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; Martino, Anna Di; Ricozzi, Carmen; Imbriani, Simona; Sasso, Ferdinando Carlo

doi:10.3390/biomedicines9010003

Cited by 79 publications

(76 citation statements)

References 240 publications

(123 reference statements)

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“…Our in vitro results showing a dose-dependent beneficial action of metformin on high-glucose-induced endothelial leakage, oxidative stress, and cell death, provide a molecular mechanism underlying our clinical observations. Of note, these findings are consistent with previous reports [78][79][80][81][82][83][84][85][86][87].…”

Section: Discussionsupporting

confidence: 93%

Cognitive Impairment in Frail Hypertensive Elderly Patients: Role of Hyperglycemia

Mone

Gambardella

Pansini

et al. 2021

Cells

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Endothelial dysfunction is a key hallmark of hypertension, which is a leading risk factor for cognitive decline in older adults with or without frailty. Similarly, hyperglycemia is known to impair endothelial function and is a predictor of severe cardiovascular outcomes, independent of the presence of diabetes. On these grounds, we designed a study to assess the effects of high-glucose and metformin on brain microvascular endothelial cells (ECs) and on cognitive impairment in frail hypertensive patients. We tested the effects of metformin on high-glucose-induced cell death, cell permeability, and generation of reactive oxygen species in vitro, in human brain microvascular ECs. To investigate the consequences of hyperglycemia and metformin in the clinical scenario, we recruited frail hypertensive patients and we evaluated their Montreal Cognitive Assessment (MoCA) scores, comparing them according to the glycemic status (normoglycemic vs. hyperglycemic) and the use of metformin. We enrolled 376 patients, of which 209 successfully completed the study. We observed a significant correlation between MoCA score and glycemia. We found that hyperglycemic patients treated with metformin had a significantly better MoCA score than hyperglycemic patients treated with insulin (18.32 ± 3.9 vs. 14.94 ± 3.8; p < 0.001). Our in vitro assays confirmed the beneficial effects of metformin on human brain microvascular ECs. To our knowledge, this is the first study correlating MoCA score and glycemia in frail and hypertensive older adults, showing that hyperglycemia aggravates cognitive impairment.

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Section: Discussionsupporting

confidence: 93%

Cognitive Impairment in Frail Hypertensive Elderly Patients: Role of Hyperglycemia

Mone

Gambardella

Pansini

et al. 2021

Cells

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“…The obvious question is : “Does metformin exert a direct anti-aging effect on the endothelium?” . 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 ). There is an extensive literature based on data from pre-clinical and clinical studies that indicates metformin protects endothelial function from the effects of diabetes ( 33 ).…”

Section: Metformin and Endothelial Function And Cardiovascular Diseasementioning

confidence: 99%

A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan

et al. 2021

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The numerous beneficial health outcomes associated with the use of metformin to treat patients with type 2 diabetes (T2DM), together with data from pre-clinical studies in animals including the nematode, C. elegans, and mice have prompted investigations into whether metformin has therapeutic utility as an anti-aging drug that may also extend lifespan. Indeed, clinical trials, including the MILES (Metformin In Longevity Study) and TAME (Targeting Aging with Metformin), have been designed to assess the potential benefits of metformin as an anti-aging drug. Preliminary analysis of results from MILES indicate that metformin may induce anti-aging transcriptional changes; however it remains controversial as to whether metformin is protective in those subjects free of disease. Furthermore, despite clinical use for over 60 years as an anti-diabetic drug, the cellular mechanisms by which metformin exerts either its actions remain unclear. In this review, we have critically evaluated the literature that has investigated the effects of metformin on aging, healthspan and lifespan in humans as well as other species. In preparing this review, particular attention has been placed on the strength and reproducibility of data and quality of the study protocols with respect to the pharmacokinetic and pharmacodynamic properties of metformin. We conclude that despite data in support of anti-aging benefits, the evidence that metformin increases lifespan remains controversial. However, via its ability to reduce early mortality associated with various diseases, including diabetes, cardiovascular disease, cognitive decline and cancer, metformin can improve healthspan thereby extending the period of life spent in good health. Based on the available evidence we conclude that the beneficial effects of metformin on aging and healthspan are primarily indirect via its effects on cellular metabolism and result from its anti-hyperglycemic action, enhancing insulin sensitivity, reduction of oxidative stress and protective effects on the endothelium and vascular function.

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“…ROS can exert numerous detrimental effects that induce and aggravate diabetes, including diminishing glucose transport channels, reducing insulin secretion, protein fragmentation and oxidation, DNA damage, free fatty acid generation, and increased vascular permeability. Moreover, oxidative stress induces the formation of AGEs contributing to endothelial dysfunction and the development of microvascular and macrovascular complications of T2DM (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

The Effects of Curcumin on Diabetes Mellitus: A Systematic Review

et al. 2021

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Diabetes mellitus (DM) is an ensemble of metabolic conditions that have reached pandemic proportions worldwide. Pathology’s multifactorial nature makes patient management, including lifelong drug therapy and lifestyle modification, extremely challenging. Currently, there is growing evidence about the effectiveness of using herbal supplements in preventing and controlling DM. Curcumin is a bioactive component found Curcuma longa, which exhibits several physiological and pharmacological properties such as antioxidant, anti-inflammatory, anticancer, neuroprotective, and anti-diabetic activities. For these reasons, our objective is to systematically review the effects of Curcuma longa or curcumin on DM. Databases such as PUBMED and EMBASE were searched, and the final selection included sixteen studies that fulfilled the inclusion criteria. The results showed that curcumin’s anti-diabetic activity might be due to its capacity to suppress oxidative stress and inflammatory process. Also, it significantly reduces fasting blood glucose, glycated hemoglobin, and body mass index. Nanocurcumin is also associated with a significant reduction in triglycerides, VLDL-c, total cholesterol, LDL-c, HDL-c, serum C reactive protein, and plasma malonaldehyde. Therefore, it can be considered in the therapeutic approach of patients with DM.

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

Cited by 79 publications

References 240 publications

Cognitive Impairment in Frail Hypertensive Elderly Patients: Role of Hyperglycemia

Cognitive Impairment in Frail Hypertensive Elderly Patients: Role of Hyperglycemia

A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan

The Effects of Curcumin on Diabetes Mellitus: A Systematic Review

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