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Metformin: The Scope for New Applications

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 28097

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Dr. Jolanta Weaver

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Guest Editor

Institute of Cellular Medicine, Newcastle University, Newcastle, UK
Interests: cardiovascular disease; diabetes mellitus; vascular stem cells; endothelial progenitor cells; repurposing metformin for CVD; risk factors for CVD; in-vitro models of CVD
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Dear Colleagues,

The facination on the pleiotrophic actions of metformin has fueled further interest in the clinical application of this safe drug. Although metformin has been available for almost a century, Europe only discovered it 60 years ago. However, it took a further 38 years for America to appreciate its virtues. Metformin has been shown to be the first cardioprotective drug in type 2 diabetes, as born by UKPDS trial, and others that followed. The scientific interest in metformin has recently re-emerged with clinical studies in treatment of malignacies, explorations of rejuvenation potentials of metformin not to mention the use of it in a wide range of patients outside licensed indications. The array of metformin actions stretch from improving insulin resistance, membrane-related effects to cardioprotective mechanism via CD34+ umbilical cord blood stem cells, reduction of myocardial infarct size to potential anti-cancer therapies.

This Special Issue of the International Journal of Molecular Sciences has the aspiration of addressing (nonexclusively) the mechanisms of metformin action in different tissues from cancer cells, endothelial cells, hepatocytes, myocytes to clinical studies of translational design supported by laboratory investigations. The purpose of this invitation is to enhance our knowledge on potential of metformin in human health to aid further applications and development of novel therapies.

Dr. Jolanta Weaver
Guest Editor

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Keywords

metformin
energy metabolism
AMPK
hepatocytes
adipocytes
endothelial progenitor cells
enothelial cells
microparticles
angiogenesis
VEGFR
eNOS
cardiovascular disease
diabetes
cancer
rejuvenation
anti-aging

Related Special Issue

Metformin: Mechanism and Application in International Journal of Molecular Sciences (12 articles)

Published Papers (7 papers)

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Research

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8 pages, 1316 KiB

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Effect of Metformin on T2D-Induced MAM Ca²⁺ Uncoupling and Contractile Dysfunction in an Early Mouse Model of Diabetic HFpEF

by Maya Dia, Christelle Leon, Stephanie Chanon, Nadia Bendridi, Ludovic Gomez, Jennifer Rieusset, Helene Thibault and Melanie Paillard

Int. J. Mol. Sci. 2022, 23(7), 3569; https://doi.org/10.3390/ijms23073569 - 25 Mar 2022

Cited by 9 | Viewed by 2658

Abstract

Diabetic cardiomyopathy (DCM) is a leading complication in type 2 diabetes patients. Recently, we have shown that the reticulum-mitochondria Ca²⁺ uncoupling is an early and reversible trigger of the cardiac dysfunction in a diet-induced mouse model of DCM. Metformin is a first-line antidiabetic drug with recognized cardioprotective effect in myocardial infarction. Whether metformin could prevent the progression of DCM remains not well understood. We therefore investigated the effect of a chronic 6-week metformin treatment on the reticulum-mitochondria Ca²⁺ coupling and the cardiac function in our high-fat high-sucrose diet (HFHSD) mouse model of DCM. Although metformin rescued the glycemic regulation in the HFHSD mice, it did not preserve the reticulum-mitochondria Ca²⁺ coupling either structurally or functionally. Metformin also did not prevent the progression towards cardiac dysfunction, i.e., cardiac hypertrophy and strain dysfunction. In summary, despite its cardioprotective role, metformin is not sufficient to delay the progression to early DCM. Full article

(This article belongs to the Special Issue Metformin: The Scope for New Applications)

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35 pages, 3490 KiB

Open AccessArticle

The Effects of Separate and Combined Treatment of Male Rats with Type 2 Diabetes with Metformin and Orthosteric and Allosteric Agonists of Luteinizing Hormone Receptor on Steroidogenesis and Spermatogenesis

by Andrey A. Bakhtyukov, Kira V. Derkach, Viktor N. Sorokoumov, Anna M. Stepochkina, Irina V. Romanova, Irina Yu. Morina, Irina O. Zakharova, Liubov V. Bayunova and Alexander O. Shpakov

Int. J. Mol. Sci. 2022, 23(1), 198; https://doi.org/10.3390/ijms23010198 - 24 Dec 2021

Cited by 23 | Viewed by 3258

Abstract

In men with type 2 diabetes mellitus (T2DM), steroidogenesis and spermatogenesis are impaired. Metformin and the agonists of luteinizing hormone/human chorionic gonadotropin(hCG)-receptor (LH/hCG-R) (hCG, low-molecular-weight allosteric LH/hCG-R-agonists) can be used to restore them. The aim was to study effectiveness of separate and combined administration of metformin, hCG and 5-amino-N-tert-butyl-2-(methylsulfanyl)-4-(3-(nicotinamido)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide (TP3) on steroidogenesis and spermatogenesis in male rats with T2DM. hCG (15 IU/rat/day) and TP3 (15 mg/kg/day) were injected in the last five days of five-week metformin treatment (120 mg/kg/day). Metformin improved testicular steroidogenesis and spermatogenesis and restored LH/hCG-R-expression. Compared to control, in T2DM, hCG stimulated steroidogenesis and StAR-gene expression less effectively and, after five-day administration, reduced LH/hCG-R-expression, while TP3 effects changed weaker. In co-administration of metformin and LH/hCG-R-agonists, on the first day, stimulating effects of LH/hCG-R-agonists on testosterone levels and hCG-stimulated expression of StAR- and CYP17A1-genes were increased, but on the 3–5th day, they disappeared. This was due to reduced LH/hCG-R-gene expression and increased aromatase-catalyzed estradiol production. With co-administration, LH/hCG-R-agonists did not contribute to improving spermatogenesis, induced by metformin. Thus, in T2DM, metformin and LH/hCG-R-agonists restore steroidogenesis and spermatogenesis, with metformin being more effective in restoring spermatogenesis, and their co-administration improves LH/hCG-R-agonist-stimulating testicular steroidogenesis in acute but not chronic administration. Full article

(This article belongs to the Special Issue Metformin: The Scope for New Applications)

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19 pages, 2541 KiB

Open AccessArticle

Effects of Metformin on Spontaneous Ca²⁺ Signals in Cultured Microglia Cells under Normoxic and Hypoxic Conditions

by Silvija Jankeviciute, Natasa Svirskiene, Gytis Svirskis and Vilmante Borutaite

Int. J. Mol. Sci. 2021, 22(17), 9493; https://doi.org/10.3390/ijms22179493 - 31 Aug 2021

Cited by 2 | Viewed by 2060

Abstract

Microglial functioning depends on Ca²⁺ signaling. By using Ca²⁺ sensitive fluorescence dye, we studied how inhibition of mitochondrial respiration changed spontaneous Ca²⁺ signals in soma of microglial cells from 5–7-day-old rats grown under normoxic and mild-hypoxic conditions. In microglia under normoxic conditions, metformin or rotenone elevated the rate and the amplitude of Ca²⁺ signals 10–15 min after drug application. Addition of cyclosporin A, a blocker of mitochondrial permeability transition pore (mPTP), antioxidant trolox, or inositol 1,4,5-trisphosphate receptor (IP3R) blocker caffeine in the presence of rotenone reduced the elevated rate and the amplitude of the signals implying sensitivity to reactive oxygen species (ROS), and involvement of mitochondrial mPTP together with IP3R. Microglial cells exposed to mild hypoxic conditions for 24 h showed elevated rate and increased amplitude of Ca²⁺ signals. Application of metformin or rotenone but not phenformin before mild hypoxia reduced this elevated rate. Thus, metformin and rotenone had the opposing fast action in normoxia after 10–15 min and the slow action during 24 h mild-hypoxia implying activation of different signaling pathways. The slow action of metformin through inhibition of complex I could stabilize Ca²⁺ homeostasis after mild hypoxia and could be important for reduction of ischemia-induced microglial activation. Full article

(This article belongs to the Special Issue Metformin: The Scope for New Applications)

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Review

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19 pages, 1502 KiB

Open AccessReview

Metformin and Breast Cancer: Where Are We Now?

by Mónica Cejuela, Begoña Martin-Castillo, Javier A. Menendez and Sonia Pernas

Int. J. Mol. Sci. 2022, 23(5), 2705; https://doi.org/10.3390/ijms23052705 - 28 Feb 2022

Cited by 32 | Viewed by 7991

Abstract

Breast cancer is the most prevalent cancer and the leading cause of cancer-related death among women worldwide. Type 2 diabetes–associated metabolic traits such as hyperglycemia, hyperinsulinemia, inflammation, oxidative stress, and obesity are well-known risk factors for breast cancer. The insulin sensitizer metformin, one of the most prescribed oral antidiabetic drugs, has been suggested to function as an antitumoral agent, based on epidemiological and retrospective clinical data as well as preclinical studies showing an antiproliferative effect in cultured breast cancer cells and animal models. These benefits provided a strong rationale to study the effects of metformin in routine clinical care of breast cancer patients. However, the initial enthusiasm was tempered after disappointing results in randomized controlled trials, particularly in the metastatic setting. Here, we revisit the current state of the art of metformin mechanisms of action, critically review past and current metformin-based clinical trials, and briefly discuss future perspectives on how to incorporate metformin into the oncologist’s armamentarium for the prevention and treatment of breast cancer. Full article

(This article belongs to the Special Issue Metformin: The Scope for New Applications)

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10 pages, 798 KiB

Open AccessReview

Metformin’s Mechanism of Action Is Stimulation of the Biosynthesis of the Natural Cyclic AMP Antagonist Prostaglandylinositol Cyclic Phosphate (Cyclic PIP)

by Heinrich K. Wasner

Int. J. Mol. Sci. 2022, 23(4), 2200; https://doi.org/10.3390/ijms23042200 - 16 Feb 2022

Cited by 5 | Viewed by 2109

Abstract

Metformin is the leading drug for treating type 2 diabetics, but the mechanism of action of metformin, despite some suggested mechanisms such as the activation of the AMP-kinase, is largely unknown. Among its many positive effects are the reduction of blood glucose levels, the inhibition of cyclic AMP synthesis, gluconeogenesis and an increase in sensitivity to insulin. Recent studies have described the natural antagonist of cyclic AMP, prostaglandylinositol cyclic phosphate. Synthesis of cyclic PIP is stimulated in all organs by hormones such as insulin and also by drugs such as metformin. Its primary action is to trigger the dephosphorylation of proteins/enzymes, phosphorylated on serine/threonine residues. Cyclic PIP triggers many of the regulations requested by insulin. The parallels between the beneficial effects of metformin and the regulations triggered by cyclic PIP suggest that the mechanism of action of this key drug may well be explained by its stimulation of the synthesis of cyclic PIP. Full article

(This article belongs to the Special Issue Metformin: The Scope for New Applications)

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17 pages, 613 KiB

Open AccessReview

Metformin Repurposing for Parkinson Disease Therapy: Opportunities and Challenges

by Francesco Agostini, Anna Masato, Luigi Bubacco and Marco Bisaglia

Int. J. Mol. Sci. 2022, 23(1), 398; https://doi.org/10.3390/ijms23010398 - 30 Dec 2021

Cited by 29 | Viewed by 5473

Abstract

Parkinson disease (PD) is a severe neurodegenerative disorder that affects around 2% of the population over 65 years old. It is characterized by the progressive loss of nigrostriatal dopaminergic neurons, resulting in motor disabilities of the patients. At present, only symptomatic cures are available, without suppressing disease progression. In this frame, the anti-diabetic drug metformin has been investigated as a potential disease modifier for PD, being a low-cost and generally well-tolerated medication, which has been successfully used for decades in the treatment of type 2 diabetes mellitus. Despite the precise mechanisms of action of metformin being not fully elucidated, the drug has been known to influence many cellular pathways that are associated with PD pathology. In this review, we present the evidence in the literature supporting the neuroprotective role of metformin, i.e., autophagy upregulation, degradation of pathological α-synuclein species, and regulation of mitochondrial functions. The epidemiological studies conducted in diabetic patients under metformin therapy aimed at evaluating the correlation between long-term metformin consumption and the risk of developing PD are also discussed. Finally, we provide an interpretation for the controversial results obtained both in experimental models and in clinical studies, thus providing a possible rationale for future investigations for the repositioning of metformin for PD therapy. Full article

(This article belongs to the Special Issue Metformin: The Scope for New Applications)

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44 pages, 2462 KiB

Open AccessReview

Integrated or Independent Actions of Metformin in Target Tissues Underlying Its Current Use and New Possible Applications in the Endocrine and Metabolic Disorder Area

by Giovanni Tulipano

Int. J. Mol. Sci. 2021, 22(23), 13068; https://doi.org/10.3390/ijms222313068 - 02 Dec 2021

Cited by 13 | Viewed by 3289

Abstract

Metformin is considered the first-choice drug for type 2 diabetes treatment. Actually, pleiotropic effects of metformin have been recognized, and there is evidence that this drug may have a favorable impact on health beyond its glucose-lowering activity. In summary, despite its long history, metformin is still an attractive research opportunity in the field of endocrine and metabolic diseases, age-related diseases, and cancer. To this end, its mode of action in distinct cell types is still in dispute. The aim of this work was to review the current knowledge and recent findings on the molecular mechanisms underlying the pharmacological effects of metformin in the field of metabolic and endocrine pathologies, including some endocrine tumors. Metformin is believed to act through multiple pathways that can be interconnected or work independently. Moreover, metformin effects on target tissues may be either direct or indirect, which means secondary to the actions on other tissues and consequent alterations at systemic level. Finally, as to the direct actions of metformin at cellular level, the intracellular milieu cooperates to cause differential responses to the drug between distinct cell types, despite the primary molecular targets may be the same within cells. Cellular bioenergetics can be regarded as the primary target of metformin action. Metformin can perturb the cytosolic and mitochondrial NAD/NADH ratio and the ATP/AMP ratio within cells, thus affecting enzymatic activities and metabolic and signaling pathways which depend on redox- and energy balance. In this context, the possible link between pyruvate metabolism and metformin actions is extensively discussed. Full article

(This article belongs to the Special Issue Metformin: The Scope for New Applications)

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