Whole-blood transcriptome profiling reveals signatures of metformin and its therapeutic response
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA644109 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12145800.fastq.gz | Fastqsanger.gz | |||
| SRR12145801.fastq.gz | Fastqsanger.gz | |||
| SRR12145802.fastq.gz | Fastqsanger.gz | |||
| SRR12145803.fastq.gz | Fastqsanger.gz | |||
| SRR12145804.fastq.gz | Fastqsanger.gz |
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Project description:Metformin, a biguanide agent, is the first-line treatment for type 2 diabetes mellitus due to its glucose-lowering effect. Despite its wide application in the treatment of multiple health conditions, the glycemic response to metformin is highly variable, emphasizing the need for reliable biomarkers. We chose the RNA-Seq-based comparative transcriptomics approach to evaluate the systemic effect of metformin and highlight potential predictive biomarkers of metformin response in drug-naïve type 2 diabetes patient volunteers in vivo. Longitudinal blood-derived transcriptome analysis revealed metformin-induced differential expression of novel and previously described genes involved in cholesterol homeostasis (SLC46A1 and LRP1), cancer development (CYP1B1, STAB1, CCR2, TMEM176B) and immune responses (CD14, CD163) after administration of metformin for three months. We demonstrate for the first time transcriptome-based molecular discrimination between metformin responders (delta HbA1c ≥ 1% or 12.6 mmol/mol) and non-responders (delta HbA1c < 1% or 12.6 mmol/mol) determined by expression levels of 56 genes, explaining 13.9% of the variance in the therapeutic efficacy of the drug. Moreover, we found a significant upregulation of IRS2 gene (log2FC 0.89) in responders compared to non-responders before the use of metformin. Finally, we provide evidence for the mitochondrial respiratory complex I as one of the factors related to the high variability of the therapeutic response to metforminin patients with type 2 diabetes mellitus.
2020-07-05 | GSE153792 | GEO
Project description:Metformin, a biguanide agent, is the first-line treatment for type 2 diabetes mellitus due to its glucose-lowering effect. Despite its wide application in the treatment of multiple health conditions, the glycemic response to metformin is highly variable, emphasizing the need for reliable biomarkers. We chose the RNA-Seq-based comparative transcriptomics approach to evaluate the systemic effect of metformin and highlight potential predictive biomarkers of metformin response in drug-naïve volunteers with type 2 diabetes in vivo. The longitudinal blood-derived transcriptome analysis revealed metformin-induced differential expression of novel and previously described genes involved in cholesterol homeostasis (SLC46A1 and LRP1), cancer development (CYP1B1, STAB1, CCR2, TMEM176B), and immune responses (CD14, CD163) after administration of metformin for three months. We demonstrate for the first time a transcriptome-based molecular discrimination between metformin responders (delta HbA1c ? 1% or 12.6 mmol/mol) and non-responders (delta HbA1c < 1% or 12.6 mmol/mol), that is determined by expression levels of 56 genes, explaining 13.9% of the variance in the therapeutic efficacy of the drug. Moreover, we found a significant upregulation of IRS2 gene (log2FC 0.89) in responders compared to non-responders before the use of metformin. Finally, we provide evidence for the mitochondrial respiratory complex I as one of the factors related to the high variability of the therapeutic response to metformin in patients with type 2 diabetes mellitus.
| S-EPMC7418999 | biostudies-literature
Project description:Metformin is among the most prescribed anti-diabetic drugs, but the primary molecular mechanism by which metformin lowers blood glucose levels is unknown. Previous studies have proposed numerous mechanisms by which acute metformin lowers blood glucose, including the inhibition of mitochondrial complex I of the electron transport chain (ETC). Here, we used transgenic mice that globally express the Saccharomyces cerevisiae protein NDI1 to determine whether the glucose lowering effect of acute oral administration of metformin requires inhibition of mitochondrial complex I of the ETC in vivo. NDI1 is a yeast NADH dehydrogenase enzyme that complements the loss of mammalian mitochondrial complex I electron transport function and is insensitive to pharmacologic mitochondrial complex I inhibitors including metformin. We demonstrate that NDI1 expression attenuates metformin’s ability to lower blood glucose levels under standard chow and high-fat diet conditions. Our results indicate that acute oral administration of metformin targets mitochondrial complex I to lower blood glucose.
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Project description:Metformin is a commonly used antihyperglycaemic agent for the treatment of type 2 diabetes. Nevertheless, the exact mechanisms of action, underlying the various therapeutic effects of metformin, remain elusive. The goal of this study was to evaluate the alterations in longitudinal whole-blood transcriptome profiles of healthy individuals after a one-week metformin intervention in order to identify the novel molecular targets and further prompt the discovery of predictive biomarkers of metformin response. Next generation sequencing-based transcriptome analysis revealed four clusters of functionally related genes with a subject-specific differential expression even after a single dose of metformin: ribosomal genes and their pseudogenes (e.g., RNA5-8SN1, RNA5-8SN5, RNY4P10), small nuclear RNAs (e.g., SNORA20, SCARNA5, SNORA80E), genes relevant to insulin production (HNF1B, HNF1A, HNF4A, GCK, INS, NEUROD1, PAX4, PDX1, ABCC8, KCNJ11) and cholesterol homeostasis (APOB, LDLR, PCSK9). After accounting for subject-specific expression, the enrichment of pathways associated with immune responses, such as intestinal immune network for IgA production and cytokine-cytokine receptor interaction were observed for the majority of the cohort. The results of the study reveal for the first time a strong inter-individual variation of the metformin effect on the transcriptional regulation, that goes in line with well-known variability of the therapeutic response to the drug.
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Project description:Metformin is a classic type II diabetes drug which has possessed anti-tumor properties for various cancers. However, different cancers do not respond to metformin with the same effectiveness or acquire resistance. Thus, searching for vulnerabilities of metformin-resistant prostate cancer is a promising strategy to improve the therapeutic efficiency. A genome-scale CRISPR-Cas9 activation library targeting 23430 genes is conducted to identify the genes that confer resistance to metformin in prostate cancer cells.
2020-10-14 | GSE159467 | GEO
Project description:We implemented transcriptomic analyses of blood of 8-10M mice; These mice with the treatment of metformin for 30 days.
2020-09-23 | GSE140715 | GEO
Project description:Metformin, the most widely administered diabetes drug, has been proposed as a candidate for host directed therapy for tuberculosis although very little is known about its effects on human host responses to Mycobacterium tuberculosis. When added in vitro to PBMCs isolated from healthy non-diabetic volunteers, metformin increased glycolysis, inhibited the mTOR targets, strongly reduced M. tuberculosis induced production of TNF-α (-58%), IFN-gamma (-47%) and IL-1β (-20%), while increasing phagocytosis. In healthy subjects, in vivo metformin intake induced significant transcriptional changes in whole blood and isolated PBMCs, with substantial down-regulation of genes related to inflammation and the type 1 interferon response. Metformin intake also increased monocyte phagocytosis (by 1.5 to 2 fold) and ROS production (+20%). These results show that metformin in humans has a range of potentially beneficial effects on cellular metabolism, immune function and gene-transcriptional level, that affect innate host responses to M. tuberculosis. This underlines the importance of cellular metabolism for host immunity and supports a role for metformin as host-directed therapy for tuberculosis.
2019-06-16 | GSE102633 | GEO
Project description:Metformin targets mitochondrial complex I to lower blood glucose levels
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Project description:Metformin is the most popular drug to treat type II diabetes. Besides lowering blood sugar, it is proven to have more beneficial effects, including extending life expectancy. However, the underlying mechanisms remain largely elusive. Here, we systematically studied the proteome thermal stability changes induced by a wide dosage range of metformin in a liver cancer cell line using the proteome integral solubility alteration (PISA) assay. This work provides valuable and unique information about the interactions between proteins and this drug, which is not able to obtain using commonly used abundance-based proteomics. The current results demonstrated that the most acceptable target of metformin responsible for lowering blood glucose levels, complex I, was stabilized only under the high-concentration metformin treatment. Intriguingly, the complex IV subunits were significantly stabilized by low concentrations of (such as 0.2 μM) metformin, indicating that the complex IV may play an important role in the sugar-lowering effect. Moreover, low-dose metformin significantly altered ribosome and histone protein stabilities, correlated with the inhibitive effect of cell proliferation by metformin. We further found that low-concentration metformin impacted mitochondrial cargo transport and vesicle transport, while high-concentration metformin affected cell redox responses and cell membrane protein sorting. Systematic investigation of metformin-induced proteome thermal stability changes provides intriguing insights into the molecular mechanisms of lowering blood sugar and the pleiotropic effects of metformin.
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