Diverse Applications of the Anti-Diabetic Drug Metformin in Treating Human Disease

Abstract

Metformin is a commonly used drug for treating type 2 diabetes. Metformin is an inexpensive drug with low/no side effects and is well tolerated in human patients of different ages. Recent therapeutic strategies for human disease have considered the benefits of drug repurposing. This includes the use of the anti-diabetic drug metformin. Accordingly, the anti-inflammatory, anti-cancer, anti-viral, neuroprotective, and cardioprotective potentials of metformin have deemed it a suitable candidate for treating a plethora of human diseases. As results from preclinical studies using cellular and animal model systems appear promising, clinical trials with metformin in the context of non-diabetes-related illnesses have been started. Here, we aim to provide a comprehensive overview of the therapeutic potential of metformin in different animal models of human disease and its suggested relationship to epigenetics and ailments with epigenetic components.

Keywords: drug repurposing; epigenetics; human disease; metformin; type 2 diabetes.

Figure 3

Proposed mechanism of metformin action in neurons and astrocytes of the mammalian brain. Metformin entry into excitatory pre- and post-synaptic neurons, as well as astrocytes, may be mediated by OCT. In excitatory pre-synaptic neurons, metformin may increase glutamate (Glu) release while mitigating reactive astrogliosis and the release of pro-inflammatory cytokines from astrocytes. In post-synaptic neurons, metformin may alter the expression of synaptic markers (such as PSD95), inhibit complex I of the mitochondrial electron transport chain, inhibit mTORC1, and mediate AMPK-dependent activation of FoxO3a. Metformin-mediated activation of FoxO3a may promote the insertion of GABA receptors at the post-synaptic membrane as an indirect effect of the drug, involving inhibitory presynaptic neurons. Adapted from Bak et al., 2006 and Li et al., 2022 with additional information extracted from Barini et al., 2016, Oner et al., 2024, Yoval-Sanchez et al., 2022, Fan et al., 2019 [111,118,119,120,121,122,123]. Abbreviations: AMPK: 5′ adenosine monophosphate (AMP)-activated protein kinase; FoxO3a: forkhead box O3a; GAD: glutamate decarboxylase; mTORC1: mechanistic target of rapamycin complex; PSD95: postsynaptic density protein 95; SNAP25: synaptosomal associated protein 25. Illustration created with BioRender.com.

Figure 1

Overview of metformin chemical structure, clinical use, and pharmacokinetics. Chemically, metformin is a biguanide (1,1-dimethylbiguanide) used in the treatment/management of type 2 diabetes, gestational diabetes, and polycystic ovary syndrome. Metformin is administered orally in immediate- or extended-release form. Between 40–60% of metformin enters systemic circulation and is eliminated from the body in about 6.2 h. For pre-clinical studies in animal models, 250 mg/kg/day in mice corresponds to 20 mg/kg/day in humans [10,12]. Illustration created in BioRender.com.

Figure 2

A proposed mechanism for the entry of metformin into the brain via the blood–brain barrier (BBB). The BBB is comprised of neurovascular units composed of brain endothelial cells, supporting cells (astrocytes, microglia, pericytes, and neurons), and tight junctional proteins. Endothelial cells of the neurovascular unit possess OCT1 transporters, which metformin can use to pass through the BBB. The physicochemical properties of metformin (small, hydrophilic, and positively charged molecule) suggest that metformin may use OCT for transporting across the BBB [83,84]. CLDN: claudins, OCLDN: occlusins, JAM: junction adhesion molecules, OCT: organic cation transporters, PC: permeability coefficient. Illustration created with BioRender.com.

Figure 4

Summary of the potential effect of metformin in different human diseases. The pleiotropic effects of metformin are observed in the context of different diseases, including neurological and cardiovascular diseases, as well as in cancer and viral infection. Metformin may be a promising therapeutic agent in various diseases. Information obtained from: [18,40,46,47,48,49,50,51,52,59,61,65,91,93,94,95,109]. Illustration created in BioRender.com.