTSA and PFOS were found in the gallbladder, implying the important role of enterohepatic circulation in PFASs reabsorption. The role of enterohepatic circulation was further evaluated through co-exposure of 8:2 FTSA and PFOS with medicines (namely metformin (MET) and ursodeoxycholic acid (UDCA)). MET reduced accumulation of 8:2 FTSA and PFOS in the liver by 68.6 % and 65.8 %, through down-regulation of bile acid transporter (Asbt) and enhancement of fecal excretion. Conversely, UDCA raised their concentrations by 21.9 % and 34.6 % compared to that exposed solely to PFASs. A strong positive correlation was identified between PFASs serum levels and Asbt expression. This study illuminated PFAS bioaccumulation mechanisms and suggested potential strategies to mitigate the exposure risks.
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Affiliation(s)
- Yong Wen
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, China
| | - Albert Juhasz
- Future Industries Institute, University of South Australia, Mawson Lakes, South Australia 5095, Australia
| | - Xinyi Cui
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, China.
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Szymczak-Pajor I, Drzewoski J, Wenclewska S, Śliwińska A. Metformin-Associated Gastrointestinal Adverse Events Are Reduced by Probiotics: A Meta-Analysis. Pharmaceuticals (Basel) 2024; 17:898. [PMID: 39065748 PMCID: PMC11279730 DOI: 10.3390/ph17070898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 06/27/2024] [Accepted: 07/01/2024] [Indexed: 07/28/2024] Open
Abstract
Metformin, one of the most frequently used oral glucose-lowering drugs (GLDs), is associated with the occurrence of gastrointestinal (GI) adverse events in approximately 20% of users. These unwanted actions result in non-compliance or even discontinuation of metformin therapy. The aim of the presented meta-analysis was to determine whether adding a drug from the group of sulfonylureas, glitazones, DPP-IV inhibitors, or probiotics to metformin monotherapy may affect the risk of GI side effects. The material for this meta-analysis comprised data from 26 randomized controlled clinical trials (RCTs) published in English. This meta-analysis included 41,048 patients. The PubMed, Cochrane Library, and Clinical Trials databases were thoroughly searched to find relevant RCTs. The Population, Intervention, Comparison, Outcomes, and Study Type (PICOT) structure was used to formulate study selection criteria and the research question. Cochrane Review Manager Software 5.4 was used to carry out analysis of collected data. The results were presented as relative risk (RR) and 95% confidence interval (95% CI) for each group, and p < 0.05 was considered as statistically significant. As expected from clinical practice, metformin was associated with a markedly increased risk of abdominal pain, nausea, and vomiting compared to placebo. In comparison to other GLDs, taking metformin was related to an elevated risk of diarrhea and abdominal pain and to a lowered risk of vomiting and bloating. In turn, adding other GLDs to metformin treatment was associated with an elevated risk of nausea and vomiting than treatment with metformin in monotherapy. However, adding probiotics to metformin therapy was related to a decreased risk of diarrhea, bloating, and constipation. The obtained results demonstrate that the combination of metformin with other GLDs may elevate the risk of nausea and vomiting, whereas combination with probiotics decreases the risk of diarrhea, bloating, and constipation. Thus, the results of our meta-analysis suggest that probiotics may reduce the risk of some GI side effects in people with type 2 diabetes mellitus (T2DM) who started treatment with metformin.
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Affiliation(s)
- Izabela Szymczak-Pajor
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska Str., 92-213 Lodz, Poland
| | - Józef Drzewoski
- Central Teaching Hospital of the Medical University of Lodz, 251 Pomorska Str., 92-213 Lodz, Poland;
| | - Sylwia Wenclewska
- Provincial Hospital Named after Primate Cardinal Stefan Wyszyński, 7 Armii Krajowej Str., 98-200 Sieradz, Poland;
| | - Agnieszka Śliwińska
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska Str., 92-213 Lodz, Poland
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Xie C, Iroga P, Bound MJ, Grivell J, Huang W, Jones KL, Horowitz M, Rayner CK, Wu T. Impact of the timing of metformin administration on glycaemic and glucagon-like peptide-1 responses to intraduodenal glucose infusion in type 2 diabetes: a double-blind, randomised, placebo-controlled, crossover study. Diabetologia 2024; 67:1260-1270. [PMID: 38561463 PMCID: PMC11153273 DOI: 10.1007/s00125-024-06131-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 02/14/2024] [Indexed: 04/04/2024]
Abstract
AIMS/HYPOTHESIS Metformin lowers postprandial glycaemic excursions in individuals with type 2 diabetes by modulating gastrointestinal function, including the stimulation of glucagon-like peptide-1 (GLP-1). The impact of varying the timing of metformin administration on postprandial glucose metabolism is poorly defined. We evaluated the effects of metformin, administered at different intervals before an intraduodenal glucose infusion, on the subsequent glycaemic, insulinaemic and GLP-1 responses in metformin-treated type 2 diabetes. METHODS Sixteen participants with type 2 diabetes that was relatively well-controlled by metformin monotherapy were studied on four separate days in a crossover design. On each day, participants were randomised to receive a bolus infusion of metformin (1000 mg in 50 ml 0.9% saline) via a nasoduodenal catheter at t = -60, -30 or 0 min (and saline at the other timepoints) or saline at all timepoints (control), followed by an intraduodenal glucose infusion of 12.56 kJ/min (3 kcal/min) at t = 0-60 min. The treatments were blinded to both participants and investigators involved in the study procedures. Plasma glucose, insulin and total GLP-1 levels were measured every 30 min between t = -60 min and t = 120 min. RESULTS There was a treatment-by-time interaction for metformin in reducing plasma glucose levels and increasing plasma GLP-1 and insulin levels (p<0.05 for each). The reduction in plasma glucose levels was greater when metformin was administered at t = -60 or -30 min vs t = 0 min (p<0.05 for each), and the increases in plasma GLP-1 levels were evident only when metformin was administered at t = -60 or -30 min (p<0.05 for each). Although metformin did not influence insulin sensitivity, it enhanced glucose-induced insulin secretion (p<0.05), and the increases in plasma insulin levels were comparable on the 3 days when metformin was given. CONCLUSIONS/INTERPRETATION In well-controlled metformin-treated type 2 diabetes, glucose-lowering by metformin is greater when it is given before, rather than with, enteral glucose, and this is associated with a greater GLP-1 response. These observations suggest that administration of metformin before meals may optimise its effect in improving postprandial glycaemic control. TRIAL REGISTRATION www.anzctr.org.au ACTRN12621000878875 FUNDING: The study was not funded by a specific research grant.
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Affiliation(s)
- Cong Xie
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia
| | - Peter Iroga
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
| | - Michelle J Bound
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
| | - Jacqueline Grivell
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
| | - Weikun Huang
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
| | - Karen L Jones
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia
| | - Michael Horowitz
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia
| | - Christopher K Rayner
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia
| | - Tongzhi Wu
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia.
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia.
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Cheng M, Jia X, Ren L, Chen S, Wang W, Wang J, Cong B. Region-Specific Effects of Metformin on Gut Microbiome and Metabolome in High-Fat Diet-Induced Type 2 Diabetes Mouse Model. Int J Mol Sci 2024; 25:7250. [PMID: 39000356 PMCID: PMC11241422 DOI: 10.3390/ijms25137250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 06/26/2024] [Accepted: 06/26/2024] [Indexed: 07/16/2024] Open
Abstract
The glucose-lowering drug metformin alters the composition of the gut microbiome in patients with type 2 diabetes mellitus (T2DM) and other diseases. Nevertheless, most studies on the effects of this drug have relied on fecal samples, which provide limited insights into its local effects on different regions of the gut. Using a high-fat diet (HFD)-induced mouse model of T2DM, we characterize the spatial variability of the gut microbiome and associated metabolome in response to metformin treatment. Four parts of the gut as well as the feces were analyzed using full-length sequencing of 16S rRNA genes and targeted metabolomic analyses, thus providing insights into the composition of the microbiome and associated metabolome. We found significant differences in the gut microbiome and metabolome in each gut region, with the most pronounced effects on the microbiomes of the cecum, colon, and feces, with a significant increase in a variety of species belonging to Akkermansiaceae, Lactobacillaceae, Tannerellaceae, and Erysipelotrichaceae. Metabolomics analysis showed that metformin had the most pronounced effect on microbiome-derived metabolites in the cecum and colon, with several metabolites, such as carbohydrates, fatty acids, and benzenoids, having elevated levels in the colon; however, most of the metabolites were reduced in the cecum. Thus, a wide range of beneficial metabolites derived from the microbiome after metformin treatment were produced mainly in the colon. Our study highlights the importance of considering gut regions when understanding the effects of metformin on the gut microbiome and metabolome.
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Affiliation(s)
- Meihui Cheng
- Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Shijiazhuang 050017, China
- College of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang 050017, China
- National Health Commission Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 102629, China
| | - Xianxian Jia
- Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Shijiazhuang 050017, China
- College of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang 050017, China
- Department of Pathogen Biology, Institute of basic Medicine, Hebei Medical University, Shijiazhuang 050017, China
| | - Lili Ren
- Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Shijiazhuang 050017, China
- National Health Commission Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 102629, China
| | - Siqian Chen
- Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Shijiazhuang 050017, China
- College of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang 050017, China
- National Health Commission Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 102629, China
| | - Wei Wang
- Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Shijiazhuang 050017, China
- College of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang 050017, China
| | - Jianwei Wang
- Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Shijiazhuang 050017, China
- National Health Commission Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 102629, China
| | - Bin Cong
- Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Shijiazhuang 050017, China
- College of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang 050017, China
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Banerjee Y, Patti AM, Giglio RV, Ciaccio M, Vichithran S, Faisal S, Stoian AP, Rizvi AA, Rizzo M. The role of atherogenic lipoproteins in diabetes: Molecular aspects and clinical significance. J Diabetes Complications 2023; 37:108517. [PMID: 37329706 DOI: 10.1016/j.jdiacomp.2023.108517] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 05/21/2023] [Accepted: 05/21/2023] [Indexed: 06/19/2023]
Abstract
Dyslipidaemia plays a prominent role in the genesis of atherosclerotic plaque and the increased cardiovascular risk in diabetes. Macrophages readily take up atherogenic lipoproteins, transforming into foam cells and amplifying vascular damage in the presence of endothelial dysfunction. We discuss the importance of distinct lipoprotein subclasses in atherogenic diabetic dyslipidaemia as well as the effects of novel anti-diabetic agents on lipoprotein fractions and ultimately on cardiovascular risk prevention. In patients with diabetes, lipid abnormalities should be aggressively identified and treated in conjunction with therapeutical agents used to prevent cardiovascular disease. The use of drugs that improve diabetic dyslipidaemia plays a prominent role in conferring cardiovascular benefit in individuals with diabetes.
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Affiliation(s)
- Yajnavalka Banerjee
- Department of Basic Sciences, College of Medicine and Health Sciences, Mohammed Bin Rashid University (MBRU), Dubai, United Arab Emirates.
| | - Angelo M Patti
- Internal Medicine Unit, "Vittorio Emanuele II" Hospital, Castelvetrano, Trapani, Italy
| | - Rosaria V Giglio
- Department of Biomedicine, Neuroscience, and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine, and Laboratory Medicine, University of Palermo, Palermo, Italy; Department of Laboratory Medicine, University Hospital "P. Giaccone", Palermo, Italy
| | - Marcello Ciaccio
- Department of Biomedicine, Neuroscience, and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine, and Laboratory Medicine, University of Palermo, Palermo, Italy; Department of Laboratory Medicine, University Hospital "P. Giaccone", Palermo, Italy
| | - Suhina Vichithran
- Department of Basic Sciences, College of Medicine and Health Sciences, Mohammed Bin Rashid University (MBRU), Dubai, United Arab Emirates
| | - Shemima Faisal
- Department of Basic Sciences, College of Medicine and Health Sciences, Mohammed Bin Rashid University (MBRU), Dubai, United Arab Emirates
| | - Anca Panta Stoian
- Department of Diabetes, Nutrition, and Metabolic Diseases, Carol Davila University of Medicine, Bucharest, Romania; "Prof. Dr.N.C.Paulescu" National Institute of Diabetes, Nutrition and Metabolic Diseases, Bucharest, Romania
| | - Ali Abbas Rizvi
- Department of Medicine, University of Central Florida College of Medicine, Orlando, FL, USA
| | - Manfredi Rizzo
- Department of Basic Sciences, College of Medicine and Health Sciences, Mohammed Bin Rashid University (MBRU), Dubai, United Arab Emirates; Department of Diabetes, Nutrition, and Metabolic Diseases, Carol Davila University of Medicine, Bucharest, Romania; "Prof. Dr.N.C.Paulescu" National Institute of Diabetes, Nutrition and Metabolic Diseases, Bucharest, Romania; School of Medicine, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (Promise), University of Palermo, Italy
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10
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Zubiaga L, Briand O, Auger F, Touche V, Hubert T, Thevenet J, Marciniak C, Quenon A, Bonner C, Peschard S, Raverdy V, Daoudi M, Kerr-Conte J, Pasquetti G, Koepsell H, Zdzieblo D, Mühlemann M, Thorens B, Delzenne ND, Bindels LB, Deprez B, Vantyghem MC, Laferrère B, Staels B, Huglo D, Lestavel S, Pattou F. Oral metformin transiently lowers post-prandial glucose response by reducing the apical expression of sodium-glucose co-transporter 1 in enterocytes. iScience 2023; 26:106057. [PMID: 36942050 PMCID: PMC10024157 DOI: 10.1016/j.isci.2023.106057] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 12/18/2022] [Accepted: 01/20/2023] [Indexed: 01/26/2023] Open
Abstract
Metformin (MET) is the most prescribed antidiabetic drug, but its mechanisms of action remain elusive. Recent data point to the gut as MET's primary target. Here, we explored the effect of MET on the gut glucose transport machinery. Using human enterocytes (Caco-2/TC7 cells) in vitro, we showed that MET transiently reduced the apical density of sodium-glucose transporter 1 (SGLT1) and decreased the absorption of glucose, without changes in the mRNA levels of the transporter. Administered 1 h before a glucose challenge in rats (Wistar, GK), C57BL6 mice and mice pigs, oral MET reduced the post-prandial glucose response (PGR). This effect was abrogated in SGLT1-KO mice. MET also reduced the luminal clearance of 2-(18F)-fluoro-2-deoxy-D-glucose after oral administration in rats. In conclusion, oral metformin transiently lowers post-prandial glucose response by reducing the apical expression of SGLT1 in enterocytes, which may contribute to the clinical effects of the drug.
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Affiliation(s)
- Lorea Zubiaga
- University of Lille, Centre Hospitalier Universitaire de Lille, European Genomic Institute for Diabetes, Inserm UMR-1190, 59000 Lille, France
| | - Olivier Briand
- University of Lille, Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, U1011-EGID, 59000 Lille, France
| | - Florent Auger
- University of Lille, Preclinical Imaging Core Facility, 59000 Lille, France
| | - Veronique Touche
- University of Lille, Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, U1011-EGID, 59000 Lille, France
| | - Thomas Hubert
- University of Lille, Centre Hospitalier Universitaire de Lille, European Genomic Institute for Diabetes, Inserm UMR-1190, 59000 Lille, France
| | - Julien Thevenet
- University of Lille, Centre Hospitalier Universitaire de Lille, European Genomic Institute for Diabetes, Inserm UMR-1190, 59000 Lille, France
| | - Camille Marciniak
- University of Lille, Centre Hospitalier Universitaire de Lille, European Genomic Institute for Diabetes, Inserm UMR-1190, 59000 Lille, France
| | - Audrey Quenon
- University of Lille, Centre Hospitalier Universitaire de Lille, European Genomic Institute for Diabetes, Inserm UMR-1190, 59000 Lille, France
| | - Caroline Bonner
- University of Lille, Centre Hospitalier Universitaire de Lille, European Genomic Institute for Diabetes, Inserm UMR-1190, 59000 Lille, France
- Institut Pasteur de Lille, 59000 Lille, France
| | - Simon Peschard
- University of Lille, Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, U1011-EGID, 59000 Lille, France
| | - Violeta Raverdy
- University of Lille, Centre Hospitalier Universitaire de Lille, European Genomic Institute for Diabetes, Inserm UMR-1190, 59000 Lille, France
| | - Mehdi Daoudi
- University of Lille, Centre Hospitalier Universitaire de Lille, European Genomic Institute for Diabetes, Inserm UMR-1190, 59000 Lille, France
| | - Julie Kerr-Conte
- University of Lille, Centre Hospitalier Universitaire de Lille, European Genomic Institute for Diabetes, Inserm UMR-1190, 59000 Lille, France
| | - Gianni Pasquetti
- University of Lille, Centre Hospitalier Universitaire de Lille, European Genomic Institute for Diabetes, Inserm UMR-1190, 59000 Lille, France
| | - Hermann Koepsell
- Institute of Anatomy and Cell Biology, University of Würzburg, 97070 Würzburg, Germany
| | - Daniela Zdzieblo
- Institute of Anatomy and Cell Biology, University of Würzburg, 97070 Würzburg, Germany
| | - Markus Mühlemann
- Institute of Anatomy and Cell Biology, University of Würzburg, 97070 Würzburg, Germany
| | - Bernard Thorens
- University of Lausanne, Center for Integrative Genomics, Lausanne, Switzerland
| | - Nathalie D. Delzenne
- Université catholique de Louvain, Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Brussels, Belgium
| | - Laure B. Bindels
- Université catholique de Louvain, Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Brussels, Belgium
| | - Benoit Deprez
- University of Lille, Centre Hospitalier Universitaire de Lille, European Genomic Institute for Diabetes, Inserm UMR-1177, 59000 Lille, France
| | - Marie C. Vantyghem
- University of Lille, Centre Hospitalier Universitaire de Lille, European Genomic Institute for Diabetes, Inserm UMR-1190, 59000 Lille, France
| | - Blandine Laferrère
- Department of Medicine, New York Nutrition Obesity Research Center, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Bart Staels
- University of Lille, Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, U1011-EGID, 59000 Lille, France
| | - Damien Huglo
- University of Lille, Preclinical Imaging Core Facility, 59000 Lille, France
| | - Sophie Lestavel
- University of Lille, Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, U1011-EGID, 59000 Lille, France
| | - François Pattou
- University of Lille, Centre Hospitalier Universitaire de Lille, European Genomic Institute for Diabetes, Inserm UMR-1190, 59000 Lille, France
- Corresponding author
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11
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Barlow GM, Celly S, Mathur R. Changes in the Gut Microbiome as Seen in Diabetes and Obesity. CLINICAL UNDERSTANDING OF THE HUMAN GUT MICROBIOME 2023:61-81. [DOI: 10.1007/978-3-031-46712-7_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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12
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Abstract
Diabetes represents one of the most significant, and rapidly escalating, global healthcare crises we face today. Diabetes already affects one-tenth of the world's adults-more than 537 million people, numbers that have tripled since 2000 and are estimated to reach 643 million by 2030. Type 2 diabetes (T2D), the most prevalent form, is a complex disease with numerous contributing factors, including genetics, epigenetics, diet, lifestyle, medication use, and socioeconomic factors. In addition, the gut microbiome has emerged as a significant potential contributing factor in T2D development and progression. Gut microbes and their metabolites strongly influence host metabolism and immune function, and are now known to contribute to vitamin biosynthesis, gut hormone production, satiety, maintenance of gut barrier integrity, and protection against pathogens, as well as digestion and nutrient absorption. In turn, gut microbes are influenced by diet and lifestyle factors such as alcohol and medication use, including antibiotic use and the consumption of probiotics and prebiotics. Here we review current evidence regarding changes in microbial populations in T2D and the mechanisms by which gut microbes influence glucose metabolism and insulin resistance, including inflammation, gut permeability, and bile acid production. We also explore the interrelationships between gut microbes and different T2D medications and other interventions, including prebiotics, probiotics, and bariatric surgery. Lastly, we explore the particular role of the small bowel in digestion and metabolism and the importance of studying small bowel microbes directly in our search to find metabolically relevant biomarkers and therapeutic targets for T2D.
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Affiliation(s)
- Gillian M Barlow
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, Los Angeles, CA, USA
| | - Ruchi Mathur
- Correspondence: Ruchi Mathur, MD, FRCPC, Director, Clinical Diabetes, Cedars-Sinai, 700 N San Vicente, Ste G271, West Hollywood, CA 90069, USA.
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13
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Dobrică EC, Banciu ML, Kipkorir V, Khazeei Tabari MA, Cox MJ, Simhachalam Kutikuppala LV, Găman MA. Diabetes and skin cancers: Risk factors, molecular mechanisms and impact on prognosis. World J Clin Cases 2022; 10:11214-11225. [PMID: 36387789 PMCID: PMC9649529 DOI: 10.12998/wjcc.v10.i31.11214] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/20/2022] [Accepted: 09/21/2022] [Indexed: 02/05/2023] Open
Abstract
Diabetes and skin cancers have emerged as threats to public health worldwide. However, their association has been less intensively studied. In this narrative review, we explore the common risk factors, molecular mechanisms, and prognosis of the association between cutaneous malignancies and diabetes. Hyperglycemia, oxidative stress, low-grade chronic inflammation, genetic, lifestyle, and environmental factors partially explain the crosstalk between skin cancers and this metabolic disorder. In addition, diabetes and its related complications may interfere with the appropriate management of cutaneous malignancies. Antidiabetic medication seems to exert an antineoplastic effect, however, future large, observation studies with a prospective design are needed to clarify its impact on the risk of malignancy in diabetes. Screening for diabetes in skin cancers, as well as close follow-up for the development of cutaneous malignancies in subjects suffering from diabetes, is warranted.
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Affiliation(s)
- Elena-Codruta Dobrică
- Doctoral School, University of Medicine and Pharmacy of Craiova, Craiova 200349, Romania
| | - Madalina Laura Banciu
- Department of Dermatology, "Elias" University Emergency Hospital, Bucharest 011461, Romania
| | - Vincent Kipkorir
- Department of Human Anatomy, University of Nairobi, College of Health Sciences, Nairobi 00100, Kenya
| | | | - Madeleine Jemima Cox
- University of New South Wales, University of New South Wales, Sydney 2052, Australia
| | | | - Mihnea-Alexandru Găman
- Faculty of Medicine, "Carol Davila" University of Medicine and Pharmacy, Bucharest 050474, Romania
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14
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Triggle CR, Mohammed I, Bshesh K, Marei I, Ye K, Ding H, MacDonald R, Hollenberg MD, Hill MA. Metformin: Is it a drug for all reasons and diseases? Metabolism 2022; 133:155223. [PMID: 35640743 DOI: 10.1016/j.metabol.2022.155223] [Citation(s) in RCA: 135] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 05/22/2022] [Accepted: 05/25/2022] [Indexed: 12/15/2022]
Abstract
Metformin was first used to treat type 2 diabetes in the late 1950s and in 2022 remains the first-choice drug used daily by approximately 150 million people. An accumulation of positive pre-clinical and clinical data has stimulated interest in re-purposing metformin to treat a variety of diseases including COVID-19. In polycystic ovary syndrome metformin improves insulin sensitivity. In type 1 diabetes metformin may help reduce the insulin dose. Meta-analysis and data from pre-clinical and clinical studies link metformin to a reduction in the incidence of cancer. Clinical trials, including MILES (Metformin In Longevity Study), and TAME (Targeting Aging with Metformin), have been designed to determine if metformin can offset aging and extend lifespan. Pre-clinical and clinical data suggest that metformin, via suppression of pro-inflammatory pathways, protection of mitochondria and vascular function, and direct actions on neuronal stem cells, may protect against neurodegenerative diseases. Metformin has also been studied for its anti-bacterial, -viral, -malaria efficacy. Collectively, these data raise the question: Is metformin a drug for all diseases? It remains unclear as to whether all of these putative beneficial effects are secondary to its actions as an anti-hyperglycemic and insulin-sensitizing drug, or result from other cellular actions, including inhibition of mTOR (mammalian target for rapamycin), or direct anti-viral actions. Clarification is also sought as to whether data from ex vivo studies based on the use of high concentrations of metformin can be translated into clinical benefits, or whether they reflect a 'Paracelsus' effect. The environmental impact of metformin, a drug with no known metabolites, is another emerging issue that has been linked to endocrine disruption in fish, and extensive use in T2D has also raised concerns over effects on human reproduction. The objectives for this review are to: 1) evaluate the putative mechanism(s) of action of metformin; 2) analyze the controversial evidence for metformin's effectiveness in the treatment of diseases other than type 2 diabetes; 3) assess the reproducibility of the data, and finally 4) reach an informed conclusion as to whether metformin is a drug for all diseases and reasons. We conclude that the primary clinical benefits of metformin result from its insulin-sensitizing and antihyperglycaemic effects that secondarily contribute to a reduced risk of a number of diseases and thereby enhancing healthspan. However, benefits like improving vascular endothelial function that are independent of effects on glucose homeostasis add to metformin's therapeutic actions.
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Affiliation(s)
- Chris R Triggle
- Department of Pharmacology, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar; Department of Medical Education, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar.
| | - Ibrahim Mohammed
- Department of Medical Education, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar
| | - Khalifa Bshesh
- Department of Medical Education, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar
| | - Isra Marei
- Department of Pharmacology, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar
| | - Kevin Ye
- Department of Biomedical Physiology & Kinesiology, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada
| | - Hong Ding
- Department of Pharmacology, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar; Department of Medical Education, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar
| | - Ross MacDonald
- Distribution eLibrary, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar
| | - Morley D Hollenberg
- Department of Physiology & Pharmacology, a Cumming School of Medicine, University of Calgary, T2N 4N1, Canada
| | - Michael A Hill
- Dalton Cardiovascular Research Center, Department of Medical Pharmacology & Physiology, School of Medicine, University of Missouri, Columbia 65211, MO, USA
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15
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Khodadadi M, Jafari-Gharabaghlou D, Zarghami N. An update on mode of action of metformin in modulation of meta-inflammation and inflammaging. Pharmacol Rep 2022; 74:310-322. [PMID: 35067907 DOI: 10.1007/s43440-021-00334-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 10/11/2021] [Accepted: 10/13/2021] [Indexed: 12/13/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is the most common chronic metabolic condition. Several genetic and environmental factors are involved in developing T2DM. Aging, inflammation, and obesity are the main contributors to the initiation of T2DM. They cause chronic sterile meta-inflammation and insulin resistance, thereby making a person more susceptible to developing T2DM. Metformin, a natural cationic biguanide, is widely used as the first-line treatment of T2DM. The exact action mechanism behind the glucose-lowering effect of metformin is not clear, but, presumably, metformin utilizes a broad spectrum of molecular mechanisms to control blood glucose including decreasing intestinal glucose absorption, inhibition of the hepatic gluconeogenesis, decreasing insulin resistance, etc. Recent studies have shown that metformin exerts its effects through the inhibition of mitochondrial respiratory chain complex 1 and the AMP-activated protein kinase (AMPK) activation, but it has been identified in the other studies that AMPK is not the sole hub in metformin mode of action or there are other unknown mechanisms which are involved and yet to be explored. Therefore, here, we discuss the updated findings of the mechanism of action of metformin that contributes to the meta-inflammation and inflammaging action. It is proposed that figuring out the precise mechanism of action of metformin could improve its application in the fields of obesity, inflammation, aging, and inflammaging.
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Affiliation(s)
- Meysam Khodadadi
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Davoud Jafari-Gharabaghlou
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nosratollah Zarghami
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Medical Biochemistry, Faculty of Medicine, Istanbul Aydin University, Istanbul, Turkey. .,Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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16
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Nabrdalik K, Skonieczna-Żydecka K, Irlik K, Hendel M, Kwiendacz H, Łoniewski I, Januszkiewicz K, Gumprecht J, Lip GYH. Gastrointestinal adverse events of metformin treatment in patients with type 2 diabetes mellitus: A systematic review, meta-analysis and meta-regression of randomized controlled trials. Front Endocrinol (Lausanne) 2022; 13:975912. [PMID: 36187122 PMCID: PMC9524196 DOI: 10.3389/fendo.2022.975912] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 08/16/2022] [Indexed: 01/10/2023] Open
Abstract
INTRODUCTION Metformin is the first choice drug in the treatment of type 2 diabetes mellitus but its administration may be linked to gastrointestinal adverse events limiting its use. OBJECTIVES The objective of this systematic review and meta-analysis was to assess the risk of gastrointestinal adverse events related to metformin use in patients with type 2 diabetes treated with metformin. METHODS PUB MED/CINAHL/Web of Science/Scopus were searched from database inception until 08.11.2020 for articles in English and randomized controlled trials related to patients with type 2 diabetes treated with metformin were included. RESULTS From 5315 publications, we identified 199 potentially eligible full-text articles. Finally, 71 randomized controlled trials were included in the meta-analysis. In these studies, metformin use was associated with higher risk of abdominal pain, diarrhea and nausea comparing to control. The risks of abdominal pain and nausea were highest comparing to placebo. Bloating risk was only elevated when metformin treatment was compared to DPP4i. CONCLUSIONS The risk of gastrointestinal adverse events such as abdominal pain, nausea and diarrhea is higher in type 2 diabetes patients treated with metformin compared to other antidiabetic drugs. There is a higher risk of bloating and diarrhea with metformin immediate-release than with metformin extended release formulation. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021289975, identifier CRD42021289975.
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Affiliation(s)
- Katarzyna Nabrdalik
- Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
- Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom
| | - Karolina Skonieczna-Żydecka
- Department of Biochemical Science, Pomeranian Medical University, Szczecin, Poland
- *Correspondence: Karolina Skonieczna-Żydecka,
| | - Krzysztof Irlik
- Students’ Scientific Association by the Department of Internal Medicine, Diabetology and Nephrology in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Mirela Hendel
- Students’ Scientific Association by the Department of Internal Medicine, Diabetology and Nephrology in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Hanna Kwiendacz
- Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Igor Łoniewski
- Department of Biochemical Science, Pomeranian Medical University, Szczecin, Poland
| | | | - Janusz Gumprecht
- Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Gregory Y. H. Lip
- Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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17
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Pilmark NS, Oberholzer L, Halling JF, Kristensen JM, Bønding CP, Elkjær I, Lyngbæk M, Elster G, Siebenmann C, Holm NF, Birk JBB, Larsen EL, Meinild-Lundby AK, Wojtaszewski JF, Pilegaard H, Poulsen H, Pedersen BK, Hansen KB, Karstoft K. Skeletal muscle adaptations to exercise are not influenced by metformin treatment in humans: secondary analyses of two randomised, clinical trials. Appl Physiol Nutr Metab 2021; 47:309-320. [PMID: 34784247 DOI: 10.1139/apnm-2021-0194] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Metformin and exercise both improve glycemic control, but in vitro studies have indicated that an interaction between metformin and exercise occurs in skeletal muscle, suggesting a blunting effect of metformin on exercise training adaptations. Two studies (a double-blind, parallel-group, randomized clinical trial conducted in 29 glucose-intolerant individuals and a double-blind, cross-over trial conducted in 15 healthy lean males) were included in this paper. In both studies, the effect of acute exercise +/- metformin treatment on different skeletal muscle variables, previously suggested to be involved in a pharmaco-physiological interaction between metformin and exercise, was assessed. Furthermore, in the parallel-group trial, the effect of 12 weeks of exercise training was assessed. Skeletal muscle biopsies were obtained before and after acute exercise and 12 weeks of exercise training, and mitochondrial respiration, oxidative stress and AMPK activation was determined. Metformin did not significantly affect the effects of acute exercise or exercise training on mitochondrial respiration, oxidative stress or AMPK activation, indicating that the response to acute exercise and exercise training adaptations in skeletal muscle is not affected by metformin treatment. Further studies are needed to investigate whether an interaction between metformin and exercise is present in other tissues, e.g. the gut. Trial registration: ClinicalTrials.gov (NCT03316690 and NCT02951260). Novelty bullets • Metformin does not affect exercise-induced alterations in mitochondrial respiratory capacity in human skeletal muscle • Metformin does not affect exercise-induced alterations in systemic levels of oxidative stress nor emission of reactive oxygen species from human skeletal muscle • Metformin does not affect exercise-induced AMPK activation in human skeletal muscle.
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Affiliation(s)
- Nanna Skytt Pilmark
- Rigshospitalet, 53146, Centre for Physical Activity Research (CFAS), Copenhagen, Denmark;
| | - Laura Oberholzer
- Center for Physical Activity Research, University Hospital of Copenhagen, Blegdamsvej 9, Copenhagen, Denmark, 2100;
| | - Jens Frey Halling
- university of copenhagen, department of biology, , copenhagen, Denmark;
| | - Jonas M Kristensen
- University of Copenhagen, Denmark, Department of Nutrition, Exercise and Sports,, copenhagen, Denmark;
| | | | - Ida Elkjær
- Center for Physical Activity Research, University Hospital of Copenhagen, Copenhagen, Denmark;
| | - Mark Lyngbæk
- Center for Physical Activity Research, University Hospital of Copenhagen, Copenhagen, Denmark;
| | - Grit Elster
- Center for Physical Activity Research, University Hospital of Copenhagen, Copenhagen, Denmark;
| | - Christoph Siebenmann
- Institute of Mountain Emergency Medicine,, EURAC Research, Bolzano, Italy, bolzano, Italy;
| | - Niels Frederich Holm
- Center for Physical Activity Research, University Hospital of Copenhagen, Copenhagen, Denmark;
| | - Jesper Bratz Bratz Birk
- University of Copenhagen, Denmark, Department of Nutrition, Exercise and Sports,, copenhagen, Denmark;
| | - Emil List Larsen
- Copenhagen University Hospital, 53146, Department of Clinical Pharmacology, Bispebjerg and Frederiksberg Hospital, Kobenhavn, Denmark;
| | | | - J F Wojtaszewski
- University of Copenhagen, Denmark, Department of Nutrition, Exercise and Sports,, copenhagen, Denmark;
| | | | - Henrik Poulsen
- Copenhagen University Hospital, 53146, Department of Clinical Pharmacology, Bispebjerg and Frederiksberg Hospital, Kobenhavn, Denmark;
| | - Bente Klarlund Pedersen
- Rigshospitalet, 53146, Centre of Inflammation and Metabolism / Centre for Physical Activity Research (CIM/CFAS), København, Denmark;
| | - Katrine Bagge Hansen
- Steno Diabetes Center Copenhagen, 53138, Steno Diabetes Center Copenhagen, Gentofte, Denmark, Gentofte, Denmark;
| | - Kristian Karstoft
- Rigshospitalet, 53146, Centre for Physical Activity Research (CFAS), Blegdamsvej 9, Copenhagen, Denmark, 2100.,Bispebjerg Hospital, 53166, Department of Clinical Pharmacology, Copenhagen, Denmark, 2400;
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18
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Eibl G, Rozengurt E. Metformin: review of epidemiology and mechanisms of action in pancreatic cancer. Cancer Metastasis Rev 2021; 40:865-878. [PMID: 34142285 DOI: 10.1007/s10555-021-09977-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 05/27/2021] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma continues to be a lethal disease, for which efficient treatment options are very limited. Increasing efforts have been taken to understand how to prevent or intercept this disease at an early stage. There is convincing evidence from epidemiologic and preclinical studies that the antidiabetic drug metformin possesses beneficial effects in pancreatic cancer, including reducing the risk of developing the disease and improving survival in patients with early-stage disease. This review will summarize the current literature about the epidemiological data on metformin and pancreatic cancer as well as describe the preclinical evidence illustrating the anticancer effects of metformin in pancreatic cancer. Underlying mechanisms and targets of metformin will also be discussed. These include direct effects on transformed pancreatic epithelial cells and indirect, systemic effects on extra-pancreatic tissues.
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Affiliation(s)
- Guido Eibl
- Department of Surgery, David Geffen School of Medicine At UCLA, Los Angeles, CA, USA.
| | - Enrique Rozengurt
- Department of Medicine, David Geffen School of Medicine At UCLA, Los Angeles, CA, USA
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19
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Lee CB, Chae SU, Jo SJ, Jerng UM, Bae SK. The Relationship between the Gut Microbiome and Metformin as a Key for Treating Type 2 Diabetes Mellitus. Int J Mol Sci 2021; 22:ijms22073566. [PMID: 33808194 PMCID: PMC8037857 DOI: 10.3390/ijms22073566] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/22/2021] [Accepted: 03/27/2021] [Indexed: 02/08/2023] Open
Abstract
Metformin is the first-line pharmacotherapy for treating type 2 diabetes mellitus (T2DM); however, its mechanism of modulating glucose metabolism is elusive. Recent advances have identified the gut as a potential target of metformin. As patients with metabolic disorders exhibit dysbiosis, the gut microbiome has garnered interest as a potential target for metabolic disease. Henceforth, studies have focused on unraveling the relationship of metabolic disorders with the human gut microbiome. According to various metagenome studies, gut dysbiosis is evident in T2DM patients. Besides this, alterations in the gut microbiome were also observed in the metformin-treated T2DM patients compared to the non-treated T2DM patients. Thus, several studies on rodents have suggested potential mechanisms interacting with the gut microbiome, including regulation of glucose metabolism, an increase in short-chain fatty acids, strengthening intestinal permeability against lipopolysaccharides, modulating the immune response, and interaction with bile acids. Furthermore, human studies have demonstrated evidence substantiating the hypotheses based on rodent studies. This review discusses the current knowledge of how metformin modulates T2DM with respect to the gut microbiome and discusses the prospect of harnessing this mechanism in treating T2DM.
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Affiliation(s)
- Chae Bin Lee
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon 14662, Korea; (C.B.L.); (S.U.C.); (S.J.J.)
| | - Soon Uk Chae
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon 14662, Korea; (C.B.L.); (S.U.C.); (S.J.J.)
| | - Seong Jun Jo
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon 14662, Korea; (C.B.L.); (S.U.C.); (S.J.J.)
| | - Ui Min Jerng
- Department of Internal Medicine, College of Korean Medicine, Sangji University, Wonju 26339, Korea;
| | - Soo Kyung Bae
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon 14662, Korea; (C.B.L.); (S.U.C.); (S.J.J.)
- Correspondence: ; Tel.: +82-2-2164-4054
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20
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Rajjoub Al-Mahdi EA, Barrios V, Zamorano JL. Metformin in the era of new antidiabetics. Future Cardiol 2021; 17:475-485. [PMID: 33754810 DOI: 10.2217/fca-2020-0195] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Type II diabetes mellitus is a known cardiovascular risk factor and its prevalence continues to increase. A revolution in the Type II diabetes mellitus treatment has occurred with the arrival of new antidiabetic drugs, which are thought to compromise metformin place. We aim to review the pharmacology, available evidence and clinical aspects of metformin use in the era of new antidiabetics.
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Affiliation(s)
| | - Vivencio Barrios
- Department of Cardiology, University Hospital Ramon y Cajal, Madrid, Spain.,Faculty of Medicine & Health Sciences, University of Alcalá, Madrid, Spain
| | - Jose L Zamorano
- Department of Cardiology, University Hospital Ramon y Cajal, Madrid, Spain.,Faculty of Medicine & Health Sciences, University of Alcalá, Madrid, Spain
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21
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Silamiķele L, Silamiķelis I, Ustinova M, Kalniņa Z, Elbere I, Petrovska R, Kalniņa I, Kloviņš J. Metformin Strongly Affects Gut Microbiome Composition in High-Fat Diet-Induced Type 2 Diabetes Mouse Model of Both Sexes. Front Endocrinol (Lausanne) 2021; 12:626359. [PMID: 33815284 PMCID: PMC8018580 DOI: 10.3389/fendo.2021.626359] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 02/23/2021] [Indexed: 12/13/2022] Open
Abstract
Effects of metformin, the first-line drug for type 2 diabetes therapy, on gut microbiome composition in type 2 diabetes have been described in various studies both in human subjects and animals. However, the details of the molecular mechanisms of metformin action have not been fully understood. Moreover, there is a significant lack of information on how metformin affects gut microbiome composition in female mouse models, depending on sex and metabolic status in well controlled experimental setting. Our study aimed to examine metformin-induced alterations in gut microbiome diversity, composition, and functional implications of high-fat diet-induced type 2 diabetes mouse model, using, for the first time in mice study, the shotgun metagenomic sequencing that allows estimation of microorganisms at species level. We also employed a randomized block, factorial study design, and including 24 experimental units allocated to 8 treatment groups to systematically evaluate the effect of sex and metabolic status on metformin interaction with microbiome. We used DNA obtained from fecal samples representing gut microbiome before and after ten weeks-long metformin treatment. We identified 100 metformin-related differentially abundant species in high-fat diet-fed mice before and after the treatment, with most of the species relative abundances increased. In contrast, no significant changes were observed in control diet-fed mice. Functional analysis targeted to carbohydrate, lipid, and amino acid metabolism pathways revealed 14 significantly altered hierarchies. We also observed sex-specific differences in response to metformin treatment. Males experienced more pronounced changes in metabolic markers, while in females the extent of changes in gut microbiome representatives was more marked, indicated by 53 differentially abundant species with more remarkable Log fold changes compared to the combined-sex analysis. The same pattern manifested regarding the functional analysis, where we discovered 5 significantly affected hierarchies in female groups but not in males. Our results suggest that both sexes of animals should be included in future studies focusing on metformin effects on the gut microbiome.
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Affiliation(s)
| | | | | | | | | | | | | | - Jānis Kloviņš
- Latvian Biomedical Research and Study Centre, Riga, Latvia
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22
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Dąbrowski M. Diabetes, Antidiabetic Medications and Cancer Risk in Type 2 Diabetes: Focus on SGLT-2 Inhibitors. Int J Mol Sci 2021; 22:1680. [PMID: 33562380 PMCID: PMC7915237 DOI: 10.3390/ijms22041680] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/31/2021] [Accepted: 02/03/2021] [Indexed: 12/14/2022] Open
Abstract
In the last decade, cancer became the leading cause of death in the population under 65 in the European Union. Diabetes is also considered as a factor increasing risk of cancer incidence and mortality. Type 2 diabetes is frequently associated with being overweight and obese, which also plays a role in malignancy. Among biological mechanisms linking diabetes and obesity with cancer hyperglycemia, hyperinsulinemia, insulin resistance, increased levels of growth factors, steroid and peptide hormones, oxidative stress and increased activity of pro-inflammatory cytokines are listed. Antidiabetic medications can modulate cancer risk through directly impacting metabolism of cancer cells as well as indirectly through impact on risk factors of malignancy. Some of them are considered beneficial (metformin and thiazolidinedions-with the exception of bladder cancer); on the other hand, excess of exogenous insulin may be potentially harmful, while other medications seem to have neutral impact on cancer risk. Inhibitors of the sodium-glucose cotransporter-2 (SGLT-2) are increasingly used in the treatment of type 2 diabetes. However, their association with cancer risk is unclear. The aim of this review was to analyze the anticancer potential of this class of drugs, as well as risks of site-specific malignancies associated with their use.
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Affiliation(s)
- Mariusz Dąbrowski
- College of Medical Sciences, University of Rzeszów, Al. Rejtana 16C, 35-959 Rzeszów, Poland
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23
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Mohammed I, Hollenberg MD, Ding H, Triggle CR. A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan. Front Endocrinol (Lausanne) 2021; 12:718942. [PMID: 34421827 PMCID: PMC8374068 DOI: 10.3389/fendo.2021.718942] [Citation(s) in RCA: 155] [Impact Index Per Article: 38.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 07/15/2021] [Indexed: 12/11/2022] Open
Abstract
The numerous beneficial health outcomes associated with the use of metformin to treat patients with type 2 diabetes (T2DM), together with data from pre-clinical studies in animals including the nematode, C. elegans, and mice have prompted investigations into whether metformin has therapeutic utility as an anti-aging drug that may also extend lifespan. Indeed, clinical trials, including the MILES (Metformin In Longevity Study) and TAME (Targeting Aging with Metformin), have been designed to assess the potential benefits of metformin as an anti-aging drug. Preliminary analysis of results from MILES indicate that metformin may induce anti-aging transcriptional changes; however it remains controversial as to whether metformin is protective in those subjects free of disease. Furthermore, despite clinical use for over 60 years as an anti-diabetic drug, the cellular mechanisms by which metformin exerts either its actions remain unclear. In this review, we have critically evaluated the literature that has investigated the effects of metformin on aging, healthspan and lifespan in humans as well as other species. In preparing this review, particular attention has been placed on the strength and reproducibility of data and quality of the study protocols with respect to the pharmacokinetic and pharmacodynamic properties of metformin. We conclude that despite data in support of anti-aging benefits, the evidence that metformin increases lifespan remains controversial. However, via its ability to reduce early mortality associated with various diseases, including diabetes, cardiovascular disease, cognitive decline and cancer, metformin can improve healthspan thereby extending the period of life spent in good health. Based on the available evidence we conclude that the beneficial effects of metformin on aging and healthspan are primarily indirect via its effects on cellular metabolism and result from its anti-hyperglycemic action, enhancing insulin sensitivity, reduction of oxidative stress and protective effects on the endothelium and vascular function.
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Affiliation(s)
- Ibrahim Mohammed
- Department of Medical Education, Weill Cornell Medicine-Qatar, Al-Rayyan, Qatar
- *Correspondence: Chris R. Triggle, ; Ibrahim Mohammed,
| | - Morley D. Hollenberg
- Inflammation Research Network and Snyder Institute for Chronic Diseases, Department of Physiology & Pharmacology, University of Calgary Cumming School of Medicine, Calgary, AB, Canada
- Department of Medicine, University of Calgary Cumming School of Medicine, Calgary, AB, Canada
| | - Hong Ding
- Department of Medical Education, Weill Cornell Medicine-Qatar, Al-Rayyan, Qatar
- Departments of Medical Education and Pharmacology, Weill Cornell Medicine-Qatar, Al-Rayyan, Qatar
| | - Chris R. Triggle
- Department of Medical Education, Weill Cornell Medicine-Qatar, Al-Rayyan, Qatar
- Departments of Medical Education and Pharmacology, Weill Cornell Medicine-Qatar, Al-Rayyan, Qatar
- *Correspondence: Chris R. Triggle, ; Ibrahim Mohammed,
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24
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Borg MJ, Rayner CK, Jones KL, Horowitz M, Xie C, Wu T. Gastrointestinal Mechanisms Underlying the Cardiovascular Effect of Metformin. Pharmaceuticals (Basel) 2020; 13:410. [PMID: 33266396 PMCID: PMC7700183 DOI: 10.3390/ph13110410] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 11/20/2020] [Accepted: 11/20/2020] [Indexed: 02/07/2023] Open
Abstract
Metformin, the most widely prescribed drug therapy for type 2 diabetes, has pleiotropic benefits, in addition to its capacity to lower elevated blood glucose levels, including mitigation of cardiovascular risk. The mechanisms underlying the latter remain unclear. Mechanistic studies have, hitherto, focused on the direct effects of metformin on the heart and vasculature. It is now appreciated that effects in the gastrointestinal tract are important to glucose-lowering by metformin. Gastrointestinal actions of metformin also have major implications for cardiovascular function. This review summarizes the gastrointestinal mechanisms underlying the action of metformin and their potential relevance to cardiovascular benefits.
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Affiliation(s)
- Malcolm J. Borg
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5000, Australia; (M.J.B.); (C.K.R.); (K.L.J.); (M.H.); (C.X.)
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide 5000, Australia
| | - Christopher K. Rayner
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5000, Australia; (M.J.B.); (C.K.R.); (K.L.J.); (M.H.); (C.X.)
| | - Karen L. Jones
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5000, Australia; (M.J.B.); (C.K.R.); (K.L.J.); (M.H.); (C.X.)
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide 5000, Australia
| | - Michael Horowitz
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5000, Australia; (M.J.B.); (C.K.R.); (K.L.J.); (M.H.); (C.X.)
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide 5000, Australia
| | - Cong Xie
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5000, Australia; (M.J.B.); (C.K.R.); (K.L.J.); (M.H.); (C.X.)
| | - Tongzhi Wu
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5000, Australia; (M.J.B.); (C.K.R.); (K.L.J.); (M.H.); (C.X.)
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide 5000, Australia
- Institute of Diabetes, School of Medicine, Southeast University, Nanjing 210096, China
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25
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Cioce M, Pulito C, Strano S, Blandino G, Fazio VM. Metformin: Metabolic Rewiring Faces Tumor Heterogeneity. Cells 2020; 9:E2439. [PMID: 33182253 PMCID: PMC7695274 DOI: 10.3390/cells9112439] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 10/13/2020] [Accepted: 11/03/2020] [Indexed: 02/07/2023] Open
Abstract
Tumor heterogeneity impinges on all the aspects of tumor history, from onset to metastasis and relapse. It is growingly recognized as a propelling force for tumor adaptation to environmental and micro-environmental cues. Metabolic heterogeneity perfectly falls into this process. It strongly contributes to the metabolic plasticity which characterizes cancer cell subpopulations-capable of adaptive switching under stress conditions, between aerobic glycolysis and oxidative phosphorylation-in both a convergent and divergent modality. The mitochondria appear at center-stage in this adaptive process and thus, targeting mitochondria in cancer may prove of therapeutic value. Metformin is the oldest and most used anti-diabetic medication and its relationship with cancer has witnessed rises and falls in the last 30 years. We believe it is useful to revisit the main mechanisms of action of metformin in light of the emerging views on tumor heterogeneity. We first analyze the most consolidated view of its mitochondrial mechanism of action and then we frame the latter in the context of tumor adaptive strategies, cancer stem cell selection, metabolic zonation of tumors and the tumor microenvironment. This may provide a more critical point of view and, to some extent, may help to shed light on some of the controversial evidence for metformin's anticancer action.
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Affiliation(s)
- Mario Cioce
- Department of Medicine, R.U. in Molecular Medicine and Biotechnology, University Campus Bio-Medico of Rome, 00128 Rome, Italy;
| | - Claudio Pulito
- Oncogenomic and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.P.); (G.B.)
| | - Sabrina Strano
- SAFU Unit, Department of Research, Diagnosis and Innovative Technologies, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy;
| | - Giovanni Blandino
- Oncogenomic and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.P.); (G.B.)
| | - Vito Michele Fazio
- Department of Medicine, R.U. in Molecular Medicine and Biotechnology, University Campus Bio-Medico of Rome, 00128 Rome, Italy;
- Institute of Translation Pharmacology, National Research Council of Italy (CNR), 00133 Rome, Italy
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Zeng Z, Huang SY, Sun T. Pharmacogenomic Studies of Current Antidiabetic Agents and Potential New Drug Targets for Precision Medicine of Diabetes. Diabetes Ther 2020; 11:2521-2538. [PMID: 32930968 PMCID: PMC7548012 DOI: 10.1007/s13300-020-00922-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Indexed: 12/29/2022] Open
Abstract
Diabetes is a major threat to people's health and has become a burden worldwide. Current drugs for diabetes have limitations, such as different drug responses among individuals, failure to achieve glycemic control, and adverse effects. Exploring more effective therapeutic strategies for patients with diabetes is crucial. Currently pharmacogenomics has provided potential for individualized drug therapy based on genetic and genomic information of patients, and has made precision medicine possible. Responses and adverse effects to antidiabetic drugs are significantly associated with gene polymorphisms in patients. Many new targets for diabetes also have been discovered and developed, and even entered clinical trial phases. This review summarizes pharmacogenomic evidence of some current antidiabetic agents applied in clinical settings, and highlights potential drugs with new targets for diabetes, which represent a more effective treatment in the future.
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Affiliation(s)
- Zhiwei Zeng
- Center for Precision Medicine, School of Medicine and School of Biomedical Sciences, Huaqiao University, Xiamen, 361021, China
| | - Shi-Ying Huang
- College of Food and Biological Engineering, Jimei University, Xiamen, 361021, China
| | - Tao Sun
- Center for Precision Medicine, School of Medicine and School of Biomedical Sciences, Huaqiao University, Xiamen, 361021, China.
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27
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Xiao F, Gao F, Zhou S, Wang L. The therapeutic effects of silymarin for patients with glucose/lipid metabolic dysfunction: A meta-analysis. Medicine (Baltimore) 2020; 99:e22249. [PMID: 33019400 PMCID: PMC7535778 DOI: 10.1097/md.0000000000022249] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND To comprehensively evaluate the treatment efficacy and safety of silymarin for patients with glucose/lipid metabolic dysfunction using a meta-analysis. METHODS A systematic literature search in PubMed, EMBASE and Cochrane Library databases was performed up to October 1, 2019. STATA 13.0 software was used to estimate pooled standardized mean difference (SMD) and 95% confidence interval (95% CI). RESULTS Sixteen studies involving 1358 patients were identified. Overall meta-analysis showed that compared with control, silymarin significantly reduced levels of fasting blood glucose (SMD: -1.27, 95% CI = [-1.78, -0.76]; P < .001), homeostatic model assessment for insulin resistance (SMD: -0.41, 95% CI = [-0.70, -0.12]; P = .005), hemoglobin A1c (SMD: -1.88, 95% CI = [-2.57, -1.20]; P < .001), total cholesterol (SMD: -1.13, 95% CI = [-1.82, -0.77]; P < .001), triglyceride (SMD: -0.37, 95% CI = [-0.69, -0.05]; P = .025), low-density lipoprotein-cholesterol (SMD: -1.30, 95% CI = [-1.93, -0.67]; P < .001), C-reactive protein (SMD: -0.63, 95% CI = [-1.01, -0.27]; P = .001), and increased high-density lipoprotein-cholesterol (SMD: 0.17, 95% CI = [0.05, 0.29]; P = .005), but had no impacts on function indicators of liver and kidney (alanine transaminase, aspartate aminotransferase, creatinine phosphokinase, creatinine) and the complication rate. Subgroup analyses indicated that insulin (which was negative in overall analysis) was significantly decreased in patients undergoing silymarin monotherapy (SMD: -2.03, 95% CI = [-3.03, -1.04]; P = .044) for more than 3 months (SMD: -0.01, 95% CI = [-0.25, -0.24]; P = .035). CONCLUSION Supplementation of silymarin may be effective and safe for the management of diabetes mellitus and hyperlipidemia.
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Affiliation(s)
- Fengyan Xiao
- College of Chinese Medicine, Jilin Agricultural Science and Technology College, Jilin City
| | - Feng Gao
- College of Chinese Medicine, Jilin Agricultural Science and Technology College, Jilin City
- YanBian Han Gong Fang Health Products Limited Company, YanBian City
| | - Shengxue Zhou
- College of Chinese Medicine, Jilin Agricultural Science and Technology College, Jilin City
| | - Lina Wang
- School of Pharmacy, Jilin Pharmaceutical College, Jilin City, Jilin Province, China
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28
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Is metformin a geroprotector? A peek into the current clinical and experimental data. Mech Ageing Dev 2020; 191:111350. [DOI: 10.1016/j.mad.2020.111350] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/25/2020] [Accepted: 09/01/2020] [Indexed: 02/08/2023]
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29
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The Hepatic Plasma Membrane Citrate Transporter NaCT (SLC13A5) as a Molecular Target for Metformin. Sci Rep 2020; 10:8536. [PMID: 32444674 PMCID: PMC7244496 DOI: 10.1038/s41598-020-65621-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 04/23/2020] [Indexed: 12/17/2022] Open
Abstract
Metformin is the first-line treatment for type 2 diabetes. Inhibition of hepatic gluconeogenesis is the primary contributor to its anti-diabetic effect. Metformin inhibits complex I and α-glycerophosphate shuttle, and the resultant increase in cytoplasmic NADH/NAD+ ratio diverts glucose precursors away from gluconeogenesis. These actions depend on metformin-mediated activation of AMP kinase (AMPK). Here we report on a hitherto unknown mechanism. Metformin inhibits the expression of the plasma membrane citrate transporter NaCT in HepG2 cells and decreases cellular levels of citrate. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator, elicits a similar effect. The process involves a decrease in maximal velocity with no change in substrate affinity. The decrease in NaCT expression is associated with decreased mRNA levels. AMPK inhibits mTOR, and the mTOR inhibitor rapamycin also decreases NaCT expression. The transcription factor downstream of AMPK that is relevant to cAMP signaling is CREB; decreased levels of phospho-CREB seem to mediate the observed effects of metformin on NaCT. Citrate is known to suppress glycolysis by inhibiting phosphofructokinase-1 and activate gluconeogenesis by stimulating fructose-1,6-bisphophatase; therefore, the decrease in cellular levels of citrate would stimulate glycolysis and inhibit gluconeogenesis. These studies uncover a novel mechanism for the anti-diabetic actions of metformin.
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30
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Sansome DJ, Xie C, Veedfald S, Horowitz M, Rayner CK, Wu T. Mechanism of glucose-lowering by metformin in type 2 diabetes: Role of bile acids. Diabetes Obes Metab 2020; 22:141-148. [PMID: 31468642 DOI: 10.1111/dom.13869] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 08/07/2019] [Accepted: 08/28/2019] [Indexed: 02/05/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is an increasingly prevalent chronic condition, characterized by abnormally elevated blood glucose concentrations and, as a consequence, increased risk of micro- and macrovascular complications. Metformin is usually the first-line glucose-lowering medication in T2DM; however, despite being used for more than 60 years, the mechanism underlying the glucose-lowering action of metformin remains incompletely understood. Although metformin reduces hepatic glucose production, there is persuasive evidence that the gastrointestinal tract is crucial in mediating this effect, particularly via secretion of the incretin hormone glucagon-like peptide 1 (GLP-1). It is now well recognized that bile acids, in addition to their established function in fat digestion and absorption, are important regulators of glucose metabolism. Exposure of the small and large intestine to bile acids induces GLP-1 secretion, modulates the composition of the gut microbiota, and reduces postprandial blood glucose excursions in humans with and without T2DM. Metformin reduces intestinal bile acid resorption substantially, such that intraluminal bile acids may, at least in part, account for its glucose-lowering effect. The present review focuses on the conceptual shift in our understanding as to how metformin lowers blood glucose in T2DM, with a particular emphasis on the role of intestinal bile acids.
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Affiliation(s)
- Daniel J Sansome
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, South Australia, Australia
| | - Cong Xie
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, South Australia, Australia
| | - Simon Veedfald
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, South Australia, Australia
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Michael Horowitz
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, South Australia, Australia
| | - Christopher K Rayner
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, South Australia, Australia
| | - Tongzhi Wu
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, South Australia, Australia
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
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31
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Markowicz-Piasecka M, Sadkowska A, Huttunen KM, Podsiedlik M, Mikiciuk-Olasik E, Sikora J. An investigation into the pleiotropic activity of metformin. A glimpse of haemostasis. Eur J Pharmacol 2020; 872:172984. [PMID: 32017937 DOI: 10.1016/j.ejphar.2020.172984] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 01/08/2020] [Accepted: 01/31/2020] [Indexed: 02/07/2023]
Abstract
The most characteristic features of type 2 diabetes mellitus (T2DM) are hyperglycaemia and insulin resistance, however, patients with T2DM are at higher risk of cardiovascular disease (CVD) and atherosclerosis. Diabetes, frequently related to metabolic and vascular impairments, is also associated with thrombosis, increased blood coagulation and an imbalance between coagulation and fibrinolysis. Metformin is the most often used oral glucose-lowering agent; its beneficial properties include lowering insulin resistance, weight reduction and cardioprotection. Available data suggest that the advantageous properties of metformin stem from its favourable effects on endothelium, and anti-oxidative and anti-inflammatory properties. This paper reviews the favourable impact of metformin on endothelial function, with particular emphasis on the release of endogenous molecules modulating the state of the vascular endothelium and coagulation. It also summarizes the present knowledge on the influence of metformin on platelet activity and plasma haemostasis, including clot formation, stabilization and fibrinolysis. Its findings confirm that metformin should constitute first line therapy of T2DM subjects; however, more comprehensive methodical studies are required to discover the full potential of this drug.
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Affiliation(s)
- Magdalena Markowicz-Piasecka
- Laboratory of Bioanalysis, Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University of Lodz, ul. Muszyńskiego 1, 90-151, Lodz, Poland.
| | - Adrianna Sadkowska
- Students Research Group, Laboratory of Bioanalysis, Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University of Lodz, ul. Muszyńskiego 1, 90-151, Lodz, Poland.
| | - Kristiina M Huttunen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, POB 1627, 70211, Kuopio, Finland.
| | - Maria Podsiedlik
- Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University of Lodz, ul. Muszyńskiego 1, 90-151, Lodz, Poland.
| | - Elżbieta Mikiciuk-Olasik
- Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University of Lodz, ul. Muszyńskiego 1, 90-151, Lodz, Poland.
| | - Joanna Sikora
- Laboratory of Bioanalysis, Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University of Lodz, ul. Muszyńskiego 1, 90-151, Lodz, Poland.
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Pascale A, Marchesi N, Govoni S, Coppola A, Gazzaruso C. The role of gut microbiota in obesity, diabetes mellitus, and effect of metformin: new insights into old diseases. Curr Opin Pharmacol 2019; 49:1-5. [DOI: 10.1016/j.coph.2019.03.011] [Citation(s) in RCA: 173] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 03/21/2019] [Indexed: 02/06/2023]
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Pharmacology of metformin - An update. Eur J Pharmacol 2019; 865:172782. [PMID: 31705902 DOI: 10.1016/j.ejphar.2019.172782] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 10/24/2019] [Accepted: 11/04/2019] [Indexed: 02/06/2023]
Abstract
Despite being a successful diabetes type 2 drug for more than a half-century in Europe, the mode of action of metformin is still debated. It is the purpose of this review to inform the reader about most recent findings for metformin with respect to its antidiabetic activity as well as proposed benefits beyond glucose control in humans. Clinical evidence now suggests that most of metformin benefits originate from its actions in the gut, involving hormone signaling by glucagon-like peptide 1 and peptide YY. Growth differentiation factor 15, also mainly produced in the gut, was first identified as a biomarker for metformin use but is now suggested to play a significant role in e.g. weight loss of prediabetics. The pharmacokinetics of the drug in humans as basis for pharmacodynamics, resulting in high tissue levels of the intestinal wall, including the colon, proven by biopsies, is presented. A critical survey of metformin actions on mitochondria, increasing the AMP/ATP ratio but also acting as a mild uncoupler, and of postulated new cellular targets (lysosomes) is included.
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Foretz M, Guigas B, Viollet B. Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat Rev Endocrinol 2019; 15:569-589. [PMID: 31439934 DOI: 10.1038/s41574-019-0242-2] [Citation(s) in RCA: 396] [Impact Index Per Article: 66.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/11/2019] [Indexed: 02/07/2023]
Abstract
Despite its position as the first-line drug for treatment of type 2 diabetes mellitus, the mechanisms underlying the plasma glucose level-lowering effects of metformin (1,1-dimethylbiguanide) still remain incompletely understood. Metformin is thought to exert its primary antidiabetic action through the suppression of hepatic glucose production. In addition, the discovery that metformin inhibits the mitochondrial respiratory chain complex 1 has placed energy metabolism and activation of AMP-activated protein kinase (AMPK) at the centre of its proposed mechanism of action. However, the role of AMPK has been challenged and might only account for indirect changes in hepatic insulin sensitivity. Various mechanisms involving alterations in cellular energy charge, AMP-mediated inhibition of adenylate cyclase or fructose-1,6-bisphosphatase 1 and modulation of the cellular redox state through direct inhibition of mitochondrial glycerol-3-phosphate dehydrogenase have been proposed for the acute inhibition of gluconeogenesis by metformin. Emerging evidence suggests that metformin could improve obesity-induced meta-inflammation via direct and indirect effects on tissue-resident immune cells in metabolic organs (that is, adipose tissue, the gastrointestinal tract and the liver). Furthermore, the gastrointestinal tract also has a major role in metformin action through modulation of glucose-lowering hormone glucagon-like peptide 1 and the intestinal bile acid pool and alterations in gut microbiota composition.
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Affiliation(s)
- Marc Foretz
- INSERM, U1016, Institut Cochin, Paris, France
- CNRS, UMR8104, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Bruno Guigas
- Department of Parasitology, Leiden University Medical Centre, Leiden, Netherlands
| | - Benoit Viollet
- INSERM, U1016, Institut Cochin, Paris, France.
- CNRS, UMR8104, Paris, France.
- Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
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Glossmann HH, Lutz OMD. Metformin and Aging: A Review. Gerontology 2019; 65:581-590. [PMID: 31522175 DOI: 10.1159/000502257] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 07/22/2019] [Indexed: 01/18/2023] Open
Abstract
Metformin is sometimes proposed to be an "anti-aging" drug, based on preclinical experiments with lower-order organisms and numerous retrospective data on beneficial health outcomes for type 2 diabetics. Large prospective, placebo-controlled trials are planned, in pilot stage or running, to find a new use (or indication) for an aging population. As one of the metformin trials has "frailty" as its endpoint, similar to a trial with a plant-derived senolytic, the latter class of novel anti-aging drugs is briefly discussed. Concerns exist not only for vitamin B12 and B6 deficiencies, but also about whether there are adverse effects of metformin on individuals who try to remain healthy by maintaining cardiovascular fitness via exercise.
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Affiliation(s)
- Hartmut H Glossmann
- Institute for Biochemical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria,
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Jia D, Li ZW, Zhou X, Gao Y, Feng Y, Ma M, Wu Z, Li W. A novel berberine-metformin hybrid compound exerts therapeutic effects on obese type 2 diabetic rats. Clin Exp Pharmacol Physiol 2019; 46:533-544. [PMID: 30883863 DOI: 10.1111/1440-1681.13085] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 02/19/2019] [Accepted: 03/12/2019] [Indexed: 12/11/2022]
Abstract
In this study, we investigated the biological activities of a novel berberine-metformin hybrid compound (BMH473) as an anti-diabetic agent. BMH473 exhibited significant anti-hyperglycaemic and anti-hyperlipidaemic effects on T2DM rats. In white adipose tissue, BMH473 reduced the perirenal and epididymal adipose tissue mass and modulated the lesions in perirenal adipose tissue, by inhibiting the protein expressions of PPAR-Ɣ, C/EBP-α and SREBP-1c as well as the mRNA expressions of lipogenic genes. Moreover, BMH473 downregulated the levels of pro-inflammatory cytokines in perirenal adipose tissue through the suppression of p-NF-κB. In liver, BMH473 reduced liver ectopic fat accumulation, by regulating the protein expression levels of SREBP-1c and PPAR-α as well as the mRNA expression levels of lipogenic genes. In addition, BMH473 inhibited hepatic gluconeogenesis by promoting the phosphorylation levels of AMPK α and ACC, and down-regulating the mRNA expression levels of FBPase, G6Pase and PEPCK. Furthermore, BMH473 exhibited significant inhibitory effects on lipogenesis and lipid accumulation in 3T3-L1 adipocytes by modulating the protein expression levels of PPAR-Ɣ, C/EBP-α and SREBP-1 c as well as the mRNA expression levels of lipogenic genes. In conclusion, our results suggest that the newly synthesized BMH473 is beneficial for maintaining glucose and lipid homeostasis in type 2 diabetic rats, and exhibits better anti-hyperlipidaemic effects compared to metformin and berberine.
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Affiliation(s)
- Dan Jia
- Integrated Chinese and Western Medicine Post-doctoral Research Station, Jinan University, Guangzhou, China.,The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China.,Shenzhen Institute of Geriatrics, Shenzhen, China
| | - Zi Wen Li
- Shenzhen Institute of Geriatrics, Shenzhen, China
| | - Xinxin Zhou
- Academy of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ying Gao
- Academy of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yifan Feng
- Central Laboratory of Guangdong Pharmaceutical University, GuangZhou, China
| | - Min Ma
- Integrated Chinese and Western Medicine Post-doctoral Research Station, Jinan University, Guangzhou, China
| | - Zhengzhi Wu
- The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China.,Shenzhen Institute of Geriatrics, Shenzhen, China
| | - Weimin Li
- Academy of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
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Borg MJ, Bound M, Grivell J, Sun Z, Jones KL, Horowitz M, Rayner CK, Wu T. Comparative effects of proximal and distal small intestinal administration of metformin on plasma glucose and glucagon-like peptide-1, and gastric emptying after oral glucose, in type 2 diabetes. Diabetes Obes Metab 2019; 21:640-647. [PMID: 30370686 DOI: 10.1111/dom.13567] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 10/17/2018] [Accepted: 10/25/2018] [Indexed: 02/05/2023]
Abstract
AIMS The gastrointestinal tract, particularly the lower gut, may be key to the anti-diabetic action of metformin. We evaluated whether administration of metformin into the distal, vs the proximal, small intestine would be more effective in lowering plasma glucose by stimulating glucagon-like pepetide-1 (GLP-1) and/or slowing gastric emptying (GE) in type 2 diabetes (T2DM). MATERIALS AND METHODS Ten diet-controlled T2DM patients were studied on three occasions. A transnasal catheter was positioned with proximal and distal infusion ports located 13 and 190 cm beyond the pylorus, respectively. Participants received infusions of (a) proximal + distal saline (control), (b) proximal metformin (1000 mg) + distal saline or (c) proximal saline + distal metformin (1000 mg) over 5 minutes, followed 60 minutes later by a glucose drink containing 50 g glucose and 150 mg 13 C-acetate. "Arterialized" venous blood and breath samples were collected over 3 hours for measurements of plasma glucose, GLP-1, insulin and glucagon, and GE, respectively. RESULTS Compared with control, both proximal and distal metformin reduced plasma glucose and augmented GLP-1 responses to oral glucose comparably (P < 0.05 each), without affecting plasma insulin or glucagon. GE was slower after proximal metformin than after control (P < 0.05) and tended to be slower after distal metformin, without any difference between proximal and distal metformin. CONCLUSIONS In diet-controlled T2DM patients, glucose-lowering via a single dose of metformin administered to the upper and lower gut was comparable and was associated with stimulation of GLP-1 and slowing of GE. These observations suggest that the site of gastrointestinal administration is not critical to the glucose-lowering capacity of metformin.
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Affiliation(s)
- Malcolm J Borg
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
| | - Michelle Bound
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
| | - Jacqueline Grivell
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
| | - Zilin Sun
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Karen L Jones
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia
| | - Michael Horowitz
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia
| | - Christopher K Rayner
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
| | - Tongzhi Wu
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia
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Schulten HJ. Pleiotropic Effects of Metformin on Cancer. Int J Mol Sci 2018; 19:2850. [PMID: 30241339 PMCID: PMC6213406 DOI: 10.3390/ijms19102850] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 09/07/2018] [Accepted: 09/14/2018] [Indexed: 12/19/2022] Open
Abstract
Metformin (MTF) is a natural compound derived from the legume Galega officinalis. It is the first line antidiabetic drug for type 2 diabetes (T2D) treatment. One of its main antidiabetic effects results from the reduction of hepatic glucose release. First scientific evidence for the anticancer effects of MTF was found in animal research, published in 2001, and some years later a retrospective observational study provided evidence that linked MTF to reduced cancer risk in T2D patients. Its pleiotropic anticancer effects were studied in numerous in vitro and in vivo studies at the molecular and cellular level. Although the majority of these studies demonstrated that MTF is associated with certain anticancer properties, clinical studies and trials provided a mixed view on its beneficial anticancer effects. This review emphasizes the pleiotropic effects of MTF and recent progress made in MTF applications in basic, preclinical, and clinical cancer research.
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Affiliation(s)
- Hans-Juergen Schulten
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia.
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Proschak E, Stark H, Merk D. Polypharmacology by Design: A Medicinal Chemist's Perspective on Multitargeting Compounds. J Med Chem 2018; 62:420-444. [PMID: 30035545 DOI: 10.1021/acs.jmedchem.8b00760] [Citation(s) in RCA: 319] [Impact Index Per Article: 45.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Multitargeting compounds comprising activity on more than a single biological target have gained remarkable relevance in drug discovery owing to the complexity of multifactorial diseases such as cancer, inflammation, or the metabolic syndrome. Polypharmacological drug profiles can produce additive or synergistic effects while reducing side effects and significantly contribute to the high therapeutic success of indispensable drugs such as aspirin. While their identification has long been the result of serendipity, medicinal chemistry now tends to design polypharmacology. Modern in vitro pharmacological methods and chemical probes allow a systematic search for rational target combinations and recent innovations in computational technologies, crystallography, or fragment-based design equip multitarget compound development with valuable tools. In this Perspective, we analyze the relevance of multiple ligands in drug discovery and the versatile toolbox to design polypharmacology. We conclude that despite some characteristic challenges remaining unresolved, designed polypharmacology holds enormous potential to secure future therapeutic innovation.
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Affiliation(s)
- Ewgenij Proschak
- Institute of Pharmaceutical Chemistry , Goethe University Frankfurt , Max-von-Laue-Strasse 9 , D-60438 Frankfurt , Germany
| | - Holger Stark
- Institute of Pharmaceutical and Medicinal Chemistry , Heinrich Heine University Düsseldorf , Universitaetsstrasse 1 , D-40225 , Duesseldorf , Germany
| | - Daniel Merk
- Institute of Pharmaceutical Chemistry , Goethe University Frankfurt , Max-von-Laue-Strasse 9 , D-60438 Frankfurt , Germany.,Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences , Swiss Federal Institute of Technology (ETH) Zürich , Vladimir-Prelog-Weg 4 , CH-8093 Zürich , Switzerland
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Rodriguez J, Hiel S, Delzenne NM. Metformin: old friend, new ways of action-implication of the gut microbiome? Curr Opin Clin Nutr Metab Care 2018; 21:294-301. [PMID: 29634493 DOI: 10.1097/mco.0000000000000468] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW Gut dysbiosis was recently associated with the occurrence of type 2 diabetes (T2D). In addition to this finding, an increasing number of studies performed upon the last 5 years have also shown that metformin treatment leads to changes in gut bacterial composition in diabetic patients. This review focuses on the articles describing the effects of metformin on gut homeostasis (including the gut microbiota) and proposes potential mechanisms involved in those effects. RECENT FINDINGS Several human and animal studies emphasized that metformin alters the gut microbiota composition by enhancing the growth of some bacteria, such as Akkermansia muciniphila, Escherichia spp. or Lactobacillus and by decreasing the levels of some other ones like Intestinibacter. In-vitro studies also demonstrated a direct action of metformin on the growth of A. muciniphila and Bifidobacterium adolescentis. Moreover, in the intestines, metformin does not only improve the glucose uptake, but it also promotes the short-chain fatty acid (SCFA) production, protects the intestinal barrier and regulates the secretion of gut peptides SUMMARY: It is now clear that gut microbiota participates to the glucose-lowering effects of metformin in the context of diabetes. Further work is now needed to determine the exact mechanisms of action of the drug and to understand by which processes metformin is able to enhance the growth of some bacteria exhibiting beneficial effects for the host.
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Affiliation(s)
- Julie Rodriguez
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
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The stress polarity pathway: AMPK 'GIV'-es protection against metabolic insults. Aging (Albany NY) 2017; 9:303-314. [PMID: 28209925 PMCID: PMC5361665 DOI: 10.18632/aging.101179] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2017] [Accepted: 02/09/2017] [Indexed: 12/17/2022]
Abstract
Loss of cell polarity impairs organ development and function; it can also serve as one of the first triggers for oncogenesis. In 2006-2007 two groups simultaneously reported the existence of a special pathway for maintaining epithelial polarity in the face of environmental stressors. In this pathway, AMPK, a key sensor of metabolic stress stabilizes tight junctions, preserves cell polarity, and thereby, maintains epithelial barrier functions. Accumulating evidence since has shown that pharmacologic activation of AMPK by Metformin protects the epithelial barrier against multiple environmental and pathological stressful states and suppresses tumorigenesis. How AMPK protects the epithelium remained unknown until recently Aznar et al. identified GIV/Girdin as a novel effector of AMPK at the cell-cell junctions; phosphorylation of GIV at a single site by AMPK appears to be both necessary and sufficient for strengthening tight junctions and preserving cell polarity and epithelial barrier function in the face of energetic stress. Here we review the fundamentals of this specialized signaling pathway that buttresses cell-cell junctions against stress-induced collapse and discuss its pathophysiologic relevance in the context of a variety of diseases, including cancers, diabetes, aging, and the growing list of beneficial effects of the AMPK-activator, Metformin.
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Abstract
INTRODUCTION Novelties in the management of type 2 diabetes are dominated by the commercialisation of new glucose-lowering agents, which offer alternatives to older antidiabetic medications, and by the publication of several prospective placebo-controlled outcome trials, which demonstrated not only cardiovascular safety but also cardiovascular and renal protection with some new medications. Areas covered: Updates regarding the use of glucose-lowering agents are discussed from a clinical point of view. Some new viewpoints concern older antidiabetic agents such as metformin, sulfonylureas and glitazones whose benefit-risk balance has been revisited, especially in high risk patients. The recent data regarding DPP-4 inhibitors (gliptins) focused on the safety profile of this pharmacological class, including in patients with impaired renal function. The highlight concerns the cardiovascular (and renal) protection by some GLP-1 receptor agonists (liraglutide, semaglutide) and SGLT2 inhibitors (empagliflozin, canagliflozin) in patients with high cardiovascular risk. Finally, efficacy and safety of new combinations and advances in insulin therapy will be briefly discussed. Expert commentary: The recent data from randomized controlled trials, meta-analyses and observational real-life studies should trigger a revision of the algorithm for the treatment of hyperglycemia in type 2 diabetes, especially in patients with high cardiovascular and/or renal risk.
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Affiliation(s)
- André J Scheen
- a Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine , CHU Liège , Liège , Belgium.,b Division of Clinical Pharmacology, Center for Interdisciplinary Research on Medicines (CIRM) , University of Liège , Liège , Belgium
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