Metabolomic Approaches to Investigate the Effect of Metformin: An Overview

Kim, Hyun Woo

doi:10.3390/ijms221910275

Cited by 19 publications

(16 citation statements)

References 95 publications

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“…Gamma-glutamyltyrosine is involved in the gamma-glutamyl amino acid pathway, which is closely related to insulin sensitivity [ 20 ]. Plasma gamma-glutamyltyrosine was reported to be positively correlated with HOMA-IR (homeostasis model assessment-estimated insulin resistance) [ 21 ], and downregulated plasma levels of this metabolite were observed in T2D patients who were on metformin treatment [ 22 ]. The mediation analysis results thus implicated a plausible mechanism underlying the increased risk of severe COVID-19 in the T2D population.…”

Section: Discussionmentioning

confidence: 99%

“…Valine is a branched-chain amino acid (BCAA). Elevated circulating levels of BCAAs, frequently observed in individuals with obesity, have been reported to be associated with worse metabolic health and increased risk of insulin resistance followed by the development of T2D [ 21 , 22 , 23 ]. The causal relationship between valine and COVID-19 severity thus suggested BCAA metabolism as a potential therapeutic pathway for alleviating the disease progression in infected patients.…”

Section: Discussionmentioning

confidence: 99%

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Human Serum Metabolites as Potential Mediators from Type 2 Diabetes and Obesity to COVID-19 Severity and Susceptibility: Evidence from Mendelian Randomization Study

Huang

Shi

et al. 2022

Metabolites

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Obesity, type 2 diabetes (T2D), and severe coronavirus disease 2019 (COVID-19) are closely associated. The aim of this study was to elucidate the casual and mediating relationships of human serum metabolites on the pathways from obesity/T2D to COVID-19 using Mendelian randomization (MR) techniques. We performed two-sample MR to study the causal effects of 309 metabolites on COVID-19 severity and susceptibility, based on summary statistics from genome-wide association studies (GWAS) of metabolites (n = 7824), COVID-19 phenotypes (n = 2,586,691), and obesity (n = 322,154)/T2D traits (n = 898,130). We conducted two-sample network MR analysis to determine the mediating metabolites on the causal path from obesity/T2D to COVID-19 phenotypes. We used multivariable MR analysis (MVMR) to discover causal metabolites independent of body mass index (BMI). Our MR analysis yielded four causal metabolites that increased the risk of severe COVID-19, including 2-stearoylglycerophosphocholine (OR 2.15; 95% CI 1.48–3.11), decanoylcarnitine (OR 1.32; 95% CI 1.17–1.50), thymol sulfate (OR 1.20; 95% CI 1.10–1.30), and bradykinin-des-arg(9) (OR 1.09; 95% CI 1.05–1.13). One significant mediator, gamma-glutamyltyrosine, lay on the causal path from T2D/obesity to severe COVID-19, with 16.67% (0.64%, 32.70%) and 6.32% (1.76%, 10.87%) increased risk, respectively, per one-standard deviation increment of genetically predicted T2D and BMI. Our comprehensive MR analyses identified credible causative metabolites, mediators of T2D and obesity, and obesity-independent causative metabolites for severe COVID-19. These biomarkers provide a novel basis for mechanistic studies for risk assessment, prognostication, and therapeutic purposes in COVID-19.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Human Serum Metabolites as Potential Mediators from Type 2 Diabetes and Obesity to COVID-19 Severity and Susceptibility: Evidence from Mendelian Randomization Study

Huang

Shi

et al. 2022

Metabolites

View full text Add to dashboard Cite

show abstract

“…The rationale of metformin selection as a model drug includes the well-known safety profiles of the first line antihyperglycemic drug and its inconclusive mechanism of action. There have been several metabolomics analyses for metformin on healthy volunteers and patients, and the perturbed human metabolic pathways associated with the pharmacodynamics effects remain inconsistent [ 29 ]. Therefore, this study focussed on the individualised pharmacokinetic guided Cmax samples to investigate the dysregulation of metabolic pathways under a controlled environment.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics and Metabolomic Profiling of Metformin and Andrographis paniculata: A Protocol for a Crossover Randomised Controlled Trial

Tee

Ibrahim

Hashim

et al. 2022

JCM

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This protocol aims to profile the pharmacokinetics of metformin and Andrographis paniculata (AP) and continue with untargeted pharmacometabolomics analysis on pre-dose and post-dose samples to characterise the metabolomics profiling associated with the human metabolic pathways. This is a single-centre, open-labelled, three periods, crossover, randomised-controlled, single-dose oral administration pharmacokinetics and metabolomics trial of metformin 1000 mg (n = 18), AP 1000 mg (n = 18), or AP 2000 mg (n = 18) in healthy volunteers under the fasting condition. Subjects will be screened according to a list of inclusion and exclusion criteria. Investigational products will be administered according to the scheduled timeline. Vital signs and adverse events will be monitor periodically, and standardized meals will be provided to the subjects. Fifteen blood samples will be collected over 24 h, and four urine samples will be collected within a 12 h period. Onsite safety monitoring throughout the study and seven-day phone call safety follow-up will be compiled after the last dose of administration. The plasma samples will be analysed for the pharmacokinetics parameters to estimate the drug maximum plasma concentration. Untargeted metabolomic analysis between pre-dose and maximum plasma concentration (Cmax) samples will be performed for metabolomic profiling to identify the dysregulation of human metabolic pathways that link to the pharmacodynamics effects. The metformin arm will focus on the individualised Cmax plasma concentration for metabolomics study and used as a model drug. After this, an investigation of the dose-dependent effects will be performed between pre-dose samples and median Cmax concentration samples in the AP 1000 mg and AP 2000 mg arms for metabolomics study. The study protocol utilises a crossover study design to incorporate a metabolomics-based study into pharmacokinetics trial in the drug development program. The combination analyses will complement the interpretation of pharmacological effects according to the bioavailability of the drug.

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“…Metformin (MET) is a hypoglycemic drug commonly utilized in the treatment of type 2 diabetes [ 5 ], as it gets more out of hyperglycaemia without causing endogenous insulin secretion or hypoglycaemia [ 6 ]. In addition to its role in lowering blood glucose levels, MET has been shown to be a potent candidate for a variety of central nervous system (CNS) infections, including Parkinson's sickness, Alzheimer's illness, and ischemic cerebrum damage [ 7 – 9 ].…”

Section: Introductionmentioning

confidence: 99%

Metformin Protects against Spinal Cord Injury and Cell Pyroptosis via AMPK/NLRP3 Inflammasome Pathway

Yuan¹,

Fan

Guo³

et al. 2022

Analytical Cellular Pathology

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Spinal cord injury (SCI) is an extreme neurological impairment with few effective drug treatments. Pyroptosis is a recently found and proven type of programmed cell death that is characterized by a reliance on inflammatory caspases and the release of a large number of proinflammatory chemicals. Pyroptosis differs from other cell death mechanisms such as apoptosis and necrosis in terms of morphological traits, incidence, and regulatory mechanism. Pyroptosis is widely involved in the occurrence and development of SCI. In-depth research on pyroptosis will help researchers better understand its involvement in the onset, progression, and prognosis of SCI, as well as provide new therapeutic prevention and treatment options. Herein, we investigated the role of AMPK-mediated activation of the NLRP3 inflammasome in the neuroprotection of MET-regulated pyroptosis. We found that MET treatment reduced NLRP3 inflammasome activation by activating phosphorylated AMPK and reduced proinflammatory cytokine (IL-1β, IL-6, and TNF-α) release. At the same time, MET improved motor function recovery in rats after SCI by reducing motor neuron loss in the anterior horn of the spinal cord. Taken together, our study confirmed that MET inhibits neuronal pyroptosis after SCI via the AMPK/NLRP3 signaling pathway, which is mostly dependent on the AMPK pathway increase, hence decreasing NLRP3 inflammasome activation.

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Metabolomic Approaches to Investigate the Effect of Metformin: An Overview

Cited by 19 publications

References 95 publications

Human Serum Metabolites as Potential Mediators from Type 2 Diabetes and Obesity to COVID-19 Severity and Susceptibility: Evidence from Mendelian Randomization Study

Human Serum Metabolites as Potential Mediators from Type 2 Diabetes and Obesity to COVID-19 Severity and Susceptibility: Evidence from Mendelian Randomization Study

Pharmacokinetics and Metabolomic Profiling of Metformin and Andrographis paniculata: A Protocol for a Crossover Randomised Controlled Trial

Metformin Protects against Spinal Cord Injury and Cell Pyroptosis via AMPK/NLRP3 Inflammasome Pathway

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