The function, mechanisms, and clinical applications of metformin: potential drug, unlimited potentials

Liu, Jianhong; Zhang, Ming; Deng, Dan; Zhu, Xiao

doi:10.1007/s12272-023-01445-2

Cited by 8 publications

(4 citation statements)

References 151 publications

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“…A number of drugs used to regulate blood glucose levels in individuals with type 2 diabetes may influence postprandial lipid metabolism [ 44 ] and it is for this reason that the individuals we studied with type 2 diabetes were all on metformin as the sole agent used for glycaemic control. Metformin has been reported in some but not all studies to reduce postprandial levels of TGs, chylomicrons and chylomicron remnants [ 44 , 51 – 53 ]. The potential mechanisms of action have been reported to involve a direct effect of metformin on the expression of genes involved in intestinal lipid metabolism [ 54 ], delayed gastric emptying [ 55 ] and increased glucagon-like peptide 1 (GLP-1) secretion [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Contribution of intestinal triglyceride-rich lipoproteins to residual atherosclerotic cardiovascular disease risk in individuals with type 2 diabetes on statin therapy

Taskinen,

Matikainen,

Björnson

et al. 2023

Diabetologia

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Aims/hypothesis This study explored the hypothesis that significant abnormalities in the metabolism of intestinally derived lipoproteins are present in individuals with type 2 diabetes on statin therapy. These abnormalities may contribute to residual CVD risk. Methods To investigate the kinetics of ApoB-48- and ApoB-100-containing lipoproteins, we performed a secondary analysis of 11 overweight/obese individuals with type 2 diabetes who were treated with lifestyle counselling and on a stable dose of metformin who were from an earlier clinical study, and compared these with 11 control participants frequency-matched for age, BMI and sex. Participants in both groups were on a similar statin regimen during the study. Stable isotope tracers were used to determine the kinetics of the following in response to a standard fat-rich meal: (1) apolipoprotein (Apo)B-48 in chylomicrons and VLDL; (2) ApoB-100 in VLDL, intermediate-density lipoprotein (IDL) and LDL; and (3) triglyceride (TG) in VLDL. Results The fasting lipid profile did not differ significantly between the two groups. Compared with control participants, in individuals with type 2 diabetes, chylomicron TG and ApoB-48 levels exhibited an approximately twofold higher response to the fat-rich meal, and a twofold higher increment was observed in ApoB-48 particles in the VLDL1 and VLDL2 density ranges (all p < 0.05). Again comparing control participants with individuals with type 2 diabetes, in the latter, total ApoB-48 production was 25% higher (556 ± 57 vs 446 ± 57 mg/day; p < 0.001), conversion (fractional transfer rate) of chylomicrons to VLDL was around 40% lower (35 ± 25 vs 82 ± 58 pools/day; p=0.034) and direct clearance of chylomicrons was 5.6-fold higher (5.6 ± 2.2 vs 1.0 ± 1.8 pools/day; p < 0.001). During the postprandial period, ApoB-48 particles accounted for a higher proportion of total VLDL in individuals with type 2 diabetes (44%) compared with control participants (25%), and these ApoB-48 VLDL particles exhibited a fivefold longer residence time in the circulation (p < 0.01). No between-group differences were seen in the kinetics of ApoB-100 and TG in VLDL, or in LDL ApoB-100 production, pool size and clearance rate. As compared with control participants, the IDL ApoB-100 pool in individuals with type 2 diabetes was higher due to increased conversion from VLDL2. Conclusions/interpretation Abnormalities in the metabolism of intestinally derived ApoB-48-containing lipoproteins in individuals with type 2 diabetes on statins may help to explain the residual risk of CVD and may be suitable targets for interventions. Trial registration ClinicalTrials.gov NCT02948777. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Contribution of intestinal triglyceride-rich lipoproteins to residual atherosclerotic cardiovascular disease risk in individuals with type 2 diabetes on statin therapy

Taskinen,

Matikainen,

Björnson

et al. 2023

Diabetologia

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“…Furthermore, AMPK activation by metformin promotes autophagy, contributing to cellular health and maintenance [72]. Also, metformin has the potential to modulate the IGF-1 signaling pathway, resulting in decreased blood glucose levels, a potential slowdown of the aging process, and a potential extension of lifespan [149,150]. Metformin's anti-aging effect may be achieved by inhibiting electron transport chain complex 1, leading to a decrease in reactive oxygen species (ROS) production.…”

Section: The Putative Relationship Between Metformin and Agingmentioning

confidence: 99%

“…Metformin's anti-aging effect may be achieved by inhibiting electron transport chain complex 1, leading to a decrease in reactive oxygen species (ROS) production. This, in turn, reduces the number of electron transfers and prevents electron leakage, resulting in lower ROS generation and reduced cumulative DNA damage [43,150].…”

Section: The Putative Relationship Between Metformin and Agingmentioning

confidence: 99%

Metformin: The Winding Path from Understanding Its Molecular Mechanisms to Proving Therapeutic Benefits in Neurodegenerative Disorders

Isop,

Neculau,

Necula

et al. 2023

Pharmaceuticals

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Metformin, a widely prescribed medication for type 2 diabetes, has garnered increasing attention for its potential neuroprotective properties due to the growing demand for treatments for Alzheimer’s, Parkinson’s, and motor neuron diseases. This review synthesizes experimental and clinical studies on metformin’s mechanisms of action and potential therapeutic benefits for neurodegenerative disorders. A comprehensive search of electronic databases, including PubMed, MEDLINE, Embase, and Cochrane library, focused on key phrases such as “metformin”, “neuroprotection”, and “neurodegenerative diseases”, with data up to September 2023. Recent research on metformin’s glucoregulatory mechanisms reveals new molecular targets, including the activation of the LKB1–AMPK signaling pathway, which is crucial for chronic administration of metformin. The pleiotropic impact may involve other stress kinases that are acutely activated. The precise role of respiratory chain complexes (I and IV), of the mitochondrial targets, or of the lysosomes in metformin effects remains to be established by further research. Research on extrahepatic targets like the gut and microbiota, as well as its antioxidant and immunomodulatory properties, is crucial for understanding neurodegenerative disorders. Experimental data on animal models shows promising results, but clinical studies are inconclusive. Understanding the molecular targets and mechanisms of its effects could help design clinical trials to explore and, hopefully, prove its therapeutic effects in neurodegenerative conditions.

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“…Metformin is used as a first-line drug for the treatment of T2DM worldwide. It has multiple mechanisms of action including its ability to reduce hyperglycemia and hyperlipidemia, inhibit liver glycogenesis, and increase the uptake of glucose in the peripheral tissues [17]. Additionally, metformin also has anti-cancerous and anti-inflammatory effects [18].…”

Section: Introductionmentioning

confidence: 99%

Glucose Promotes EMMPRIN/CD147 and the Secretion of Pro-Angiogenic Factors in a Co-Culture System of Endothelial Cells and Monocytes

Ghandour,

Kassem,

Simanovich

et al. 2024

Biomedicines

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Vascular complications in Type 2 diabetes mellitus (T2DM) patients increase morbidity and mortality. In T2DM, angiogenesis is impaired and can be enhanced or reduced in different tissues (“angiogenic paradox”). The present study aimed to delineate differences between macrovascular and microvascular endothelial cells that might explain this paradox. In a monoculture system of human macrovascular (EaHy926) or microvascular (HMEC-1) endothelial cell lines and a monocytic cell line (U937), high glucose concentrations (25 mmole/L) increased the secretion of the pro-angiogenic factors CD147/EMMPRIN, VEGF, and MMP-9 from both endothelial cells, but not from monocytes. Co-cultures of EaHy926/HMEC-1 with U937 enhanced EMMPRIN and MMP-9 secretion, even in low glucose concentrations (5.5 mmole/L), while in high glucose HMEC-1 co-cultures enhanced all three factors. EMMPRIN mediated these effects, as the addition of anti-EMMPRIN antibody decreased VEGF and MMP-9 secretion, and inhibited the angiogenic potential assessed through the wound assay. Thus, the minor differences between the macrovascular and microvascular endothelial cells cannot explain the angiogenic paradox. Metformin, a widely used drug for the treatment of T2DM, inhibited EMMPRIN, VEGF, and MMP-9 secretion in high glucose concentration, and the AMPK inhibitor dorsomorphin enhanced it. Thus, AMPK regulates EMMPRIN, a key factor in diabetic angiogenesis, suggesting that targeting EMMPRIN may help in the treatment of diabetic vascular complications.

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The function, mechanisms, and clinical applications of metformin: potential drug, unlimited potentials

Cited by 8 publications

References 151 publications

Contribution of intestinal triglyceride-rich lipoproteins to residual atherosclerotic cardiovascular disease risk in individuals with type 2 diabetes on statin therapy

Contribution of intestinal triglyceride-rich lipoproteins to residual atherosclerotic cardiovascular disease risk in individuals with type 2 diabetes on statin therapy

Metformin: The Winding Path from Understanding Its Molecular Mechanisms to Proving Therapeutic Benefits in Neurodegenerative Disorders

Glucose Promotes EMMPRIN/CD147 and the Secretion of Pro-Angiogenic Factors in a Co-Culture System of Endothelial Cells and Monocytes

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