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Kakoti BB, Zothantluanga JH, Deka K, Halder RK, Roy D. In silico design and computational screening of berberine derivatives for potential antidiabetic activity through allosteric activation of the AMPK pathway. In Silico Pharmacol 2025; 13:12. [PMID: 39780772 PMCID: PMC11704122 DOI: 10.1007/s40203-024-00295-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Globally, there is an increase in the prevalence of metabolic illnesses, including diabetes mellitus. However, current therapies for diabetes and other metabolic illnesses are not well understood. Pharmacological treatment of type 2 diabetes is challenging, moreover, the majority of antidiabetic medications are incompatible with individuals who have cardiac disease, renal illness, or liver damage. Despite the ongoing development of innovative medicines, the quest for an optimal treatment that serves both as a hypoglycaemic agent and mitigates diabetes-related problems remains unattained. Recent research demonstrates that berberine has significant promise in the treatment of diabetes. Berberine influences glucose metabolism by enhancing insulin secretion, promoting glycolysis, decreasing adipogenesis, disrupting the function of the mitochondria, stimulating the 5' adenosine monophosphate-activated protein kinase (AMPK) pathway, thereby augmenting glucokinase activity. In this study, we virtually designed and synthesized 5 berberine derivatives (data not yet published) to study their impact on the AMP-activated protein kinase (AMPK) pathway through molecular docking and dynamic simulation study. Activation of AMPK plays an important role by enhancing glucose uptake in cells. Berberine and its derivatives showed potential for allosteric activation of the AMPK pathway. The allosteric activation of AMPK α- & β-subunit involves complex interactions with standard activators like A-769662. Berberine and its derivatives showed potential binding affinity at the allosteric site of AMPK α- & β-subunit, forming similar interactions to A-769662. Molecular dynamic simulations indicated stability of these complexes. However, interactions of these derivatives with the AMPK γ-subunit were less stable, suggesting limited potential for allosteric activation at this site. Further studies are required to assess the long-term stability and efficacy of berberine and its derivatives as allosteric AMPK activators. Additionally, ADMET predictions suggest these derivatives to be safe, warranting further experimental and preclinical investigations as potential antidiabetic agents. Supplementary Information The online version contains supplementary material available at 10.1007/s40203-024-00295-0.
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Affiliation(s)
- Bibhuti Bhusan Kakoti
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam 786004 India
| | - James H. Zothantluanga
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam 786004 India
| | - Kangkan Deka
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam 786004 India
- NETES Institute of Pharmaceutical Science, NEMCARE Group of Institutions, Mirza, Kamrup, Guwahati, Assam 781125 India
| | - Raj Kumar Halder
- Ruhvenile Biomedical, Plot-8 OCF Pocket Institution, Sarita Vihar, Delhi, 110076 India
| | - Dhritiman Roy
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam 786004 India
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Dayanand Y, Pather R, Xulu N, Booysen I, Sibiya N, Khathi A, Ngubane P. Exploring the Biological Effects of Anti-Diabetic Vanadium Compounds in the Liver, Heart and Brain. Diabetes Metab Syndr Obes 2024; 17:3267-3278. [PMID: 39247428 PMCID: PMC11380877 DOI: 10.2147/dmso.s417700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Accepted: 08/21/2023] [Indexed: 09/10/2024] Open
Abstract
The prevalence of diabetes mellitus and diabetes-related complications is rapidly increasing worldwide, placing a substantial financial burden on healthcare systems. Approximately 537 million adults are currently diagnosed with type 1 or type 2 diabetes globally. However, interestingly, the increasing morbidity rate is primarily influenced by the effects of long-term hyperglycemia on vital organs such as the brain, the liver and the heart rather than the ability of the body to use glucose effectively. This can be attributed to the summation of the detrimental effects of excessive glucose on major vascular systems and the harmful side effects attributed to the current treatment associated with managing the disease. These drugs have been implicated in the onset and progression of cardiovascular disease, hepatocyte injury and cognitive dysfunction, thereby warranting extensive research into alternative treatment strategies. Literature has shown significant progress in utilizing metal-based compounds, specifically those containing transition metals such as zinc, magnesium and vanadium, in managing hyperglycaemia. Amongst these metals, research carried out on vanadium reflected the most promising anti-diabetic efficacy in cell culture and animal studies. This was attributed to the ability to improve glucose management in the bloodstream by enhancing its uptake and metabolism in the kidney, brain, skeletal muscle, heart and liver. Despite this, organic vanadium was considered toxic due to its accumulative characteristics. To alleviate vanadium's toxic nature while subsequently manipulating its therapeutic properties, vanadium complexes were synthesized using either vanadate or vanadyl as a base compound. This review attempts to evaluate organic vanadium salts' therapeutic and toxic effects, highlight vanadium complexes' research and provide insight into the novel dioxidovanadium complex synthesized in our laboratory to alleviate hyperglycaemia-associated macrovascular complications in the brain, heart and liver.
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Affiliation(s)
- Yalka Dayanand
- School of Laboratory Medicine and Medical Science, University of Kwazulu-Natal, Durban, South Africa
| | - Reveshni Pather
- School of Laboratory Medicine and Medical Science, University of Kwazulu-Natal, Durban, South Africa
| | - Nombuso Xulu
- School of Laboratory Medicine and Medical Science, University of Kwazulu-Natal, Durban, South Africa
| | - Irvin Booysen
- School of Chemistry and Physics, University of Kwazulu-Natal, Pietermaritzburg, South Africa
| | - Ntethelelo Sibiya
- Pharmacology Division, Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa
| | - Andile Khathi
- School of Laboratory Medicine and Medical Science, University of Kwazulu-Natal, Durban, South Africa
| | - Phikelelani Ngubane
- School of Laboratory Medicine and Medical Science, University of Kwazulu-Natal, Durban, South Africa
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Elizalde-Velázquez GA, Herrera-Vázquez SE, Gómez-Oliván LM, García-Medina S. Health impact assessment after Danio rerio long-term exposure to environmentally relevant concentrations of metformin and guanylurea. CHEMOSPHERE 2023; 341:140070. [PMID: 37689151 DOI: 10.1016/j.chemosphere.2023.140070] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 07/19/2023] [Accepted: 09/03/2023] [Indexed: 09/11/2023]
Abstract
The antidiabetic drug metformin (MET) and its metabolite guanylurea (GUA) have been frequently and ubiquitously detected in surface water. Consequently, there has been a consistent rise in studying the toxicity of MET and GUA in fish over the past decade. Nonetheless, it is noteworthy that no study has assessed the harmful effects both compounds might trigger on fish blood and organs after chronic exposure. Taking into consideration the data above, our research strived to accomplish two primary objectives: Firstly, to assess the effect of comparable concentrations of MET and GUA (1, 40, 100 μg/L) on the liver, gills, gut, and brain of Danio rerio after six months of flow-through exposure. Secondly, to compare the outcomes to identify which compound prompts more significant oxidative stress and apoptosis in organs and blood parameter alterations. Herein, findings indicate that both compounds induced oxidative damage and increased the expression of genes associated with apoptosis (bax, bcl2, p53, and casp3). Chronic exposure to MET and GUA also generated fluctuations in glucose, creatinine, phosphorus, liver enzymes, red and white blood count, hemoglobin, and hematocrit levels. The observed biochemical changes indicate that MET and GUA are responsible for inducing hepatic damage in fish, whereas hematological alterations suggest that both compounds cause anemia. Considering GUA altered to a more considerable extent the values of all endpoints compared to the control group, it is suggested transformation product GUA is more toxic than MET. Moreover, based on the above evidence, it can be inferred that a six-month exposure to MET and GUA can impair REDOX status and generate apoptosis in fish, adversely affecting their essential organs' functioning.
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Affiliation(s)
- Gustavo Axel Elizalde-Velázquez
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma Del Estado de México. Paseo Colón Intersección Paseo Tollocan, Colonia Residencial Colón, CP 50120, Toluca, Estado de México, Mexico
| | - Selene Elizabeth Herrera-Vázquez
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma Del Estado de México. Paseo Colón Intersección Paseo Tollocan, Colonia Residencial Colón, CP 50120, Toluca, Estado de México, Mexico
| | - Leobardo Manuel Gómez-Oliván
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma Del Estado de México. Paseo Colón Intersección Paseo Tollocan, Colonia Residencial Colón, CP 50120, Toluca, Estado de México, Mexico. https://orcid.org/0000-0002-7248-3449
| | - Sandra García-Medina
- Laboratorio de Toxicología Acuática, Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional. Unidad Profesional Adolfo López Mateos, Av. Wilfrido Massieu S/n y Cerrada Manuel Stampa, Col. Industrial Vallejo, Ciudad de México, CP, 07700, Mexico
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Mian A, Bani Fawwaz BA, Singh G, Farooq A, Koteish A. Metformin-Induced Acute Hepatitis. Cureus 2023; 15:e38908. [PMID: 37309348 PMCID: PMC10257557 DOI: 10.7759/cureus.38908] [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] [Accepted: 04/30/2023] [Indexed: 06/14/2023] Open
Abstract
Metformin is considered an initial oral pharmacotherapy of choice for treating hyperglycemia in type 2 diabetes mellitus (T2DM). Although safe in the vast majority of the population, rare side effects will come to light as the prevalence of T2DM continues to rise. We present a rare case of metformin-induced hepatotoxicity and possibly the first reported case of dose-dependent metformin-induced hepatotoxicity. This case report aims to make clinicians aware of this infrequent yet significant adverse reaction that can arise with metformin therapy.
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Affiliation(s)
- Arooj Mian
- Internal Medicine, AdventHealth Orlando, Orlando, USA
| | | | - Gurdeep Singh
- Internal Medicine, AdventHealth Orlando, Orlando, USA
| | - Aimen Farooq
- Internal Medicine, AdventHealth Orlando, Orlando, USA
| | - Ayman Koteish
- Gastroenterology and Hepatology, AdventHealth Orlando, Orlando, USA
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Afshari MJ, Cheng X, Duan G, Duan R, Wu S, Zeng J, Gu Z, Gao M. Vision for Ratiometric Nanoprobes: In Vivo Noninvasive Visualization and Readout of Physiological Hallmarks. ACS NANO 2023; 17:7109-7134. [PMID: 37036400 DOI: 10.1021/acsnano.3c01641] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
Lesion areas are distinguished from normal tissues surrounding them by distinct physiological characteristics. These features serve as biological hallmarks with which targeted biomedical imaging of the lesion sites can be achieved. Although tremendous efforts have been devoted to providing smart imaging probes with the capability of visualizing the physiological hallmarks at the molecular level, the majority of them are merely able to derive anatomical information from the tissues of interest, and thus are not suitable for taking part in in vivo quantification of the biomarkers. Recent advances in chemical construction of advanced ratiometric nanoprobes (RNPs) have enabled a horizon for quantitatively monitoring the biological abnormalities in vivo. In contrast to the conventional probes whose dependency of output on single-signal profiles restricts them from taking part in quantitative practices, RNPs are designed to provide information in two channels, affording a self-calibration opportunity to exclude the analyte-independent factors from the outputs and address the issue. Most of the conventional RNPs have encountered several challenges regarding the reliability and sufficiency of the obtained data for high-performance imaging. In this Review, we have summarized the recent progresses in developing highly advanced RNPs with the capabilities of deriving maximized information from the lesion areas of interest as well as adapting themselves to the complex biological systems in order to minimize microenvironmental-induced falsified signals. To provide a better outlook on the current advanced RNPs, nanoprobes based on optical, photoacoustic, and magnetic resonance imaging modalities for visualizing a wide range of analytes such as pH, reactive species, and different derivations of amino acids have been included. Furthermore, the physicochemical properties of the RNPs, the major constituents of the nanosystems and the analyte recognition mechanisms have been introduced. Moreover, the alterations in the values of the ratiometric signal in response to the analyte of interest as well as the time at which the highest value is achieved, have been included for most of RNPs discussed in this Review. Finally, the challenges as well as future perspectives in the field are discussed.
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Affiliation(s)
- Mohammad Javad Afshari
- Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, People's Republic of China
| | - Xiaju Cheng
- Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, People's Republic of China
| | - Guangxin Duan
- Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, People's Republic of China
| | - Ruixue Duan
- Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, People's Republic of China
| | - Shuwang Wu
- Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, People's Republic of China
| | - Jianfeng Zeng
- Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, People's Republic of China
| | - Zi Gu
- School of Chemical Engineering and Australian Centre for NanoMedicine (ACN), University of New South Wales, Sydney, New South Wales 2052, Australia
| | - Mingyuan Gao
- Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, People's Republic of China
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Liu B, Xu J, Lu L, Gao L, Zhu S, Sui Y, Cao T, Yang T. Metformin induces pyroptosis in leptin receptor-defective hepatocytes via overactivation of the AMPK axis. Cell Death Dis 2023; 14:82. [PMID: 36737598 PMCID: PMC9898507 DOI: 10.1038/s41419-023-05623-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 01/05/2023] [Accepted: 01/26/2023] [Indexed: 02/05/2023]
Abstract
Metformin is the biguanide of hepatic insulin sensitizer for patients with non-alcohol fatty liver disease (NAFLD). Findings regarding its efficacy in restoring blood lipids and liver histology have been contradictory. In this study, we explore metformin's preventive effects on NAFLD in leptin-insensitive individuals. We used liver tissue, serum exosomes and isolated hepatocytes from high-fat diet (HFD)-induced Zucker diabetic fatty (ZDF) rats and leptin receptor (Lepr) knockout rats to investigate the correlation between hepatic Lepr defective and liver damage caused by metformin. Through immunostaining, RT-PCR and glucose uptake monitoring, we showed that metformin treatment activates adenosine monophosphate (AMP)-activated protein kinase (AMPK) and its downstream cytochrome C oxidase (CCO). This leads to overactivation of glucose catabolism-related genes, excessive energy repertoire consumption, and subsequent hepatocyte pyroptosis. Single-cell RNA sequencing further confirmed the hyper-activation of glucose catabolism after metformin treatment. Altogether, we showed that functional Lepr is necessary for metformin treatment to be effective, and that long-term metformin treatment might promote NAFLD progression in leptin-insensitive individuals. This provides important insight into the clinical application of metformin.
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Affiliation(s)
- Bingli Liu
- Department of Orthopedics, Shanghai Pudong New Area People's Hospital, Shanghai, 201299, China
| | - Jingyuan Xu
- Department of Gastroenterology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, China
| | - Linyao Lu
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, China
| | - Lili Gao
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, China
| | - Shengjuan Zhu
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, China
| | - Yi Sui
- Department of Nutrition, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Ting Cao
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, China
| | - Tao Yang
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, China.
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Zhong W, Wang X, Yang L, Wang Y, Xiao Q, Yu S, Cannon RD, Bai Y, Zhang C, Chen D, Ji P, Gao X, Song J. Nanocarrier-Assisted Delivery of Metformin Boosts Remodeling of Diabetic Periodontal Tissue via Cellular Exocytosis-Mediated Regulation of Endoplasmic Reticulum Homeostasis. ACS NANO 2022; 16:19096-19113. [PMID: 36259964 DOI: 10.1021/acsnano.2c08146] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Endoplasmic reticulum (ER) dysfunction is a potential contributor to the impaired repair capacity of periodontal tissue in diabetes mellitus (DM) patients. Restoring ER homeostasis is thus critical for successful regenerative therapy of diabetic periodontal tissue. Recent studies have shown that metformin can modulate DM-induced ER dysfunction, yet its mechanism remains unclear. Herein, we show that high glucose elevates the intracellular miR-129-3p level due to exocytosis-mediated release failure and subsequently perturbs ER calcium homeostasis via downregulating transmembrane and coiled-coil domain 1 (TMCO1), an ER Ca2+ leak channel, in periodontal ligament stem cells (PDLSCs). This results in the degradation of RUNX2 via the ubiquitination-dependent pathway, in turn leading to impaired PDLSCs osteogenesis. Interestingly, metformin could upregulate P2X7R-mediated exosome release and decrease intracellular miR-129-3p accumulation, which restores ER homeostasis and thereby rescues the impaired PDLSCs. To further demonstrate the in vivo effect of metformin, a nanocarrier for sustained local delivery of metformin (Met@HALL) in periodontal tissue is developed. Our results demonstrate that compared to controls, Met@HALL with enhanced cytocompatibility and pro-osteogenic activity could boost the remodeling of diabetic periodontal tissue in rats. Collectively, our findings unravel a mechanism of metformin in restoring cellular ER homeostasis, enabling the development of a nanocarrier-mediated ER targeting strategy for remodeling diabetic periodontal tissue.
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Affiliation(s)
- Wenjie Zhong
- College of Stomatology, Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
| | - Xinyan Wang
- College of Stomatology, Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
| | - Lanxin Yang
- College of Stomatology, Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
| | - Yue Wang
- College of Stomatology, Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
| | - Qingyue Xiao
- College of Stomatology, Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
| | - Simin Yu
- College of Stomatology, Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
| | - Richard D Cannon
- Department of Oral Sciences, Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin 9016, New Zealand
| | - Yan Bai
- Chongqing Research Center for Pharmaceutical Engineering, Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing 400016, China
| | - Chuangwei Zhang
- College of Stomatology, Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
| | - Duanjing Chen
- College of Stomatology, Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
| | - Ping Ji
- College of Stomatology, Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
| | - Xiang Gao
- College of Stomatology, Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
| | - Jinlin Song
- College of Stomatology, Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
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Fatal Fulminant Hepatitis E in a Diabetic Patient on Metformin. Diagnostics (Basel) 2022; 12:diagnostics12102385. [PMID: 36292073 PMCID: PMC9600022 DOI: 10.3390/diagnostics12102385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/19/2022] [Accepted: 09/22/2022] [Indexed: 11/16/2022] Open
Abstract
Hepatitis E is mostly autochthonous in Western developed countries, eating pig-derived products being the most frequently documented source. Hepatitis E virus (HEV) infection is usually asymptomatic or self-limiting, but it can cause acute liver failure. HEV serological testing was performed using EUROIMMUN immunoenzymatic assays. HEV RNA in the serum was determined using an in-house real-time reverse transcriptase PCR procedure. The HEV genotype was determined through phylogenetic analysis after Sanger sequencing was performed using an in-house procedure. The case patient, an immunocompetent patient in his 60s with type 2 diabetes and no documented chronic liver disease, was hospitalized in February 2021 in an intensive care unit due to an initially unexplained coma. He presented metformin overdose and fulminant hepatitis E (HEV RNA in the serum was 4,140,000 copies/mL) that evolved toward death. The HEV genotype was 3f. We identified eight previous hepatitis E in diabetic patients, but with no metformin excessive plasma concentration, in the literature. Three patients were liver transplant recipients and three died. HEV infection can be severe and life-threatening in diabetic patients, which warrants HEV testing in this special population in the case of an altered general condition and/or liver cytolysis.
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Wang C, Deng H, Xu Y, Liu Y. Literature review of the clinical characteristics of metformin-induced hepatotoxicity. Front Pharmacol 2022; 13:969505. [PMID: 36147344 PMCID: PMC9486097 DOI: 10.3389/fphar.2022.969505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 08/16/2022] [Indexed: 11/29/2022] Open
Abstract
Background: Knowledge of metformin-induced hepatotoxicity is based on case reports. The aim of this study was to investigate the clinical features of metformin-induced hepatotoxicity. Methods: We collected relevant literature on metformin-induced hepatotoxicity published from January 1994 to February 2022 by searching Chinese and English databases. Results: Thirty patients (19 males and 11 females) from 29 articles were included, with a median age of 61 years (range 29-83). The median time to onset of liver injury was 4 weeks (range 0.3-648) after metformin administration. Clinical symptoms occurred in 28 patients, including gastrointestinal reactions (56.7%), jaundice (50.0%), fatigue (36.7%), anorexia (23.3%), pruritus (13.3%), dark urine (13.3%), and clay-colored stools (10.0%). Serum alanine transaminase, aspartate transaminase, γ-glutamyl transferase, total bilirubin and alkaline phosphatase were elevated to varying degrees. Liver imaging in 26 patients showed hepatic steatosis (6 cases, 23.1%) and gallbladder wall thickening (11.5%). Liver biopsies from 13 patients showed portal phlebitis (61.5%), cholestatic hepatitis (38.5%), and parenchymal inflammation (38.5%). After metformin discontinuation, liver function returned to normal levels at a median of 6 weeks (range 2-16). Conclusions: Metformin-induced hepatotoxicity is a rare adverse reaction. Physicians and patients should be alert to metformin-induced hepatotoxicity.
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Affiliation(s)
- Chunjiang Wang
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, Hunan, China
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hongyi Deng
- Department of Pharmacy, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, China
| | - Yunfei Xu
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, Hunan, China
| | - Ying Liu
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, Hunan, China
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10
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Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways. Clin Sci (Lond) 2022; 136:1347-1366. [PMID: 36148775 PMCID: PMC9508552 DOI: 10.1042/cs20220572] [Citation(s) in RCA: 143] [Impact Index Per Article: 47.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/12/2022] [Accepted: 09/14/2022] [Indexed: 01/30/2023]
Abstract
The metabolic-associated fatty liver disease (MAFLD) is a condition of fat accumulation in the liver in combination with metabolic dysfunction in the form of overweight or obesity and insulin resistance. It is also associated with an increased cardiovascular disease risk, including hypertension and atherosclerosis. Hepatic lipid metabolism is regulated by a combination of the uptake and export of fatty acids, de novo lipogenesis, and fat utilization by β-oxidation. When the balance between these pathways is altered, hepatic lipid accumulation commences, and long-term activation of inflammatory and fibrotic pathways can progress to worsen the liver disease. This review discusses the details of the molecular mechanisms regulating hepatic lipids and the emerging therapies targeting these pathways as potential future treatments for MAFLD.
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Juneja D, Nasa P, Jain R. Metformin toxicity: A meta-summary of case reports. World J Diabetes 2022; 13:654-664. [PMID: 36159225 PMCID: PMC9412858 DOI: 10.4239/wjd.v13.i8.654] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/17/2022] [Accepted: 07/25/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Metformin is arguably the most commonly prescribed oral hypoglycemic agent for the management of diabetes. Due to the lack of randomized control trials, most of the data pertaining to the clinical course, therapeutic interventions and outcomes of patients with metformin induced toxicity has come from case reports or series.
AIM To analyse the symptomology, clinical interventions and outcomes of patients presenting with severe metformin toxicity by reviewing the published case reports and series.
METHODS We performed a systematic search from PubMed, Science Direct, Reference Citation Analysis (https://www.referencecitationanalysis.com/) and Google Scholar databases using the terms “metformin” AND “toxicity” OR “overdose” OR “lactic acidosis” OR “hyperlactatemia”. The inclusion criteria were: (1) Case reports or case series with individual patient details; and (2) Reported toxicity or overdose of metformin in adults, published in the English language. Data regarding baseline demographics, clinical presentation, therapeutic interventions, intensive care unit course and overall outcome were collected.
RESULTS Two hundred forty-two individual cases were analysed, from 158 case reports and 26 case series, with a cumulative mortality of 19.8%. 214 (88.4%) patients were diabetics on metformin. 57 (23.6%) had acute ingestion, but a great majority (76.4%) were on metformin in therapeutic doses when they developed toxicity. Metformin associated lactic acidosis (MALA) was the most commonly reported adverse effect present in 224 (92.6%) patients. Most of the patients presented with gastrointestinal and neurological symptoms and a significant number of patients had severe metabolic acidosis and hyperlactatemia. The organ support used was renal replacement therapy (RRT) (68.6%), vaso-pressors (58.7%) and invasive mechanical ventilation (52.9%). A majority of patients (68.6%) received RRT for toxin removal, renal dysfunction and correction of MALA. Patients with lowest pH and highest serum lactate and metformin levels also had favourable outcomes with use of RRT.
CONCLUSION Most of the reported cases were on therapeutic doses of metformin but developed toxicity after an acute deterioration in renal functions. These patients may develop severe lactic acidosis, leading to significant morbidity and need for organ support. Despite severe MALA and the need for multiple organ support, they may have good outcomes, especially when RRT is used. The dose of metformin, serum pH, lactate and metformin levels may indicate the severity of toxicity and the need for aggressive therapeutic measures but may not necessarily indicate poor outcomes.
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Affiliation(s)
- Deven Juneja
- Institute of Critical Care Medicine, Max Super Speciality Hospital, Saket, New Delhi 110017, India
| | - Prashant Nasa
- Department of Critical Care Medicine, NMC Specialty Hospital, Dubai 7832, United Arab Emirates
| | - Ravi Jain
- Department of Critical Care Medicine, Mahatma Gandhi Medical College and Hospital, Jaipur 302022, India
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12
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Wu R, Chen Z, Huo H, Chen L, Su L, Zhang X, Wu Y, Yao Z, Xiao S, Du W, Song J. Ratiometric Detection of H 2S in Liver Injury by Activated Two-Wavelength Photoacoustic Imaging. Anal Chem 2022; 94:10797-10804. [PMID: 35829734 DOI: 10.1021/acs.analchem.2c01571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Metformin is commonly used for clinical treatment of type-2 diabetes, but long-term or overdose intake of metformin usually causes selective upregulation of H2S level in the liver, resulting in liver injury. Therefore, tracking the changes of H2S content in the liver would contribute to the prevention and diagnosis of liver injury. However, in the literature, there are few reports on ratiometric PA molecular probes for H2S detection in drug-induced liver injury (DILI). Accordingly, here we developed a H2S-activated ratiometric PA probe, namely BDP-H2S, based Aza-BODIPY dye for detecting the H2S upregulation of metformin-induced liver injury. Due to the intramolecular charge transfer (ICT) effect, BDP-H2S exhibited a strong PA signal at 770 nm. Following the response to H2S, its ICT effect was recovered which showed a decrement of PA770 and an enhancement of PA840. The ratiometric PA signal (PA840/PA770) showed excellent H2S selectivity response with a low limit of detection (0.59 μM). Bioimaging experiments demonstrated that the probe has been successfully used for ratiometric PA imaging of H2S in cells and metformin-induced liver injury in mice. Overall, the designed probe emerges as a powerful tool for noninvasive and accurate imaging of H2S level and tracking its distribution and variation in liver in-real time.
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Affiliation(s)
- Rongrong Wu
- Fujian Science & Technology Innovation Laboratory for Optoelectronic Information of China, MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, College of Chemical Engineering, Fuzhou University, Fuzhou 350108, P. R. China
| | - Zhongxiang Chen
- Fujian Science & Technology Innovation Laboratory for Optoelectronic Information of China, MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, College of Chemical Engineering, Fuzhou University, Fuzhou 350108, P. R. China
| | - Hongqi Huo
- Department of Nuclear Medicine, Han Dan Central Hospital, Handan, Hebei 056001, P. R. China
| | - Lanlan Chen
- Fujian Science & Technology Innovation Laboratory for Optoelectronic Information of China, MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, College of Chemical Engineering, Fuzhou University, Fuzhou 350108, P. R. China
| | - Lichao Su
- Fujian Science & Technology Innovation Laboratory for Optoelectronic Information of China, MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, College of Chemical Engineering, Fuzhou University, Fuzhou 350108, P. R. China
| | - Xuan Zhang
- Fujian Science & Technology Innovation Laboratory for Optoelectronic Information of China, MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, College of Chemical Engineering, Fuzhou University, Fuzhou 350108, P. R. China
| | - Ying Wu
- Fujian Science & Technology Innovation Laboratory for Optoelectronic Information of China, MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, College of Chemical Engineering, Fuzhou University, Fuzhou 350108, P. R. China
| | - Zhicun Yao
- Fujian Science & Technology Innovation Laboratory for Optoelectronic Information of China, MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, College of Chemical Engineering, Fuzhou University, Fuzhou 350108, P. R. China
| | - Shenggan Xiao
- Fujian Science & Technology Innovation Laboratory for Optoelectronic Information of China, MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, College of Chemical Engineering, Fuzhou University, Fuzhou 350108, P. R. China
| | - Wei Du
- Fujian Science & Technology Innovation Laboratory for Optoelectronic Information of China, MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, College of Chemical Engineering, Fuzhou University, Fuzhou 350108, P. R. China
| | - Jibin Song
- Fujian Science & Technology Innovation Laboratory for Optoelectronic Information of China, MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, College of Chemical Engineering, Fuzhou University, Fuzhou 350108, P. R. China
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13
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Ali A, Unnikannan H, Shafarin J, Bajbouj K, Taneera J, Muhammad JS, Hasan H, Salehi A, Awadallah S, Hamad M. Metformin enhances LDL-cholesterol uptake by suppressing the expression of the pro-protein convertase subtilisin/kexin type 9 (PCSK9) in liver cells. Endocrine 2022; 76:543-557. [PMID: 35237909 DOI: 10.1007/s12020-022-03022-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 02/16/2022] [Indexed: 12/11/2022]
Abstract
PURPOSE Metformin (MF) intake associates with reduced levels of circulating low-density lipoprotein-cholesterol (LDL-C). This has been attributed to the activation of AMPK, which differentially regulates the expression of multiple genes involved in cholesterol synthesis and trafficking. However, the exact mechanism underlying the LDL-C lowering effect of MF remains ambiguous. METHODS MF-treated Hep-G2 and HuH7 cells were evaluated for cell viability and the expression status of key lipid metabolism-related genes along with LDL-C uptake efficiency. RESULTS MF treatment resulted in decreased expression and secretion of PCSK9, increased expression of LDLR and enhanced LDL-C uptake in hepatocytes. It also resulted in increased expression of activated AMPK (p-AMPK) and decreased expression of SREBP2 and HNF-1α proteins. Transcriptomic analysis of MF-treated Hep-G2 cells confirmed these findings and showed that other key lipid metabolism-related genes including those that encode apolipoproteins (APOB, APOC2, APOC3 and APOE), MTTP and LIPC are downregulated. Lastly, MF treatment associated with reduced HMG-CoA reductase expression and activity. CONCLUSIONS These findings suggest that MF treatment reduces circulating LDL-C levels by suppressing PCSK9 expression and enhancing LDLR expression; hence the potential therapeutic utility of MF in hypercholesterolemia.
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Affiliation(s)
- Amjad Ali
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Hema Unnikannan
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Jasmin Shafarin
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Khuloud Bajbouj
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Jalal Taneera
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Jibran Sualeh Muhammad
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Haydar Hasan
- Department of Clinical Nutrition and Dietetics, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Albert Salehi
- Department of Clinical science, UMAS, Clinical Research Center, Lund University, Malmö, Sweden
- Department of Neuroscience and Physiology, Metabolic Research Unit, University of Gothenburg, Gothenburg, Sweden
| | - Samir Awadallah
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates.
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates.
| | - Mawieh Hamad
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates.
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates.
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14
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Huang KH, Lee CH, Cheng YD, Gau SY, Tsai TH, Chung NJ, Lee CY. Correlation between long-term use of metformin and incidence of NAFLD among patients with type 2 diabetes mellitus: A real-world cohort study. Front Endocrinol (Lausanne) 2022; 13:1027484. [PMID: 36531446 PMCID: PMC9748475 DOI: 10.3389/fendo.2022.1027484] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 11/09/2022] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND AND AIMS Studies have demonstrated that the short-term use of metformin benefits liver function among patients with type 2 diabetes mellitus (T2DM). However, few studies have reported on the effects of long-term metformin treatment on liver function or liver histology. This study investigated the correlation between metformin use and the incidence of nonalcoholic fatty liver disease (NAFLD) among patients with T2DM. METHODS This population-based study investigated the risk of NAFLD among patients with T2DM who received metformin treatment between 2001-2018. Metformin users and metformin nonusers were enrolled and matched to compare the risk of NAFLD. RESULTS After 3 years, the patients who received <300 cDDD of metformin and those with metformin use intensity of <10 and 10-25 DDD/month had odds ratios (ORs) of 1.11 (95% confidence interval [CI] = 1.06-1.16), 1.08 (95% CI = 1.02-1.13), and 1.18 (95% CI = 1.11-1.26) for NAFLD, respectively. Moreover, metformin users who scored high on the Diabetes Complications and Severity Index (DCSI) were at high risk of NAFLD. Patients with comorbid hyperlipidemia, hyperuricemia, obesity, and hepatitis C were also at high risk of NAFLD. CONCLUSION Patients with T2DM who received metformin of <300 cDDD or used metformin at an intensity of <10 and 10-25 DDD/month were at a high risk of developing NAFLD. The results of this study also indicated that patients with T2DM receiving metformin and with high scores on the DCSI were at a high risk of developing NAFLD.
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Affiliation(s)
- Kuang-Hua Huang
- Department of Health Services Administration, China Medical University, Taichung, Taiwan
| | - Chiu-Hsiang Lee
- School of Nursing, Chung Shan Medical University, Taichung, Taiwan
- Department of Nursing, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Yih-Dih Cheng
- School of Pharmacy, China Medical University, Taichung, Taiwan
- Department of Pharmacy, China Medical University Hospital, Taichung, Taiwan
| | - Shuo-Yan Gau
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Tung-Han Tsai
- Department of Health Services Administration, China Medical University, Taichung, Taiwan
| | - Ning-Jen Chung
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Chien-Ying Lee
- Department of Pharmacology, Chung Shan Medical University, Taichung, Taiwan
- Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan
- *Correspondence: Chien-Ying Lee,
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15
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Induri SNR, Kansara P, Thomas SC, Xu F, Saxena D, Li X. The Gut Microbiome, Metformin, and Aging. Annu Rev Pharmacol Toxicol 2021; 62:85-108. [PMID: 34449247 DOI: 10.1146/annurev-pharmtox-051920-093829] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Metformin has been extensively used for the treatment of type 2 diabetes, and it may also promote healthy aging. Despite its widespread use and versatility, metformin's mechanisms of action remain elusive. The gut typically harbors thousands of bacterial species, and as the concentration of metformin is much higher in the gut as compared to plasma, it is plausible that microbiome-drug-host interactions may influence the functions of metformin. Detrimental perturbations in the aging gut microbiome lead to the activation of the innate immune response concomitant with chronic low-grade inflammation. With the effectiveness of metformin in diabetes and antiaging varying among individuals, there is reason to believe that the gut microbiome plays a role in the efficacy of metformin. Metformin has been implicated in the promotion and maintenance of a healthy gut microbiome and reduces many age-related degenerative pathologies. Mechanistic understanding of metformin in the promotion of a healthy gut microbiome and aging will require a systems-level approach. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Sri Nitya Reddy Induri
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USA;
| | - Payalben Kansara
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USA;
| | - Scott C Thomas
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USA;
| | - Fangxi Xu
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USA;
| | - Deepak Saxena
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USA; .,Department of Surgery, New York University School of Medicine, New York, NY 10016, USA
| | - Xin Li
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USA;
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16
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The Hormetic Effect of Metformin: "Less Is More"? Int J Mol Sci 2021; 22:ijms22126297. [PMID: 34208371 PMCID: PMC8231127 DOI: 10.3390/ijms22126297] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/06/2021] [Accepted: 06/10/2021] [Indexed: 02/06/2023] Open
Abstract
Metformin (MTF) is the first-line therapy for type 2 diabetes (T2DM). The euglycemic effect of MTF is due to the inhibition of hepatic glucose production. Literature reports that the principal molecular mechanism of MTF is the activation of 5′-AMP-activated protein kinase (AMPK) due to the decrement of ATP intracellular content consequent to the inhibition of Complex I, although this effect is obtained only at millimolar concentrations. Conversely, micromolar MTF seems to activate the mitochondrial electron transport chain, increasing ATP production and limiting oxidative stress. This evidence sustains the idea that MTF exerts a hormetic effect based on its concentration in the target tissue. Therefore, in this review we describe the effects of MTF on T2DM on the principal target organs, such as liver, gut, adipose tissue, endothelium, heart, and skeletal muscle. In particular, data indicate that all organs, except the gut, accumulate MTF in the micromolar range when administered in therapeutic doses, unmasking molecular mechanisms that do not depend on Complex I inhibition.
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Kim YJ, Park SY, Lee JH. Berteroin ameliorates lipid accumulation through AMPK-mediated regulation of hepatic lipid metabolism and inhibition of adipocyte differentiation. Life Sci 2021; 282:119668. [PMID: 34087283 DOI: 10.1016/j.lfs.2021.119668] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/17/2021] [Accepted: 05/24/2021] [Indexed: 12/12/2022]
Abstract
AIMS Berteroin (5-methylthiopentyl isothiocyanate) is a naturally occurring sulforaphane analog containing a non-oxidized sulfur atom in cruciferous vegetables. The objectives of the present study were to determine the effects of berteroin on lipid metabolism in hepatocytes and adipocytes and to elucidate the mechanisms involved. MAIN METHODS The effect of berteroin on lipid metabolism were evaluated in liver X receptor α agonist-stimulated HepG2 cells and adipocyte differentiation-induced 3T3-L1 cells using MTT assay, western blot, real time polymerase chain reaction, oil red O staining, and triglyceride assay. KEY FINDINGS T0901317 treatment increased the expression of sterol regulatory element binding protein (SREBP)-1c, a major transcription factor that mediates lipogenesis, and berteroin pretreatment significantly inhibited the expressions of T0901317-induced SREBP-1c and lipogenic genes. Especially, berteroin had a greater inhibitory effect on T0901317-induced SREBP-1c activation than sulforaphane, AICAR, or metformin. Berteroin also markedly suppressed lipid droplet formations and triglyceride accumulations caused by both T0901317 stimulation in HepG2 hepatocytes and differentiation induction in 3T3-L1 preadipocytes. However, berteroin significantly increased the expression of mitochondrial fatty acid oxidation-related genes (carnitine palmitoyltransferase 1 (CPT-1) and peroxisome proliferator-activated receptor gamma coactivator-1α) and the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) in HepG2 cells. Interestingly, effects of berteroin on the expressions of SREBP-1c protein and CPT-1 mRNA were remarkably prevented by compound C (an AMPK inhibitor). SIGNIFICANCE Our results suggest berteroin-inhibited hepatic lipid accumulation and adipocyte differentiation might be mediated by AMPK activation and that berteroin might be useful for the prevention, amelioration, and treatment of metabolic diseases, including hepatic steatosis.
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Affiliation(s)
- Yeon Ju Kim
- Department of Medical Biotechnology, Dongguk University, Seoul 04620, Republic of Korea
| | - Sung Yun Park
- College of Korean Medicine, Dongguk University, Goyang 10326, Republic of Korea.
| | - Ju-Hee Lee
- College of Korean Medicine, Dongguk University, Goyang 10326, Republic of Korea.
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Faradonbeh FA, Sa II, Lastuvkova H, Cermanova J, Hroch M, Faistova H, Mokry J, Nova Z, Uher M, Nachtigal P, Pavek P, Micuda S. Metformin impairs bile acid homeostasis in ethinylestradiol-induced cholestasis in mice. Chem Biol Interact 2021; 345:109525. [PMID: 34058177 DOI: 10.1016/j.cbi.2021.109525] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 02/28/2021] [Accepted: 05/16/2021] [Indexed: 12/12/2022]
Abstract
Metformin, an oral antidiabetic drug, recently demonstrated a reducing effect on bile acids (BA) plasma concentrations in one patient with intrahepatic cholestasis of pregnancy (ICP) by unknown mechanism. Therefore, the aim of the present study was to examine the effect of metformin on BA homeostasis and related molecular pathways in the liver and intestine using a mouse model of ICP. The cholestasis was induced in female C57BL/6 mice by repeated administration of ethinylestradiol (10 mg/kg BW s.c.) and/or metformin (150 mg/kg BW orally) over 5 consecutive days with subsequent bile collection and molecular analysis of samples. We demonstrated that metformin significantly increased the rate of bile secretion in control mice. This increase was BA dependent and was produced both by increased liver BA synthesis via induced cholesterol 7α-hydroxylase (Cyp7a1) and by increased BA reabsorption in the ileum via induction of the apical sodium-dependent BA transporter (Asbt). In contrast, metformin further worsened ethinylestradiol-induced impairment of bile secretion. This reduction was also BA dependent and corresponded with significant downregulation of Bsep, and Ntcp, major excretory and uptake transporters for BA in hepatocytes, respectively. The plasma concentrations of BA were consequently significantly increased in the metformin-treated mice. Altogether, our data indicate positive stimulation of bile secretion by metformin in the intact liver, but this drug also induces serious impairment of BA biliary secretion, with a marked increase in plasma concentrations in estrogen-induced cholestasis. Our results imply that metformin should be used with caution in situations with hormone-dependent cholestasis, such as ICP.
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Affiliation(s)
- Fatemeh Alaei Faradonbeh
- Department of Pharmacology, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic
| | - Ivone Igreja Sa
- Department of Biological and Medical Sciences, Charles University, Faculty of Pharmacy in Hradec Kralove, Hradec Kralove, Czech Republic
| | - Hana Lastuvkova
- Department of Pharmacology, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic
| | - Jolana Cermanova
- Department of Pharmacology, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic
| | - Milos Hroch
- Department of Medical Biochemistry, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic
| | - Hana Faistova
- Department of Pathology, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic
| | - Jaroslav Mokry
- Department of Histology and Embryology, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic
| | - Zuzana Nova
- Department of Pharmacology, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic
| | - Martin Uher
- Department of Medical Biochemistry, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic
| | - Petr Nachtigal
- Department of Biological and Medical Sciences, Charles University, Faculty of Pharmacy in Hradec Kralove, Hradec Kralove, Czech Republic
| | - Petr Pavek
- Department of Pharmacology and Toxicology, Charles University, Faculty of Pharmacy in Hradec Kralove, Hradec Kralove, Czech Republic
| | - Stanislav Micuda
- Department of Pharmacology, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic.
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Deng Z, Bi S, Jiang M, Zeng S. Endogenous H 2S-Activated Orthogonal Second Near-Infrared Emissive Nanoprobe for In Situ Ratiometric Fluorescence Imaging of Metformin-Induced Liver Injury. ACS NANO 2021; 15:3201-3211. [PMID: 33481569 DOI: 10.1021/acsnano.0c09799] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
Metformin as a hypoglycemic drug for antidiabetic treatment has emerged as a multipotential drug for many disease treatments such as cognitive disorders, cancers, promoting weight loss. However, overdose uptake may upregulate the hepatic H2S level, subsequently leading to serious liver injury and toxicity. Therefore, developing intelligent second near-infrared (NIR-II) emitting nanoprobes by using endogenous H2S as a smart trigger for noninvasive highly specific in situ monitoring of the metformin-induced hepatotoxicity is highly desirable, which is rarely explored. Herein, an endogenous H2S activated orthogonal NIR-II emitting myrica rubra-like nanoprobe based on NaYF4:Gd/Yb/Er@NaYF4:Yb@SiO2 coated with Ag nanodots was explored for highly specific in vivo ratiometrically monitoring of hepatotoxicity. The designed nanoprobes were mainly uptaken by the liver and subsequently converted to NaYF4:Gd/Yb/Er@NaYF4:Yb@SiO2@Ag2S via in situ sulfuration reaction triggered by the overexpressed endogenous H2S in the injured liver tissues, finally leading to a turn-on orthogonal emission centered at 1053 nm (irradiation by 808 nm laser) and 1525 nm (irradiation by 980 nm laser). The designed nanoprobe presents a high detection limit down to 0.7 nM of H2S. More importantly, the in situ highly specific ratiometric imaging of the metformin-induced hepatotoxicity was successfully achieved by using the activatable orthogonal NIR-II emitting probe. Our results provide an NIR-II ratiometric fluorescence imaging strategy for highly sensitive/specific diagnosis of hepatotoxicity levels induced by metformin.
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Affiliation(s)
- Zhiming Deng
- Synergetic Innovation Center for Quantum Effects and Application, Key Laboratory of Low-dimensional Quantum Structures and Quantum Control of Ministry of Education, Key Laboratory for Matter Microstructure and Function of Hunan Province, School of Physics and Electronics, Hunan Normal University, Changsha 410081, P.R. China
| | - Shenghui Bi
- Synergetic Innovation Center for Quantum Effects and Application, Key Laboratory of Low-dimensional Quantum Structures and Quantum Control of Ministry of Education, Key Laboratory for Matter Microstructure and Function of Hunan Province, School of Physics and Electronics, Hunan Normal University, Changsha 410081, P.R. China
| | - Mingyang Jiang
- Synergetic Innovation Center for Quantum Effects and Application, Key Laboratory of Low-dimensional Quantum Structures and Quantum Control of Ministry of Education, Key Laboratory for Matter Microstructure and Function of Hunan Province, School of Physics and Electronics, Hunan Normal University, Changsha 410081, P.R. China
| | - Songjun Zeng
- Synergetic Innovation Center for Quantum Effects and Application, Key Laboratory of Low-dimensional Quantum Structures and Quantum Control of Ministry of Education, Key Laboratory for Matter Microstructure and Function of Hunan Province, School of Physics and Electronics, Hunan Normal University, Changsha 410081, P.R. China
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Abstract
Metformin is a widely used biguanide drug due to its safety and low cost. It has been used for over 60 years to treat type 2 diabetes at the early stages because of its outstanding ability to decrease plasma glucose levels. Over time, different uses of metformin were discovered, and the benefits of metformin for various diseases and even aging were verified. These diseases include cancers (e.g., breast cancer, endometrial cancer, bone cancer, colorectal cancer, and melanoma), obesity, liver diseases, cardiovascular disease, and renal diseases. Metformin exerts different effects through different signaling pathways. However, the underlying mechanisms of these different benefits remain to be elucidated. The aim of this review is to provide a brief summary of the benefits of metformin and to discuss the possible underlying mechanisms.
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Affiliation(s)
- Ziquan Lv
- Department of Molecular Epidemiology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Yajie Guo
- The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
- *Correspondence: Yajie Guo
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Mundi MS, Velapati S, Patel J, Kellogg TA, Abu Dayyeh BK, Hurt RT. Evolution of NAFLD and Its Management. Nutr Clin Pract 2019; 35:72-84. [PMID: 31840865 DOI: 10.1002/ncp.10449] [Citation(s) in RCA: 185] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The global prevalence of nonalcoholic fatty liver disease (NAFLD) is estimated to be 25% and continues to rise worldwide in the setting of the obesity epidemic. This increase is especially concerning because NAFLD is often a progressive disease that can be associated with significant complications such as liver cirrhosis, hepatocellular carcinoma, and an increase in liver-related and overall mortality. Because of the devastating complications and comorbidities, NAFLD is a very costly disease for the healthcare system, with estimated annual direct medical costs exceeding $100 billion in the United States alone. Given this progressive course, it is imperative to make the diagnosis in patients with risk factors (metabolic syndrome, weight gain, and insulin resistance/diabetes). Once the diagnosis is made, the focus should shift to treatment and monitoring for the development of associated complications. Given that currently no pharmaceutical intervention is approved for the treatment of NAFLD, focus shifts instead to mitigation of risk factors through avoidance of foods that are rich in red meat, trans fats, refined carbohydrates, and high-fructose corn syrup; are low fiber; and have high energy density. The landmark of treatment, however, continues to be weight loss and improvement of insulin resistance, often through a multimodality approach. The current manuscript reviews the clinical phenotypes of NAFLD, its risk factors, and pathogenesis, as well as treatment options including lifestyle modifications and dietary interventions, medical therapies, endoscopic bariatric interventions, and bariatric surgery.
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Affiliation(s)
- Manpreet S Mundi
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | - Saketh Velapati
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | - Janki Patel
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | - Todd A Kellogg
- Division of Breast, Endocrine, Metabolic, and GI surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Barham K Abu Dayyeh
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Ryan T Hurt
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA.,Division of Breast, Endocrine, Metabolic, and GI surgery, Mayo Clinic, Rochester, Minnesota, USA.,Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.,Division of General Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.,Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville, Louisville, Kentucky, USA
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22
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Sun L, Wu Y, Chen J, Zhong J, Zeng F, Wu S. A Turn-On Optoacoustic Probe for Imaging Metformin-Induced Upregulation of Hepatic Hydrogen Sulfide and Subsequent Liver Injury. Theranostics 2019; 9:77-89. [PMID: 30662555 PMCID: PMC6332797 DOI: 10.7150/thno.30080] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 11/19/2018] [Indexed: 01/10/2023] Open
Abstract
Metformin is currently the most prescribed oral agent for diabetes treatment; however the overdose or long-term use may cause some severe side effects such as liver injury. Researches indicate that metformin-induced liver injury is closely related to upregulation of hepatic H2S. Hence, monitoring hepatic H2S generation induced by metformin could be an effective approach for evaluating hepatoxicity of the drug. Methods: We present a novel turn-on and dual-mode probe for detecting and imaging metformin-induced liver injury by specifically tracking the upregulation of hepatic H2S with fluorescent and optoacoustic methods. After reaction with H2S, the strong electron-withdrawing group dinitrophenyl ether (which acts as both the recognition moiety and the fluorescence quencher) was cleaved and replaced by an electron-donating group hydroxyl. This correspondingly leads to the changes of the probe's electronic state and absorption red-shifting as well as the subsequent turn-on fluorescent and optoacoustic signals. Results: The probe was applied to the colon tumor-bearing mice model and the metformin-induced liver injury mice model to achieve tumor imaging and liver injury assessment. The biosafety of the probe was verified by histological analysis (hematoxylin and eosin staining) and serum biochemical assays. Conclusion: The probe responds quickly to H2S in tumors and the liver, and MSOT imaging with the probe offers cross-secitonal and 3D spatial information of liver injury. This study may provide an effective approach for accessing medication side effects by tracking drug-metabolism-related products.
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Affiliation(s)
| | | | | | | | - Fang Zeng
- State Key Laboratory of Luminescent Materials & Devices, College of Materials Science & Engineering, South China University of Technology, Guangzhou 510640, China
| | - Shuizhu Wu
- State Key Laboratory of Luminescent Materials & Devices, College of Materials Science & Engineering, South China University of Technology, Guangzhou 510640, China
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23
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Sui Y, Kong X, Fan R, Ye Y, Mai H, Zhuo S, Lu W, Ruan P, Fang S, Yang T. Long-term treatment with metformin in the prevention of fatty liver in Zucker diabetic fatty rats. Diabetol Metab Syndr 2019; 11:94. [PMID: 31749893 PMCID: PMC6852932 DOI: 10.1186/s13098-019-0491-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 11/04/2019] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Treatment with metformin, the biguanide of hepatic insulin sensitizer, in patients with non-alcoholic fatty liver disease (NAFLD) has been reported with contradictory findings regarding the effectiveness on blood lipids and liver histology. In this study, we aimed to explore the preventive effects of metformin on NAFLD in Zucker diabetic fatty (ZDF) rats. METHODS Male ZDF rats and Zucker lean rats aged 4-8 weeks were subjected to vehicle or metformin treatment for 6 months. Liver cDNA microarray assay, and protein semiquantitative and histological examinations were performed. RESULTS Data demonstrated that ZDF rats developed hyperglycemia, hyperlipidemia, liver deficiency and hepatocyte degeneration. The metformin treatment significantly reduced post-load blood glucose levels, but not blood lipid profiles or liver enzyme levels. Hepatocyte degeneration was not attenuated after the treatment. The metformin-treated ZDF rats showed activation of AMP-activated protein kinase by Western blot and overexpression of cytochrome c oxidase by immunofluorescent microscopy. Gene expression microarray assay demonstrated that a panel of genes participating in glucose and lipid metabolisms were changed in the ZDF rats, and most of the altered genes involved in glucose and cholesterol metabolisms, but not those in fatty acid metabolisms, were corrected by the metformin treatment. No genes associated with inflammation, apoptosis, fibrosis, or cell death were overexpressed in the metformin-treated ZDF rats. CONCLUSIONS These results suggest that long-term metformin treatment presents no preventive effect for NAFLD in ZDF rats.
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Affiliation(s)
- Yi Sui
- Department of Clinical Nutrition, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Xianhe Kong
- Endoscopy Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655 China
| | - Rongrong Fan
- Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
| | - Yanbin Ye
- Department of Clinical Nutrition, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Haiyan Mai
- Department of Clinical Nutrition, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Shuyu Zhuo
- Department of Clinical Nutrition, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Wei Lu
- Department of Clinical Nutrition, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Peishan Ruan
- Department of Clinical Nutrition, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Shi Fang
- Department of Clinical Nutrition, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Tao Yang
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399 China
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24
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Abstract
In the 1920s, guanidine, the active component of Galega officinalis, was shown to lower glucose levels and used to synthesize several antidiabetic compounds. Metformin (1,1 dimethylbiguanide) is the most well-known and currently the only marketed biguanide in the United States, United Kingdom, Canada, and Australia for the treatment of non-insulin-dependent diabetes mellitus. Although phenformin was removed from the US market in the 1970s, it is still available around the world and can be found in unregulated herbal supplements. Adverse events associated with therapeutic use of biguanides include gastrointestinal upset, vitamin B12 deficiency, and hemolytic anemia. Although the incidence is low, metformin toxicity can lead to hyperlactatemia and metabolic acidosis. Since metformin is predominantly eliminated from the body by the kidneys, toxicity can occur when metformin accumulates due to poor clearance from renal insufficiency or in the overdose setting. The dominant source of metabolic acidosis associated with hyperlactatemia in metformin toxicity is the rapid cytosolic adenosine triphosphate (ATP) turnover when complex I is inhibited and oxidative phosphorylation cannot adequately recycle the vast quantity of H+ from ATP hydrolysis. Although metabolic acidosis and hyperlactatemia are markers of metformin toxicity, the degree of hyperlactatemia and severity of acidemia have not been shown to be of prognostic value. Regardless of the etiology of toxicity, treatment should include supportive care and consideration for adjunct therapies such as gastrointestinal decontamination, glucose and insulin, alkalinization, extracorporeal techniques to reduce metformin body burden, and metabolic rescue.
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Affiliation(s)
- George Sam Wang
- University of Colorado Anschutz Medical Campus, Aurora, CO, USA.,Children's Hospital Colorado, Aurora, CO, USA
| | - Christopher Hoyte
- University of Colorado Anschutz Medical Campus, Aurora, CO, USA.,University of Colorado Hospital, Aurora, CO, USA
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25
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Metformin as a Rare Cause of Drug-Induced Liver Injury, a Case Report and Literature Review. Am J Ther 2016; 23:e315-7. [PMID: 24263160 DOI: 10.1097/mjt.0000000000000007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Metformin is an oral hypoglycemic agent that is commonly used in the treatment of type 2 diabetes mellitus. Although metformin-associated gastrointestinal upset and metabolic acidosis is widely recognized side effect of this drug, metformin-induced liver injury has been rarely reported in the literature. In most cases reported, metformin-induced liver injury was associated with concomitant intake of other hepatotoxic drugs. Here, we report a case of a 70-year-old white woman who suffered metformin-induced liver injury 5 weeks after starting on this medication, and she was not on any other hepatotoxic agent. With increasing prescription of metformin, this case deserves particular attention for this rare but important side effect.
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26
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Evidence-based selection of training compounds for use in the mechanism-based integrated prediction of drug-induced liver injury in man. Arch Toxicol 2016; 90:2979-3003. [PMID: 27659300 PMCID: PMC5104805 DOI: 10.1007/s00204-016-1845-1] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Accepted: 08/29/2016] [Indexed: 12/16/2022]
Abstract
The current test systems employed by pharmaceutical industry are poorly predictive for drug-induced liver injury (DILI). The ‘MIP-DILI’ project addresses this situation by the development of innovative preclinical test systems which are both mechanism-based and of physiological, pharmacological and pathological relevance to DILI in humans. An iterative, tiered approach with respect to test compounds, test systems, bioanalysis and systems analysis is adopted to evaluate existing models and develop new models that can provide validated test systems with respect to the prediction of specific forms of DILI and further elucidation of mechanisms. An essential component of this effort is the choice of compound training set that will be used to inform refinement and/or development of new model systems that allow prediction based on knowledge of mechanisms, in a tiered fashion. In this review, we focus on the selection of MIP-DILI training compounds for mechanism-based evaluation of non-clinical prediction of DILI. The selected compounds address both hepatocellular and cholestatic DILI patterns in man, covering a broad range of pharmacologies and chemistries, and taking into account available data on potential DILI mechanisms (e.g. mitochondrial injury, reactive metabolites, biliary transport inhibition, and immune responses). Known mechanisms by which these compounds are believed to cause liver injury have been described, where many if not all drugs in this review appear to exhibit multiple toxicological mechanisms. Thus, the training compounds selection offered a valuable tool to profile DILI mechanisms and to interrogate existing and novel in vitro systems for the prediction of human DILI.
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27
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Ghadge A, Harsulkar A, Karandikar M, Pandit V, Kuvalekar A. Comparative anti-inflammatory and lipid-normalizing effects of metformin and omega-3 fatty acids through modulation of transcription factors in diabetic rats. GENES AND NUTRITION 2016; 11:10. [PMID: 27551311 PMCID: PMC4968436 DOI: 10.1186/s12263-016-0518-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 12/11/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Emerging evidence suggests beneficial effects of omega-3 fatty acids on diabetic complications. The present study compared the progressive effects of metformin and flax/fish oil on lipid metabolism, inflammatory markers, and liver and renal function test markers in streptozotocin-nicotinamide-induced diabetic rats. METHODS Streptozotocin-induced diabetic rats were randomized into control and four diabetic groups: streptozotocin (STZ), metformin (200 mg/kg body weight (b.w)/day (D)), flax and fish oil (500 mg/kg b.w/D). RESULTS Metformin and flax and fish oil exhibited increased expression of transcription factor peroxisome proliferator-activated receptor γ while the treatment downregulated sterol regulatory element-binding protein 1 and nuclear factor kβ as compared to those of the STZ group. Apart from modulation of transcription factor expression, the expression of fatty acid synthase, long chain acyl CoA synthase, and malonyl-CoA-acyl carrier protein transacylase was lowered by flax/fish oil treatment. Serum cholesterol, triglycerides, and VLDL were also significantly reduced in the treatment groups as compared to those in the STZ group. Although pathological abnormalities were seen in the liver and kidneys of rats on metformin, no significant changes in liver/renal function markers were observed at day 15 and day 30 of the treatment groups. Flax/fish oil had protective effects toward pathological abnormalities in the liver and kidney. Flax/fish oil improved lipid profile and alkaline phosphatase at day 30 as compared to that at day 15. CONCLUSIONS The present study demonstrates potential beneficial effects of metformin and flax/fish oil intervention in improving serum lipid profile by regulating the expression of transcription factors and genes involved in lipid metabolism in diabetic rats. In addition, these interventions also lowered the expression of atherogenic cytokines. The protective effects of flax/fish oil are worth investigating in human subjects on metformin monotherapy.
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Affiliation(s)
- Abhijit Ghadge
- Nutrigenomics and Functional Foods Laboratory, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth Deemed University, Pune-Satara Road, Pune, Maharashtra 411043 India
| | - Abhay Harsulkar
- Nutrigenomics and Functional Foods Laboratory, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth Deemed University, Pune-Satara Road, Pune, Maharashtra 411043 India
| | - Manjiri Karandikar
- Department of Pathology, Bharati Vidyapeeth Medical College, Bharati Vidyapeeth Deemed University, Pune-Satara Road, Pune, Maharashtra 411043 India
| | - Vijaya Pandit
- Department of Pharmacology, Bharati Vidyapeeth Medical College, Bharati Vidyapeeth Deemed University, Pune-Satara Road, Pune, Maharashtra 411043 India
| | - Aniket Kuvalekar
- Nutrigenomics and Functional Foods Laboratory, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth Deemed University, Pune-Satara Road, Pune, Maharashtra 411043 India
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28
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García-Heredia A, Riera-Borrull M, Fort-Gallifa I, Luciano-Mateo F, Cabré N, Hernández-Aguilera A, Joven J, Camps J. Metformin administration induces hepatotoxic effects in paraoxonase-1-deficient mice. Chem Biol Interact 2016; 249:56-63. [PMID: 26945512 DOI: 10.1016/j.cbi.2016.03.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 02/23/2016] [Accepted: 03/01/2016] [Indexed: 12/11/2022]
Abstract
Metformin is the first-line pharmacological treatment of diabetes. In these patients, metformin reduces body weight and decreases the risk of diabetes-related complications such as cardiovascular disease. However, whether metformin elicits beneficial effects on liver histology is a controversial issue and, as yet, there is no consensus. Paraoxonase-1 (PON1), an enzyme synthesized mainly by the liver, degrades lipid peroxides and reduces oxidative stress. PON1 activities are decreased in chronic liver diseases. We evaluated the effects of metformin in the liver of PON1-deficient mice which, untreated, present a mild degree of liver steatosis. Metformin administration aggravated inflammation in animals given a standard mouse chow and in those fed a high-fat diet. Also, it was associated with a higher degree of steatosis in animals fed a standard chow diet. This report is a cautionary note regarding the prescription of metformin for the treatment of diabetes in patients with concomitant liver impairment.
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Affiliation(s)
- Anabel García-Heredia
- Unitat de Recerca Biomèdica (CRB-URB), Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain
| | - Marta Riera-Borrull
- Unitat de Recerca Biomèdica (CRB-URB), Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain
| | - Isabel Fort-Gallifa
- Unitat de Recerca Biomèdica (CRB-URB), Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain; Laboratori de Referència Sud, Hospital Universitari de Sant Joan, Reus, Spain
| | - Fedra Luciano-Mateo
- Unitat de Recerca Biomèdica (CRB-URB), Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain
| | - Noemí Cabré
- Unitat de Recerca Biomèdica (CRB-URB), Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain
| | - Anna Hernández-Aguilera
- Unitat de Recerca Biomèdica (CRB-URB), Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain
| | - Jorge Joven
- Unitat de Recerca Biomèdica (CRB-URB), Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain
| | - Jordi Camps
- Unitat de Recerca Biomèdica (CRB-URB), Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain.
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29
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Volarevic V, Misirkic M, Vucicevic L, Paunovic V, Simovic Markovic B, Stojanovic M, Milovanovic M, Jakovljevic V, Micic D, Arsenijevic N, Trajkovic V, Lukic ML. Metformin aggravates immune-mediated liver injury in mice. Arch Toxicol 2014; 89:437-50. [PMID: 24770553 DOI: 10.1007/s00204-014-1263-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Accepted: 04/15/2014] [Indexed: 12/16/2022]
Abstract
Hepatotoxicity of the antidiabetic drug metformin has been reported, but the underlying mechanisms remain unclear. We here investigated the effect of metformin in immune-mediated liver damage. While not hepatotoxic alone, metformin (200 mg/kg) aggravated concanavalin A (Con A, 12 mg/kg)-induced hepatitis, an experimental model of T cell-mediated liver injury, in both relatively resistant BALB/c and highly susceptible C57Bl/6 mice. Metformin + Con A-treated mice had elevated serum levels of pro-inflammatory cytokines TNF-α and IFN-γ, accompanied by a massive mononuclear cell infiltration in the liver. This was associated with the higher numbers of CD4(+) T cells producing TNF-α, IFN-γ and IL-17, CD4(+) T cells expressing chemokine receptor CXCR3 and activation marker CD27, CD4(+)CD62L(-)CCR7(-) and CD8(+)CD62L(-)CCR7(-) effector memory cells, IFN-γ producing NK cells, IL-4 and IL-17 producing NKT cells and IL-12 producing macrophages/dendritic cells. The percentage of CD4(+)CXCR3(+)Tbet(+)IL-10(+) and CD4(+)CD69(+)CD25(-) regulatory T cells was reduced. Metformin stimulated inducible nitric oxide synthase (iNOS) expression in the liver and spleen, and genetic deletion of iNOS attenuated the hepatotoxicity of metformin. Metformin increased the autophagic light chain 3 conversion and mRNA expression of important autophagy-inducing (beclin-1, Atg5 and GABARAP) and pro-apoptotic (p21, p27, Puma, Noxa, Bax, Bad, Bak1, Bim and Apaf1), but not anti-apoptotic molecules (Bcl-xL, survivin and XIAP), which correlated with the apoptotic caspase-3/PARP cleavage in the liver. The autophagy inhibitor chloroquine (20 mg/kg) prevented liver injury and apoptotic changes induced by metformin. Therefore, metformin aggravates immune-mediated hepatitis by promoting autophagy and activation of immune cells, affecting effector, as well as liver-specific regulatory T cells and iNOS expression.
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Affiliation(s)
- Vladislav Volarevic
- Centre for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozara Markovica Street, 34 000, Kragujevac, Serbia,
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30
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Alshammari TM, Larrat EP, Morrill HJ, Caffrey AR, Quilliam BJ, Laplante KL. Risk of hepatotoxicity associated with fluoroquinolones: A national case–control safety study. Am J Health Syst Pharm 2014; 71:37-43. [DOI: 10.2146/ajhp130165] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
| | - E. Paul Larrat
- College of Pharmacy, University of Rhode Island (URI), Kingston; at the time of this study, he was Professor of Pharmacy, College of Pharmacy, URI
| | - Haley J. Morrill
- Infectious Diseases Research Program, Providence Veterans Affairs Medical Center (VAMC), Providence, RI, and College of Pharmacy, URI
| | - Aisling R. Caffrey
- Infectious Diseases Research Program, Providence VAMC, and Assistant Professor of Pharmacoepidemiology, College of Pharmacy, URI
| | | | - Kerry L. Laplante
- College of Pharmacy, URI; Providence VAMC; and Adjunct Clinical Associate Professor of Medicine, Brown University, Providence
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31
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Saadi T, Waterman M, Yassin H, Baruch Y. Metformin-induced mixed hepatocellular and cholestatic hepatic injury: case report and literature review. Int J Gen Med 2013; 6:703-6. [PMID: 23983487 PMCID: PMC3751382 DOI: 10.2147/ijgm.s49657] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
INTRODUCTION Metformin is a first-line drug choice for the treatment of type 2 diabetes mellitus (DM-2). Metformin-induced hepatotoxicity has rarely been reported. We report on a case of metformin-induced mixed hepatocellular and cholestatic liver injury in an elderly patient with DM-2 as well as review and summarize case reports of metformin hepatotoxicity available in English on the PubMed database. CASE After receiving metformin 850 mg/day for 2 weeks, a 78-year-old male presented with a 10-day history of abdominal pain, vomiting, diarrhea, and jaundice. Laboratory analysis showed severe hepatocellular and cholestatic hepatic injury. Other causes for acute liver injury were ruled out. Discontinuation of metformin treatment led to significant subjective improvement after 1 week, and all hepatic abnormalities resolved by 2 months. CONCLUSION Metformin is an important drug for the treatment of DM-2, which is also used for treatment of patients with fatty liver. It can, however, induce hepatocellular and cholestatic hepatic injury; both physicians and patients should be aware of this potential side effect.
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Affiliation(s)
- Tarek Saadi
- Liver Unit, Haifa, Israel
- Department of Gastroenterology, Haifa, Israel
- Department of Internal Medicine A, Rambam Health Care Campus, Haifa, Israel
| | - Matti Waterman
- Liver Unit, Haifa, Israel
- Department of Gastroenterology, Haifa, Israel
- Department of Internal Medicine A, Rambam Health Care Campus, Haifa, Israel
- The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Heba Yassin
- Department of Internal Medicine A, Rambam Health Care Campus, Haifa, Israel
| | - Yaacov Baruch
- Liver Unit, Haifa, Israel
- The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
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32
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Lewis JH, Stine JG. Review article: prescribing medications in patients with cirrhosis - a practical guide. Aliment Pharmacol Ther 2013; 37:1132-56. [PMID: 23638982 DOI: 10.1111/apt.12324] [Citation(s) in RCA: 130] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Revised: 11/30/2012] [Accepted: 04/08/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND Most drugs have not been well studied in cirrhosis; recommendations on safe use are based largely on experience and/or expert opinion, with dosing recommendations often based on pharmacokinetic (PK) changes. AIM To provide a practical approach to prescribing medications for cirrhotic patients. METHODS An indexed MEDLINE search was conducted using keywords cirrhosis, drug-induced liver injury, pharmacodynamics (PDs), PKs, drug disposition and adverse drug reactions. Unpublished information from the Food and Drug Administration and industry was also reviewed. RESULTS Most medications have not been adequately studied in cirrhosis, and specific prescribing information is often lacking. Lower doses are generally recommended based on PK changes, but data are limited in terms of correlating PD effects with the degree of liver impairment. Very few drugs have been documented to have their hepatotoxicity potential enhanced by cirrhosis; most of these involve antituberculosis or antiretroviral agents used for HIV or viral hepatitis. Paracetamol can be used safely when prescribed in relatively small doses (2-3 g or less/day) for short durations, and is recommended as first-line treatment of pain. In contrast, NSAIDs should be used cautiously (or not at all) in advanced cirrhosis. Proton pump inhibitors have been linked to an increased risk of spontaneous bacterial peritonitis (SBP) in cirrhosis and should be used with care. CONCLUSIONS Most drugs can be used safely in cirrhosis, including those that are potentially hepatotoxic, but lower doses or reduced dosing frequency is often recommended, due to altered PKs. Drugs that can precipitate renal failure, gastrointestinal bleeding, SBP and encephalopathy should be identified and avoided.
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Affiliation(s)
- J H Lewis
- Division of Gastroenterology and Hepatology, Department of Medicine, Georgetown University Medical Center, Washington, DC 20007, USA.
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33
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34
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Miralles-Linares F, Puerta-Fernandez S, Bernal-Lopez MR, Tinahones FJ, Andrade RJ, Gomez-Huelgas R. Metformin-induced hepatotoxicity. Diabetes Care 2012; 35:e21. [PMID: 22355024 PMCID: PMC3322705 DOI: 10.2337/dc11-2306] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
| | | | - M. Rosa Bernal-Lopez
- Biomedical Research Laboratory, Endocrinology Department, Hospital Virgen de la Victoria, Malaga, Spain
- Ciber Fisiopatología de la Obesidad y la Nutricion, Instituto de Salud Carlos III, Madrid, Spain
| | - Francisco J. Tinahones
- Biomedical Research Laboratory, Endocrinology Department, Hospital Virgen de la Victoria, Malaga, Spain
- Ciber Fisiopatología de la Obesidad y la Nutricion, Instituto de Salud Carlos III, Madrid, Spain
| | - Raul J. Andrade
- Gastroenterology and Hepatology Department, Hospital Virgen de la Victoria, Malaga, Spain
| | - Ricardo Gomez-Huelgas
- Ciber Fisiopatología de la Obesidad y la Nutricion, Instituto de Salud Carlos III, Madrid, Spain
- Internal Medicine Department, Hospital Carlos Haya, Malaga, Spain
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35
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Hashmi T. Probable hepatotoxicity associated with the use of metformin in type 2 diabetes. BMJ Case Rep 2011; 2011:bcr.04.2011.4092. [PMID: 22679227 DOI: 10.1136/bcr.04.2011.4092] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
This is a case report of a 44-year-old obese female who developed subclinical hepatic injury 4 weeks after starting metformin for type 2 diabetes. She had a rise in her alanine aminotransferase which peaked at 5 months (738 U/l) and rapidly declined within days of discontinuing her metformin. No other positive evidence of alternative causes for the hepatic injury was found. The likelihood of metformin-induced injury was 7 on the Naranjo scale of adverse drug reactions. A brief review of the 11 previously reported cases in the English medical literature is also made.
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Affiliation(s)
- Taqi Hashmi
- Family Medicine Department, King Faisal Specialist Hospital & Research Centre, Jeddah, Saudi Arabia.
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36
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Richard J, Lingvay I. Hepatic steatosis and Type 2 diabetes: current and future treatment considerations. Expert Rev Cardiovasc Ther 2011; 9:321-8. [PMID: 21438811 DOI: 10.1586/erc.11.15] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Hepatic steatosis, considered the first step in the pathophysiologic continuum of non-alcoholic fatty liver disease, is estimated to afflict 30% of the US population and over 75% of patients with Type 2 diabetes. Given the expected rise in the prevalence of obesity and Type 2 diabetes in the following decades, hepatic steatosis will, if not already, become an epidemic. The consequences of hepatic steatosis are numerous, and range from progression to chronic liver disease, with its associated morbidity and mortality, to worsening insulin resistance and Type 2 diabetes, as well as being an independent contributor to cardiovascular disease. All such consequences are more likely to occur in patients with Type 2 diabetes who are already at high risk of cardiovascular events. In this article we review the evidence behind the available therapeutic options for hepatic steatosis, and identify challenges and unmet needs in the field.
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Affiliation(s)
- John Richard
- UT Southwestern Medical Center, Department of Internal Medicine - Division of Endocrinology, Dallas, TX 75390-8857, USA
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Stine JG, Lewis JH. Drug-induced liver injury: a summary of recent advances. Expert Opin Drug Metab Toxicol 2011; 7:875-90. [PMID: 21510822 DOI: 10.1517/17425255.2011.577415] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION The knowledge base of drug-induced liver injury (DILI) continues to grow each year as additional drugs are identified as hepatotoxins. There is still a need to improve our ability to predict and diagnose DILI in the preclinical and post-approval settings. AREAS COVERED This article presents the new and updated DILI registries for 2010, including the latest information on the causes and outcomes of non-acetaminophen DILI cases in the US Acute Liver Failure Study Group database. As DILI is still largely a diagnosis of exclusion, it is appropriate that causality assessment instruments are again the subject of considerable discussion. EXPERT OPINION DILI research remains extremely active including studies aimed at being better able to identify causative agents, utilize potential biomarkers, predict who is at greatest risk of injury and manage outcomes. With respect to identifying DILI risk factors at the genetic level, the field is rapidly approaching the day where 'personalized medicine' (based on pharmacogenomics) will become a reality. A large single-center series from India reminds us that geography can influence the drugs responsible for liver injury; however, Hy's law remains universal. As our DILI knowledge continues to grow, it remains essential to keep abreast of the important changes reported each year.
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Affiliation(s)
- Jonathan G Stine
- Department of Medicine, Georgetown University Hospital, Washington DC 20007, USA
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