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Tissue-Specific Direct and Indirect Effects of Metformin and Its Application 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 34379

Special Issue Editor

Dr. Young Hee Choi

E-Mail Website
Guest Editor
College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University_Seoul, 32 Dongguk-lo, Ilsandong-gu, Goyang-si 10326, Gyonggi-do, Republic of Korea
Interests: metformin; pharmacokinetics; metabolism; metabolite ID
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous special issue "Tissue-Specific Direct and Indirect Effects of Metformin and Its Application".

The pharmacological effect and clinical applications of Metformin, a drug with a long history of use, differ depending on the target tissue, in spite of regulating the same signal pathway. In this review paper, the mechanism of actions of Metformin are divided into direct effects on target tissues and indirect effects via non-targeted tissues. Beginning with the mechanism by which Metformin is distributed to the target tissue, diverse actions of Metformin in tissue-specific applications and its representative cases are introduced. In particular, DNA, RNA, protein, as well as microRNA regulation by Metformin in specific tissues are covered. In addition, indirect effects of Metformin on non-targeting tissue as well as how Metformin is applied to disease control in this indirect pathway are mentioned.

Dr. Young Hee Choi
Guest Editor

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Keywords

  • Metformin
  • Disease
  • Metabolism

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Published Papers (7 papers)

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Research

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18 pages, 2088 KiB  
Article
Lipids Alterations Associated with Metformin in Healthy Subjects: An Investigation Using Mass Spectrometry Shotgun Approach
by Lina A. Dahabiyeh, Muhammad Mujammami, Reem H. AlMalki, Tawfiq Arafat, Hicham Benabdelkamel, Assim A. Alfadda and Anas M. Abdel Rahman
Int. J. Mol. Sci. 2022, 23(19), 11478; https://doi.org/10.3390/ijms231911478 - 29 Sep 2022
Cited by 8 | Viewed by 2583
Abstract
Metformin is an orally effective insulin-sensitizing drug widely prescribed for treating type 2 diabetes mellitus (T2DM). Metformin has been reported to alter lipid metabolism. However, the molecular mechanisms behind its impact on lipid metabolism remain partially explored and understood. In the current study, [...] Read more.
Metformin is an orally effective insulin-sensitizing drug widely prescribed for treating type 2 diabetes mellitus (T2DM). Metformin has been reported to alter lipid metabolism. However, the molecular mechanisms behind its impact on lipid metabolism remain partially explored and understood. In the current study, mass spectrometry-based lipid profiling was used to investigate the lipidomic changes in the serum of 26 healthy individuals after a single-dose intake of metformin. Samples were analyzed at five-time points: preadministration, before the maximum concentration of metformin (Cmax), Cmax, after Cmax, and 36 h post-administration. A total of 762 molecules were significantly altered between the five-time points. Based on a comparison between baseline level and Cmax, metformin significantly increased and decreased the level of 33 and 192 lipids, respectively (FDR ≤ 0.05 and fold change cutoff of 1.5). The altered lipids are mainly involved in arachidonic acid metabolism, steroid hormone biosynthesis, and glycerophospholipid metabolism. Furthermore, several lipids acted in an opposed or similar manner to metformin levels and included fatty acyls, sterol lipids, glycerolipids, and glycerophospholipids. The significantly altered lipid species pointed to fundamental lipid signaling pathways that could be linked to the pleiotropic effects of metformin in T2DM, insulin resistance, polycystic ovary syndrome, cancer, and cardiovascular diseases. Full article
(This article belongs to the Special Issue Tissue-Specific Direct and Indirect Effects of Metformin and Its Application 2.0)
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18 pages, 4971 KiB  
Article
Exploring the Mechanism of Adjuvant Treatment of Glioblastoma Using Temozolomide and Metformin
by Shao-Wei Feng, Pei-Chi Chang, Hsuan-Yu Chen, Dueng-Yuan Hueng, Yao-Feng Li and Shih-Ming Huang
Int. J. Mol. Sci. 2022, 23(15), 8171; https://doi.org/10.3390/ijms23158171 - 25 Jul 2022
Cited by 18 | Viewed by 3823
Abstract
Glioblastoma is the most frequent and lethal primary central nervous system tumor in adults, accounting for around 15% of intracranial neoplasms and 40–50% of all primary malignant brain tumors, with an annual incidence of 3–6 cases per 100,000 population. Despite maximum treatment, patients [...] Read more.
Glioblastoma is the most frequent and lethal primary central nervous system tumor in adults, accounting for around 15% of intracranial neoplasms and 40–50% of all primary malignant brain tumors, with an annual incidence of 3–6 cases per 100,000 population. Despite maximum treatment, patients only have a median survival time of 15 months. Metformin is a biguanide drug utilized as the first-line medication in treating type 2 diabetes. Recently, researchers have noticed that metformin can contribute to antineoplastic activity. The objective of this study is to investigate the mechanism of metformin as a potential adjuvant treatment drug in glioblastoma. Glioblastoma cell lines U87MG, LNZ308, and LN229 were treated with metformin, and several cellular functions and metabolic states were evaluated. First, the proliferation capability was investigated using the MTS assay and BrdU assay, while cell apoptosis was evaluated using the annexin V assay. Next, a wound-healing assay and mesenchymal biomarkers (N-cadherin, vimentin, and Twist) were used to detect the cell migration ability and epithelial–mesenchymal transition (EMT) status of tumor cells. Gene set enrichment analysis (GSEA) was applied to the transcriptome of the metformin-treated glioblastoma cell line. Then, DCFH-DA and MitoSOX Red dyes were used to quantify reactive oxygen species (ROS) in the cytosol and mitochondria. JC-1 dye and Western blotting analysis were used to evaluate mitochondrial membrane potential and biogenesis. In addition, the combinatory effect of temozolomide (TMZ) with metformin treatment was assessed by combination index analysis. Metformin could decrease cell viability, proliferation, and migration, increase cell apoptosis, and disrupt EMT in all three glioblastoma cell lines. The GSEA study highlighted increased ROS and hypoxia in the metformin-treated glioblastoma cells. Metformin increased ROS production, impaired mitochondrial membrane potential, and reduced mitochondrial biogenesis. The combined treatment of metformin and TMZ had U87 as synergistic, LNZ308 as antagonistic, and LN229 as additive. Metformin alone or combined with TMZ could suppress mitochondrial transcription factor A, Twist, and O6-methylguanine-DNA methyltransferase (MGMT) proteins in TMZ-resistant LN229 cells. In conclusion, our study showed that metformin decreased metabolic activity, proliferation, migration, mitochondrial biogenesis, and mitochondrial membrane potential and increased apoptosis and ROS in some glioblastoma cells. The sensitivity of the TMZ-resistant glioblastoma cell line to metformin might be mediated via the suppression of mitochondrial biogenesis, EMT, and MGMT expression. Our work provides new insights into the choice of adjuvant agents in TMZ-resistant GBM therapy. Full article
(This article belongs to the Special Issue Tissue-Specific Direct and Indirect Effects of Metformin and Its Application 2.0)
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27 pages, 3588 KiB  
Article
Structural Comparison of Sulfonamide-Based Derivatives That Can Improve Anti-Coagulation Properties of Metformin
by Agnieszka Zajda, Joanna Sikora, Kristiina M. Huttunen and Magdalena Markowicz-Piasecka
Int. J. Mol. Sci. 2022, 23(8), 4132; https://doi.org/10.3390/ijms23084132 - 8 Apr 2022
Cited by 5 | Viewed by 3079
Abstract
Due to its high efficiency, good safety profile, and potential cardio-protective properties, metformin, a dimethyl biguanide, is the first-line medication in antihyperglycemic treatment for type 2 diabetic patients. The aim of our present study was to assess the effects of eight new sulfonamide-based [...] Read more.
Due to its high efficiency, good safety profile, and potential cardio-protective properties, metformin, a dimethyl biguanide, is the first-line medication in antihyperglycemic treatment for type 2 diabetic patients. The aim of our present study was to assess the effects of eight new sulfonamide-based derivatives of metformin on selected plasma parameters and vascular hemostasis, as well as on endothelial and smooth muscle cell function. The compounds with an alkyl chain (1–3), trifluoromethyl substituent (4), or acetyl group (5) significantly elevated glucose utilization in human umbilical endothelial cells (HUVECs), similarly to metformin. Our novel findings showed that metformin analogues 1–3 presented the most beneficial properties because of their greatest safety profile in the WST-1 cell viability assay, which was also proved in the further HUVEC integrity studies using RTCA DP. Compounds 1–3 did not affect either HUVEC or aortal smooth muscle cell (AoSMC) viability up to 3.0 mM. Importantly, these compounds beneficially affected some of the coagulation parameters, including factor X and antithrombin III activity. In contrast to the above-mentioned metformin analogues, derivatives 4 and 5 exerted more profound anticoagulation effects; however, they were also more cytotoxic towards HUVECs, as IC50 values were 1.0–1.5 mM. In conclusion, the chemical modification of a metformin scaffold into sulfonamides possessing alkyl substituents results in the formation of novel derivatives with potential bi-directional activity including anti-hyperglycemic properties and highly desirable anti-coagulant activity. Full article
(This article belongs to the Special Issue Tissue-Specific Direct and Indirect Effects of Metformin and Its Application 2.0)
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Review

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20 pages, 5644 KiB  
Review
Effects of Metformin Delivery via Biomaterials on Bone and Dental Tissue Engineering
by Minjia Zhu, Zeqing Zhao, Hockin H. K. Xu, Zixiang Dai, Kan Yu, Le Xiao, Abraham Schneider, Michael D. Weir, Thomas W. Oates, Yuxing Bai and Ke Zhang
Int. J. Mol. Sci. 2022, 23(24), 15905; https://doi.org/10.3390/ijms232415905 - 14 Dec 2022
Cited by 14 | Viewed by 3657
Abstract
Bone tissue engineering is a promising approach that uses seed-cell-scaffold drug delivery systems to reconstruct bone defects caused by trauma, tumors, or other diseases (e.g., periodontitis). Metformin, a widely used medication for type II diabetes, has the ability to enhance osteogenesis and angiogenesis [...] Read more.
Bone tissue engineering is a promising approach that uses seed-cell-scaffold drug delivery systems to reconstruct bone defects caused by trauma, tumors, or other diseases (e.g., periodontitis). Metformin, a widely used medication for type II diabetes, has the ability to enhance osteogenesis and angiogenesis by promoting cell migration and differentiation. Metformin promotes osteogenic differentiation, mineralization, and bone defect regeneration via activation of the AMP-activated kinase (AMPK) signaling pathway. Bone tissue engineering depends highly on vascular networks for adequate oxygen and nutrition supply. Metformin also enhances vascular differentiation via the AMPK/mechanistic target of the rapamycin kinase (mTOR)/NLR family pyrin domain containing the 3 (NLRP3) inflammasome signaling axis. This is the first review article on the effects of metformin on stem cells and bone tissue engineering. In this paper, we review the cutting-edge research on the effects of metformin on bone tissue engineering. This includes metformin delivery via tissue engineering scaffolds, metformin-induced enhancement of various types of stem cells, and metformin-induced promotion of osteogenesis, angiogenesis, and its regulatory pathways. In addition, the dental, craniofacial, and orthopedic applications of metformin in bone repair and regeneration are also discussed. Full article
(This article belongs to the Special Issue Tissue-Specific Direct and Indirect Effects of Metformin and Its Application 2.0)
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11 pages, 501 KiB  
Review
Mechanism Underlying Metformin Action and Its Potential to Reduce Gastric Cancer Risk
by Wen-Hsi Lan, Ting-Yu Lin, Jia-Ai Yeh, Chun-Lung Feng, Jun-Te Hsu, Hwai-Jeng Lin, Chia-Jung Kuo and Chih-Ho Lai
Int. J. Mol. Sci. 2022, 23(22), 14163; https://doi.org/10.3390/ijms232214163 - 16 Nov 2022
Cited by 7 | Viewed by 4483
Abstract
Diabetes mellitus is associated with a high risk of developing gastric cancer (GC). Metformin, which is conventionally used to treat type 2 diabetes, induces AMP-activated protein kinase signaling and suppresses gluconeogenesis. Recent studies have reported that metformin is associated with beneficial effects in [...] Read more.
Diabetes mellitus is associated with a high risk of developing gastric cancer (GC). Metformin, which is conventionally used to treat type 2 diabetes, induces AMP-activated protein kinase signaling and suppresses gluconeogenesis. Recent studies have reported that metformin is associated with beneficial effects in cancer prevention and treatment owing to its anti-tumor effects. This makes metformin a potential medication for GC therapy. However, contradicting reports have emerged regarding the efficacy of metformin in reducing the risk of GC. This review summarizes the impact of metformin on mitigating GC risk by analyzing clinical databases. The mechanism underlying the anti-tumor effect of metformin on GC is also discussed. Full article
(This article belongs to the Special Issue Tissue-Specific Direct and Indirect Effects of Metformin and Its Application 2.0)
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Graphical abstract

15 pages, 970 KiB  
Review
Metabolomic Approaches to Investigate the Effect of Metformin: An Overview
by Hyun Woo Kim
Int. J. Mol. Sci. 2021, 22(19), 10275; https://doi.org/10.3390/ijms221910275 - 24 Sep 2021
Cited by 22 | Viewed by 4517
Abstract
Metformin is the first-line antidiabetic drug that is widely used in the treatment of type 2 diabetes mellitus (T2DM). Even though the various therapeutic potential of metformin treatment has been reported, as well as the improvement of insulin sensitivity and glucose homeostasis, the [...] Read more.
Metformin is the first-line antidiabetic drug that is widely used in the treatment of type 2 diabetes mellitus (T2DM). Even though the various therapeutic potential of metformin treatment has been reported, as well as the improvement of insulin sensitivity and glucose homeostasis, the mechanisms underlying those benefits are still not fully understood. In order to explain the beneficial effects on metformin treatment, various metabolomics analyses have been applied to investigate the metabolic alterations in response to metformin treatment, and significant systemic metabolome changes were observed in biofluid, tissues, and cells. In this review, we compare the latest metabolomic research including clinical trials, animal models, and in vitro studies comprehensively to understand the overall changes of metabolome on metformin treatment. Full article
(This article belongs to the Special Issue Tissue-Specific Direct and Indirect Effects of Metformin and Its Application 2.0)
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25 pages, 3784 KiB  
Review
New Insight into the Effects of Metformin on Diabetic Retinopathy, Aging and Cancer: Nonapoptotic Cell Death, Immunosuppression, and Effects beyond the AMPK Pathway
by Sheng-Kai Hsu, Kai-Chun Cheng, Miracle Oluebube Mgbeahuruike, Yi-Hsiung Lin, Chang-Yi Wu, Hui-Min David Wang, Chia-Hung Yen, Chien-Chih Chiu and Shwu-Jiuan Sheu
Int. J. Mol. Sci. 2021, 22(17), 9453; https://doi.org/10.3390/ijms22179453 - 31 Aug 2021
Cited by 42 | Viewed by 11079
Abstract
Under metabolic stress conditions such as hypoxia and glucose deprivation, an increase in the AMP:ATP ratio activates the AMP-activated protein kinase (AMPK) pathway, resulting in the modulation of cellular metabolism. Metformin, which is widely prescribed for type 2 diabetes mellitus (T2DM) patients, regulates [...] Read more.
Under metabolic stress conditions such as hypoxia and glucose deprivation, an increase in the AMP:ATP ratio activates the AMP-activated protein kinase (AMPK) pathway, resulting in the modulation of cellular metabolism. Metformin, which is widely prescribed for type 2 diabetes mellitus (T2DM) patients, regulates blood sugar by inhibiting hepatic gluconeogenesis and promoting insulin sensitivity to facilitate glucose uptake by cells. At the molecular level, the most well-known mechanism of metformin-mediated cytoprotection is AMPK pathway activation, which modulates metabolism and protects cells from degradation or pathogenic changes, such as those related to aging and diabetic retinopathy (DR). Recently, it has been revealed that metformin acts via AMPK- and non-AMPK-mediated pathways to exert effects beyond those related to diabetes treatment that might prevent aging and ameliorate DR. This review focuses on new insights into the anticancer effects of metformin and its potential modulation of several novel types of nonapoptotic cell death, including ferroptosis, pyroptosis, and necroptosis. In addition, the antimetastatic and immunosuppressive effects of metformin and its hypothesized mechanism are also discussed, highlighting promising cancer prevention strategies for the future. Full article
(This article belongs to the Special Issue Tissue-Specific Direct and Indirect Effects of Metformin and Its Application 2.0)
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