Metformin in therapeutic applications in human diseases: its mechanism of action and clinical study

Abstract

Metformin, a biguanide drug, is the most commonly used first-line medication for type 2 diabetes mellites due to its outstanding glucose-lowering ability. After oral administration of 1 g, metformin peaked plasma concentration of approximately 20–30 μM in 3 h, and then it mainly accumulated in the gastrointestinal tract, liver and kidney. Substantial studies have indicated that metformin exerts its beneficial or deleterious effect by multiple mechanisms, apart from AMPK-dependent mechanism, also including several AMPK-independent mechanisms, such as restoring of redox balance, affecting mitochondrial function, modulating gut microbiome and regulating several other signals, such as FBP1, PP2A, FGF21, SIRT1 and mTOR. On the basis of these multiple mechanisms, researchers tried to repurpose this old drug and further explored the possible indications and adverse effects of metformin. Through investigating with clinical studies, researchers concluded that in addition to decreasing cardiovascular events and anti-obesity, metformin is also beneficial for neurodegenerative disease, polycystic ovary syndrome, aging, cancer and COVID-19, however, it also induces some adverse effects, such as gastrointestinal complaints, lactic acidosis, vitamin B12 deficiency, neurodegenerative disease and offspring impairment. Of note, the dose of metformin used in most studies is much higher than its clinically relevant dose, which may cast doubt on the actual effects of metformin on these disease in the clinic. This review summarizes these research developments on the mechanism of action and clinical evidence of metformin and discusses its therapeutic potential and clinical safety.

Novel Biomarkers for Inflammatory Bowel Disease and Colorectal Cancer: An Interplay between Metabolic Dysregulation and Excessive Inflammation

“…Indeed, hyperglycemia and hyperinsulinemia are thought to promote the growth of cancer cells in diabetic patients [ 87 ]. Metformin, the most commonly prescribed oral anti-diabetic medication and an activator of AMPK, has been shown to have strong anti-proliferative and/or pro-apoptotic properties in several cancer cell lines, and may be of benefit to diabetic cancer patients [ 88 ]. Although controversial, the anti-cancer effect may be independent of AMPK activation [ 89 ].…”

A Brief Review of Duchenne Muscular Dystrophy Treatment Options, with an Emphasis on Two Novel Strategies

“…Metformin alters cellular metabolism by reducing the efficiency of the electron transport chain and thus ‘tricking’ the cell into thinking it is low on ATP. The cell responds by increasing mitochondrial production and metabolism [ 77 ]. This increased metabolism rate is likely beneficial, but the associated signaling cascades (pAMPK and PGC1α) of a starved cell also benefit the muscle cells [ 78 ].…”

“…The most protective metabolic manipulations in mouse models are not yet decided upon, but human trials of metformin are underway. The most significant aspect of treating MD with metformin is that metformin is already FDA approved and has few lasting side-effects [ 77 ]. Metformin is the primary medication for type 2 diabetes, is now also often prescribed for clinically necessary weight loss and has proven safe for over 20 million patients in 2020 in the USA ( (accessed on 13 January 2023)).…”

Relevance of the Extraction Stage on the Anti-Inflammatory Action of Fucoidans

“…In contrast, other therapeutical strategies are based on the consumption of non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids which are used in a wide range of conditions. Nonetheless, long-term therapy with any of these drugs could have side effects which could worsen the health of the patient [ 60 , 61 , 62 ]. In this regard, the therapeutic use of natural biomolecules, like fucoidans, have gained a great interest as an alternative and complementary therapy for the treatment of different diseases characterized by chronic inflammation, on the basis of its anti-inflammatory, antioxidant, and antitumor properties among others ( Figure 2 ) [ 34 , 63 ].…”