Can Metformin Exert as an Active Drug on Endothelial Dysfunction in Diabetic Subjects

Salvatore, Teresa; Pafundi, Pia Clara; Galiero, Raffaele; Rinaldi, Luca; Caturano, Alfredo; Vetrano, Erica; Aprea, Concetta; Albanese, Gaetana; Di Martino, Anna; Ricozzi, Carmen; Imbriani, Simona; Sasso, Ferdinando Carlo

doi:10.3390/biomedicines9010003

Cited by 97Nitric Oxide and Endothelin EffectsDiabetes Treatment and ManagementMetabolism, Diabetes, and Cancer

Can Metformin Exert as an Active Drug on Endothelial Dysfunction in Diabetic Subjects

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Salvatore, Teresa, Pafundi, Pia Clara, Galiero, Raffaele, Rinaldi, Luca, Caturano, Alfredo, Vetrano, Erica, Aprea, Concetta, Albanese, Gaetana +4 more·2020·Biomedicines

DOI 10.3390/biomedicines9010003PMC PMC7822116

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Abstract

Cardiovascular mortality is a major cause of death among in type 2 diabetes (T2DM). Endothelial dysfunction (ED) is a well-known important risk factor for the development of diabetes cardiovascular complications. Therefore, the prevention of diabetic macroangiopathies by preserving endothelial function represents a major therapeutic concern for all National Health Systems. Several complex mechanisms support ED in diabetic patients, frequently cross-talking each other: uncoupling of eNOS with impaired endothelium-dependent vascular response, increased ROS production, mitochondrial dysfunction, activation of polyol pathway, generation of advanced glycation end-products (AGEs), activation of protein kinase C (PKC), endothelial inflammation, endothelial apoptosis and senescence, and dysregulation of microRNAs (miRNAs). Metformin is a milestone in T2DM treatment. To date, according to most recent EASD/ADA guidelines, it still represents the first-choice drug in these patients. Intriguingly, several extraglycemic effects of metformin have been recently observed, among which large preclinical and clinical evidence support metformin's efficacy against ED in T2DM. Metformin seems effective thanks to its favorable action on all the aforementioned pathophysiological ED mechanisms. AMPK pharmacological activation plays a key role, with metformin inhibiting inflammation and improving ED. Therefore, aim of this review is to assess metformin's beneficial effects on endothelial dysfunction in T2DM, which could preempt development of atherosclerosis.

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Based on critical reviews of the literature, the answer appears to be yes that metformin exerts a direct anti-aging effect on the endothelium, although clinical data could be interpreted as secondary to metformin's actions to enhance insulin sensitivity and lower blood glucose.
“Based on critical reviews of the literature, the answer appears to be “yes”, although the clinical data could be interpreted as secondary to metformin’s actions to enhance insulin sensitivity and lower blood glucose levels (34, 106, 173).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [173]

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Activation of the AMP-activated Protein Kinase by the Anti-diabetic Drug Metformin in Vivo
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The ROS Production Induced by a Reverse-Electron Flux at Respiratory-Chain Complex 1 is Hampered by Metformin
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Comparative Effectiveness of Sulfonylurea and Metformin Monotherapy on Cardiovascular Events in Type 2 Diabetes Mellitus
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AMPKα2 Deletion Causes Aberrant Expression and Activation of NAD(P)H Oxidase and Consequent Endothelial Dysfunction In Vivo: Role of 26S Proteasomes
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Sirtuin 1-Mediated Cellular Metabolic Memory of High Glucose via the LKB1/AMPK/ROS Pathway and Therapeutic Effects of Metformin
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Tetrahydrobiopterin Regulates Superoxide and Nitric Oxide Generation by Recombinant Endothelial Nitric Oxide Synthase
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Reduction of the Accumulation of Advanced Glycation End Products by ACE Inhibition in Experimental Diabetic Nephropathy
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Metformin Prevents High-Glucose–Induced Endothelial Cell Death Through a Mitochondrial Permeability Transition-Dependent Process
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“induced oxidative stress in several endothelial cell types [203], and the biguanide given at the time of reperfusion may reduce myocardial infarct size in the heart of both non-diabetic and diabetic rats [204].”
Background
Metformin Activates AMP Kinase through Inhibition of AMP Deaminase
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High glucose-induced apoptosis in human vascular endothelial cells is mediated through NF-κB and c-Jun NH2-terminal kinase pathway and prevented by PI3K/Akt/eNOS pathway
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Activation of the AMPK-FOXO3 Pathway Reduces Fatty Acid–Induced Increase in Intracellular Reactive Oxygen Species by Upregulating Thioredoxin
Li, X., Song, J., Zhang, L., LeMaire, S. A., Hou, X., Zhang, C., Coselli, J. S., Chen, L., Wang, X. L., Zhang, Y., et al. (2009) · Diabetes · doi:10.2337/db08-1512 · Cited by 237 · see citing works
Metformin attenuates lung fibrosis development via NOX4 suppression
Sato, N., Takasaka, N., Yoshida, M., Tsubouchi, K., Minagawa, S., Araya, J., Saito, N., Fujita, Y., Kurita, Y., Kobayashi, K., et al. (2016) · Respiratory Research · doi:10.1186/s12931-016-0420-x · Cited by 229 · see citing works
Endothelial cellular senescence is inhibited by nitric oxide: Implications in atherosclerosis associated with menopause and diabetes
Hayashi, T., Matsui‐Hirai, H., Miyazaki, A., Fukatsu, A., Funami, J., Ding, Q., Sumitra, K., Hattori, Y., Ignarro, L. J., & Iguchi, A. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0607873103 · Cited by 222 · see citing works
Metformin modulates hyperglycaemia‐induced endothelial senescence and apoptosis through <scp>SIRT1</scp>
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Mitochondrial Dynamics in Diabetes
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Hyperglycaemia-induced superoxide production decreases eNOS expression via AP-1 activation in aortic endothelial cells
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Thrombin Activates AMP-Activated Protein Kinase in Endothelial Cells via a Pathway Involving Ca2+/Calmodulin-Dependent Protein Kinase Kinase β
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Critical Role for Tetrahydrobiopterin Recycling by Dihydrofolate Reductase in Regulation of Endothelial Nitric-oxide Synthase Coupling
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Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening
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Metformin Decreases Intracellular Production of Reactive Oxygen Species in Aortic Endothelial Cells
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Metformin reduces intracellular reactive oxygen species levels by upregulating expression of the antioxidant thioredoxin via the AMPK-FOXO3 pathway
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Tetrahydrobiopterin and Cardiovascular Disease
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The permeability transition pore in cell death
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AMP-Activated Protein Kinase
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Endothelial dysfunction: a strategic target in the treatment of hypertension?
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Metformin Protects Endothelial Function in Diet-Induced Obese Mice by Inhibition of Endoplasmic Reticulum Stress Through 5′ Adenosine Monophosphate–Activated Protein Kinase–Peroxisome Proliferator–Activated Receptor δ Pathway
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Cellular basis of endothelial dysfunction in small mesenteric arteries from spontaneously diabetic (db/db−/−) mice: role of decreased tetrahydrobiopterin bioavailability
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Metformin revisited: A critical review of the benefit–risk balance in at-risk patients with type 2 diabetes
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Apoptosis signal-regulating kinase 1 mediates cellular senescence induced by high glucose in endothelial cells
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Metformin restores endothelial function in aorta of diabetic rats
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Effects of Metformin Therapy on Coronary Endothelial Dysfunction in Patients With Prediabetes With Stable Angina and Nonobstructive Coronary Artery Stenosis: The CODYCE Multicenter Prospective Study
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Self-citation
Metformin improves vascular function in insulin-resistant rats
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Stimulation of NADPH Oxidase by Oxidized Low-Density Lipoprotein Induces Proliferation of Human Vascular Endothelial Cells
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An insulin sensitizer improves the free radical defense system potential and insulin sensitivity in high fructose-fed rats.
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Acute blood glucose fluctuation enhances rat aorta endothelial cell apoptosis, oxidative stress and pro-inflammatory cytokine expression in vivo
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Glycated Collagen I Induces Premature Senescence-Like Phenotypic Changes in Endothelial Cells
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Metformin improves endothelial function in patients with metabolic syndrome
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Metformin and liraglutide ameliorate high glucose-induced oxidative stress via inhibition of PKC-NAD(P)H oxidase pathway in human aortic endothelial cells
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Metformin regulates mitochondrial biogenesis and senescence through AMPK mediated H3K79 methylation: relevance in age-associated vascular dysfunction
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Metformin in patients with and without diabetes: a paradigm shift in cardiovascular disease management
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An activator of mTOR inhibits oxLDL-induced autophagy and apoptosis in vascular endothelial cells and restricts atherosclerosis in apolipoprotein E-/- mice
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Metformin alleviates hyperglycemia-induced endothelial impairment by downregulating autophagy via the Hedgehog pathway
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Apoptosis and necrosis in health and disease: Role of mitochondria
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Exploiting the anti-inflammatory effects of AMP-activated protein kinase activation
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Malonyl-CoA and AMP-activated protein kinase (AMPK): possible links between insulin resistance in muscle and early endothelial cell damage in diabetes
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α-Lipoic Acid Prevents Endothelial Dysfunction in Obese Rats via Activation of AMP-Activated Protein Kinase
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Long-Term Effects of Metformin on Endothelial Function in Type 2 Diabetes: A Randomized Controlled Trial
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Endothelial Function and Dysfunction: Impact of Metformin
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OxLDL induces endothelial dysfunction and death via TRAF3IP2: Inhibition by HDL3 and AMPK activators
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Metformin Beyond Diabetes: Pleiotropic Benefits of Metformin in Attenuation of Atherosclerosis
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Metformin normalizes endothelial function by suppressing vasoconstrictor prostanoids in mesenteric arteries from OLETF rats, a model of type 2 diabetes
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Metformin Improves Endothelial Vascular Reactivity in First-Degree Relatives of Type 2 Diabetic Patients With Metabolic Syndrome and Normal Glucose Tolerance
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AMP‐ACTIVATED PROTEIN KINASE ACTIVATION AS A STRATEGY FOR PROTECTING VASCULAR ENDOTHELIAL FUNCTION
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Biomarkers of Endothelial Cell Activation Serve as Potential Surrogate Markers for Drug-induced Vascular Injury
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Tetrahydrobiopterin restores endothelial dysfunction induced by an oral glucose challenge in healthy subjects
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Mitofusins are required for angiogenic function and modulate different signaling pathways in cultured endothelial cells
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Cellular Responses to the Metal-Binding Properties of Metformin
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Oxidative Stress and Increased eNOS and NADPH Oxidase Expression in Mouse Microvessel Endothelial Cells
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Cyclin-Dependent Kinase 5–Mediated Hyperphosphorylation of Sirtuin-1 Contributes to the Development of Endothelial Senescence and Atherosclerosis
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Intrahepatic Mechanisms Underlying the Effect of Metformin in Decreasing Basal Glucose Production in Rats Fed a High-Fat Diet
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Metformin delays the manifestation of diabetes and vascular dysfunction in Goto–Kakizaki rats by reduction of mitochondrial oxidative stress
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Role of Tight Glycemic Control during Acute Coronary Syndrome on CV Outcome in Type 2 Diabetes
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Carbonic Anhydrase Activation Is Associated With Worsened Pathological Remodeling in Human Ischemic Diabetic Cardiomyopathy
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Metformin is not just an antihyperglycaemic drug but also has protective effects on the vascular endothelium
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Molecular Interplay between microRNA-34a and Sirtuin1 in Hyperglycemia-Mediated Impaired Angiogenesis in Endothelial Cells: Effects of Metformin
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Metformin and liraglutide ameliorate high glucose-induced oxidative stress via inhibition of PKC-NAD(P)H oxidase pathway in human aortic endothelial cells
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Role of microRNAs in endothelial inflammation and senescence
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Chronic oral supplementation with sepiapterin prevents endothelial dysfunction and oxidative stress in small mesenteric arteries from diabetic (db/db) mice
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Cardiorenal prognosis by residual proteinuria level in diabetic chronic kidney disease: pooled analysis of four cohort studies
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Pharmacological activation of AMPK ameliorates perivascular adipose/endothelial dysfunction in a manner interdependent on AMPK and SIRT1
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Generation of Reactive Oxygen Species by Endothelial and Smooth Muscle Cells: Influence of Hyperglycemia and Metformin
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Critical effect of VEGF in the process of endothelial cell apoptosis induced by high glucose
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Effect of apocynin on NADPH oxidase-mediated oxidative stress-LOX-1-eNOS pathway in human endothelial cells exposed to high glucose
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long-term effect of combined vitamins e and c on coronary and peripheral endothelial function
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Curcumin combined with metformin decreases glycemia and dyslipidemia, and increases paraoxonase activity in diabetic rats
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Peri-Procedural Tight Glycemic Control during Early Percutaneous Coronary Intervention Is Associated with a Lower Rate of In-Stent Restenosis in Patients with Acute ST-Elevation Myocardial Infarction
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Assessment and Prognosis of Peripheral Artery Measures of Vascular Function
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Dose-Dependent Modulatory Effects of Insulin on Glucose-Induced Endothelial Senescence In Vitro and In Vivo: A Relationship between Telomeres and Nitric Oxide
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Metformin Improves Hemodynamic and Rheological Responses to L-Arginine in NIDDM Patients
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Cochlear Dysfunction in Type 2 Diabetes: A complication Independent of Neuropathy and Acute Hyperglycemia
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Metformin improves endothelial function in type 1 diabetic subjects: a pilot, placebo‐controlled randomized study
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Metformin increases antitumor activity of MEK inhibitors through GLI1 downregulation in LKB1 positive human NSCLC cancer cells
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Endothelial AMP-Activated Protein Kinase Regulates Blood Pressure and Coronary Flow Responses Through Hyperpolarization Mechanism in Mice
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Metformin decreases growth of pancreatic cancer cells by decreasing reactive oxygen species: Role of NOX4
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The possible role of the ubiquitin proteasome system in the development of atherosclerosis in diabetes
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Effect of a single high-fat meal on endothelial function in patients with the metabolic syndrome: Role of tumor necrosis factor-α
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Many Americans Have Pre-Diabetes and Should Be Considered for Metformin Therapy
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Innate Immune Activity in Plaque of Patients with Untreated and l -Thyroxine-Treated Subclinical Hypothyroidism
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Metformin decreases platelet superoxide anion production in diabetic patients
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Management of cardiovascular risk factors in advanced type 2 diabetic nephropathy: a comparative analysis in nephrology, diabetology and primary care settings
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Radical‐induced oxidation of metformin
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The involvement of the opioid system in human obesity: a study in normal weight relatives of obese people.
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Vascular Endothelium: Functioning in Norm, Changes in Atherosclerosis and Current Dietary Approaches to Improve Endothelial Function
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miRNA Regulation of the Hyperproliferative Phenotype of Vascular Smooth Muscle Cells in Diabetes
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Noncoding RNA s as therapeutic targets in atherosclerosis with diabetes mellitus
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Metformin treatment decreases nitroxidative stress, restores nitric oxide bioavailability and endothelial function beyond glucose control
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AMPKα2 exerts its anti-inflammatory effects through PARP-1 and Bcl-6
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Effects of oral glucose-lowering drugs on long term outcomes in patients with diabetes mellitus following myocardial infarction not treated with emergent percutaneous coronary intervention - a retrospective nationwide cohort study
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A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan
Mohammed, I., Hollenberg, M. D., Ding, H., & Triggle, C. R. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.718942 · Cited by 278 · see citing works
Metformin: Is it a drug for all reasons and diseases?
Triggle, C. R., Mohammed, I., Bshesh, K., Marei, I., Ye, K., Ding, H., MacDonald, R. S., Hollenberg, M. D., & Hill, M. A. (2022) · Metabolism · doi:10.1016/j.metabol.2022.155223 · Cited by 282 · see citing works
Metformin: A Review of Potential Mechanism and Therapeutic Utility Beyond Diabetes
Dutta, S., Shah, R., Singhal, S., Dutta, S. B., Bansal, S., Sinha, S., & Haque, M. (2023) · Drug Design Development and Therapy · doi:10.2147/dddt.s409373 · Cited by 284 · see citing works
The Effects of Curcumin on Diabetes Mellitus: A Systematic Review
Marton, L. T., Pescinini-e-Salzedas, L. M., Camargo, M. E. C., Barbalho, S. M., Haber, J. F. D. S., Sinatora, R. V., Detregiachi, C. R. P., Gírio, R. J. S., Buchaim, D. V., & Bueno, P. C. D. S. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.669448 · Cited by 220 · see citing works
Pathophysiological Association between Diabetes Mellitus and Endothelial Dysfunction
Maruhashi, T., & Higashi, Y. (2021) · Antioxidants · doi:10.3390/antiox10081306 · Cited by 194 · see citing works
Reactive Oxygen Species Scavenging Nanomedicine for the Treatment of Ischemic Heart Disease
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Polycystic Ovary Syndrome and Oxidative Stress—From Bench to Bedside
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Gastrointestinal adverse events of metformin treatment in patients with type 2 diabetes mellitus: A systematic review, meta-analysis and meta-regression of randomized controlled trials
Nabrdalik, K., Skonieczna‐Żydecka, K., Irlik, K., Hendel, M., Kwiendacz, H., Łoniewski, I., Januszkiewicz, K., Gumprecht, J., & Lip, G. Y. H. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.975912 · Cited by 110 · see citing works
Coronary Microvascular Dysfunction in Diabetes Mellitus: Pathogenetic Mechanisms and Potential Therapeutic Options
Salvatore, T., Galiero, R., Caturano, A., Vetrano, E., Loffredo, G., Rinaldi, L., Catalini, C., Gjeloshi, K., Albanese, G., Di Martino, A., et al. (2022) · Biomedicines · doi:10.3390/biomedicines10092274 · Cited by 98 · see citing works
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Effects of Metformin in Heart Failure: From Pathophysiological Rationale to Clinical Evidence
Salvatore, T., Galiero, R., Caturano, A., Vetrano, E., Rinaldi, L., Coviello, F., Martino, A. D., Albanese, G., Marfella, R., Sardu, C., et al. (2021) · Biomolecules · doi:10.3390/biom11121834 · Cited by 97 · see citing works
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RETRACTED: Metformin and Breast Cancer: Where Are We Now?
Solís, M. C., Martı́n-Castillo, B., Menéndez, J. A., & Pernas, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052705 · Cited by 85 · see citing works
Retracted
Endothelial Dysfunction, Erectile Deficit and Cardiovascular Disease: An Overview of the Pathogenetic Links
Leonardis, F. D., Colalillo, G., Agrò, E. F., Miano, R., Fuschi, A., & Asimakopoulos, A. D. (2022) · Biomedicines · doi:10.3390/biomedicines10081848 · Cited by 79 · see citing works
Does a strict glycemic control during acute coronary syndrome play a cardioprotective effect? Pathophysiology and clinical evidence
Caturano, A., Galiero, R., Pafundi, P. C., Cesaro, A., Vetrano, E., Palmiero, G., Rinaldi, L., Salvatore, T., Marfella, R., Sardu, C., et al. (2021) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2021.108959 · Cited by 73 · see citing works
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Examining the clinical relevance of metformin as an antioxidant intervention
Buczyńska, A., Sidorkiewicz, I., Kretowski, A. J., & Adamska, A. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1330797 · Cited by 72 · see citing works
Cognitive Impairment in Frail Hypertensive Elderly Patients: Role of Hyperglycemia
Mone, P., Gambardella, J., Pansini, A., Donato, A. D., Martinelli, G., Boccalone, E., Matarese, A., Frullone, S., & Santulli, G. (2021) · Cells · doi:10.3390/cells10082115 · Cited by 70 · see citing works
Cardiovascular Benefits from Gliflozins: Effects on Endothelial Function
Salvatore, T., Caturano, A., Galiero, R., Martino, A. D., Albanese, G., Vetrano, E., Sardu, C., Marfella, R., Rinaldi, L., & Sasso, F. C. (2021) · Biomedicines · doi:10.3390/biomedicines9101356 · Cited by 71 · see citing works
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View on Metformin: Antidiabetic and Pleiotropic Effects, Pharmacokinetics, Side Effects, and Sex-Related Differences
Froldi, G. (2024) · Pharmaceuticals · doi:10.3390/ph17040478 · Cited by 68 · see citing works
Role of metformin in inflammation
Feng, Y. Y., Wang, Z., & Pang, H. (2022) · Molecular Biology Reports · doi:10.1007/s11033-022-07954-5 · Cited by 56 · see citing works
Metformin and Its Immune-Mediated Effects in Various Diseases
Nojima, I., & Wada, J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24010755 · Cited by 54 · see citing works
Current Knowledge on the Pathophysiology of Lean/Normal-Weight Type 2 Diabetes
Salvatore, T., Galiero, R., Caturano, A., Rinaldi, L., Criscuolo, L., Martino, A. D., Albanese, G., Vetrano, E., Catalini, C., Sardu, C., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms24010658 · Cited by 48 · see citing works
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Metformin Protects Against Diabetes-Induced Cognitive Dysfunction by Inhibiting Mitochondrial Fission Protein DRP1
Hu, Y. W., Zhou, Y., Yang, Y., Tang, H., Si, Y., Chen, Z., Shi, Y., & Fang, H. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.832707 · Cited by 44 · see citing works
Effects of a Combination of Empagliflozin Plus Metformin vs. Metformin Monotherapy on NAFLD Progression in Type 2 Diabetes: The IMAGIN Pilot Study
Caturano, A., Galiero, R., Loffredo, G., Vetrano, E., Medicamento, G., Acierno, C., Rinaldi, L., Marrone, A., Salvatore, T., Monda, M., et al. (2023) · Biomedicines · doi:10.3390/biomedicines11020322 · Cited by 42 · see citing works
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Metformin: When Should We Fear Lactic Acidosis?
Mauro, S. D., Filippello, A., Scamporrino, A., Purrello, F., Piro, S., & Malaguarnera, R. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23158320 · Cited by 39 · see citing works
Type 2 Diabetes Mellitus and Cancer: Epidemiology, Physiopathology and Prevention
Rey‐Reñones, C., Baena-Díez, J. M., Aguilar‐Palacio, I., Miquel, C., & Grau, M. (2021) · Biomedicines · doi:10.3390/biomedicines9101429 · Cited by 41 · see citing works
Long-Term Use of Metformin Is Associated With Reduced Risk of Cognitive Impairment With Alleviation of Cerebral Small Vessel Disease Burden in Patients With Type 2 Diabetes
Teng, Z., Feng, J., Qi, Q., Dong, Y., Xiao, Y., Xie, X., Meng, N., Chen, H.-F., Zhang, W., & Lv, P. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.773797 · Cited by 38 · see citing works
Endothelium-Derived Relaxing Factors and Endothelial Function: A Systematic Review
Nappi, F., Fiore, A., Masiglat, J., Cavuoti, T., Romandini, M., Nappi, P., Singh, S. S. A., & Couëtil, J.-P. (2022) · Biomedicines · doi:10.3390/biomedicines10112884 · Cited by 38 · see citing works
Metformin Intervention—A Panacea for Cancer Treatment?
Buczyńska, A., Sidorkiewicz, I., Kretowski, A. J., Zbucka-Krętowska, M., & Adamska, A. (2022) · Cancers · doi:10.3390/cancers14051336 · Cited by 36 · see citing works
The positive implication of natural antioxidants on oxidative stress-mediated diabetes mellitus complications
Mallik, S., Paria, B., Firdous, S. M., Ghazzawy, H. S., Alqahtani, N. K., He, Y., Li, X., & Gouda, M. (2024) · Journal of Genetic Engineering and Biotechnology · doi:10.1016/j.jgeb.2024.100424 · Cited by 40 · see citing works
Metformin in Antiviral Therapy: Evidence and Perspectives
Halabitska, I., Petakh, P., Lushchak, O. V., Kamyshna, I. I., Oksenych, V., & Kamyshnyi, O. (2024) · Viruses · doi:10.3390/v16121938 · Cited by 33 · see citing works
Gut microbiota is correlated with gastrointestinal adverse events of metformin in patients with type 2 diabetes
Huang, Y., Lou, X., Jiang, C., Ji, X., Tao, X., Sun, J., & Bao, Z. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1044030 · Cited by 32 · see citing works
Metformin use and the risk of total knee replacement among diabetic patients: a propensity-score-matched retrospective cohort study
Lai, F. T. T., Yip, B. H. K., Hunter, D. J., Rabago, D., Mallen, C. D., Yeoh, E., Wong, S. Y. S., & Sit, R. W. S. (2022) · Scientific Reports · doi:10.1038/s41598-022-15871-7 · Cited by 30 · see citing works
A Glimpse into Milestones of Insulin Resistance and an Updated Review of Its Management
Aedh, A. I., Alshahrani, M. S., Huneif, M. A., Pryme, I. F., & Oruch, R. (2023) · Nutrients · doi:10.3390/nu15040921 · Cited by 32 · see citing works
Overview of key molecular and pharmacological targets for diabetes and associated diseases
Shahcheraghi, S. H., Aljabali, A. A. A., Zoubi, M. S. A., Mishra, V. K., Charbe, N. B., Haggag, Y. A., Shrivastava, G., Almutary, A. G., Alnuqaydan, A. M., Barh, D., et al. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119632 · Cited by 29 · see citing works
Bioactive anti-inflammatory antibacterial metformin-contained hydrogel dressing accelerating wound healing
Leng, T., Wang, Y., Cheng, W., Wang, W., Qu, X., & Lei, B. (2022) · Biomaterials Advances · doi:10.1016/j.bioadv.2022.212737 · Cited by 29 · see citing works
Gastrointestinal adverse events of metformin treatment in patients with type 2 diabetes mellitus: a systematic review and meta-analysis with meta-regression of observational studies
Nabrdalik, K., Hendel, M., Irlik, K., Kwiendacz, H., Łoniewski, I., Bucci, T., Alam, U., Lip, G. Y. H., Gumprecht, J., & Skonieczna‐Żydecka, K. (2024) · BMC Endocrine Disorders · doi:10.1186/s12902-024-01727-w · Cited by 28 · see citing works
Comprehensive treatment of diabetic endothelial dysfunction based on pathophysiological mechanism
Liu, Z., Lu, J., Sha, W., & Lei, T. (2025) · Frontiers in Medicine · doi:10.3389/fmed.2025.1509884 · Cited by 32 · see citing works
Pharmacological characterization of the antidiabetic drug metformin in atherosclerosis inhibition: A comprehensive insight
Turkistani, A. A., Al‐kuraishy, H. M., Al-Gareeb, A. I., Alexiou, A. T., Papadakis, M., Bahaa, M. M., Al‐Windy, S., & Batiha, G. E. (2024) · Immunity Inflammation and Disease · doi:10.1002/iid3.1346 · Cited by 26 · see citing works
The Hormetic Effect of Metformin: “Less Is More”?
Panfoli, I., Puddu, A., Bertola, N., Ravera, S., & Maggi, D. C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126297 · Cited by 27 · see citing works
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Authors: Salvatore, T., Pafundi, P. C., Galiero, R., Rinaldi, L., Caturano, A., Vetrano, E., Aprea, C., Albanese, G., Di Martino, A., Ricozzi, C., Imbriani, S., & Sasso, F. C.
Affiliations: University of Campania "Luigi Vanvitelli" (IT)
Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, I-80138 Naples, Italy
Corresponding author: Sasso, Ferdinando Carlo
ORCID: Salvatore, Teresa
Pafundi, Pia Clara
Galiero, Raffaele
Rinaldi, Luca
Caturano, Alfredo
Sasso, Ferdinando Carlo
Venue: Biomedicines
Publisher: MDPI AG
Published: 2020-12-22
Volume: 9
Issue: 1
Pages: 3
ISSN: 2227-9059 (ISSN-L)
DOI: 10.3390/biomedicines9010003
PMC: PMC7822116
OpenAlex: W3113948922
Cited by: 97
References: 242
Citations by year: 2026: 5 · 2025: 8 · 2024: 22 · 2023: 13 · 2022: 32 · 2021: 17
FWCI: 1.98
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Biomedicines (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, other-oa)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
Archivio Istituzionale della Ricerca - Università degli Studi del Molise (submittedVersion)
Topics: Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords: metformin, endothelial dysfunction, type 2 diabetes, AMPK activation, diabetic macroangiopathy, cardiovascular complications, endothelial inflammation, oxidative stress, advanced glycation end products, polyol pathway, protein kinase C, endothelial cell apoptosis, microRNA, atherosclerosis prevention

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Can Metformin Exert as an Active Drug on Endothelial Dysfunction in Diabetic Subjects

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