A Clinical Perspective of the Multifaceted Mechanism of Metformin in Diabetes, Infections, Cognitive Dysfunction, and Cancer

Abstract

In type 2 diabetes, ecological and lifecourse factors may interact with the host microbiota to influence expression of his/her genomes causing perturbation of interconnecting biological pathways with diverse clinical course. Metformin is a plant-based or plant-derived medicinal product used for the treatment of type 2 diabetes for over 60 years and is an essential drug listed by the World Health Organization. By reducing mitochondrial oxidative phosphorylation and adenosine triphosphate (ATP) production, metformin increased AMP (adenosine monophosphate)-activated protein kinase (AMPK) activity and altered cellular redox state with reduced glucagon activity, endogenous glucose production, lipogenesis, and protein synthesis. Metformin modulated immune response by directly reducing neutrophil to lymphocyte ratio and improving the phagocytic function of immune cells. By increasing the relative abundance of mucin-producing and short-chain-fatty-acid-producing gut microbes, metformin further improved the host inflammatory and metabolic milieu. Experimentally, metformin promoted apoptosis and reduced proliferation of cancer cells by reducing their oxygen consumption and modulating the microenvironment. Both clinical and mechanistic studies support the pluripotent effects of metformin on reducing cardiovascular-renal events, infection, cancer, cognitive dysfunction, and all-cause death in type 2 diabetes, making this low-cost medication a fundamental therapy for individualization of other glucose-lowering drugs in type 2 diabetes. Further research into the effects of metformin on cognitive function, infection and cancer, especially in people without diabetes, will provide new insights into the therapeutic value of metformin in our pursuit of prevention and treatment of ageing-related as well as acute and chronic diseases beyond diabetes.

Keywords: anticancer action; cardioprotection; cognition; diabetes; infections; mechanisms; metformin.

Figure 1

Mechanisms of metformin. The multifaceted nature of the mechanisms of metformin targeting different organs, including liver, muscle, and gastrointestinal tract, including the microbiota, results in glucose-lowering, anti-inflammatory, and anti-cancer effects through AMPK and non-AMPK dependent pathways (adapted from references [16,17,18,19]).

Figure 2

Clinical benefits of metformin in multiple systems. The multi-targeted actions of metformin are mediated both by the adenosine monophosphate activated protein kinase (AMPK) pathway and non-AMPK pathways. In the liver, metformin reduces glycogenolysis, hepatic glucose production, and gluconeogenesis [37]. In the lung, metformin modulates the tumor necrosis factor (TNF)-α/NF-kB/mammalian target of rapamycin (mTOR) pathways and expression of pro-inflammatory cytokines. In the intestines, metformin modifies gut microbiome and promotes incretin (e.g., glucagon-like peptide 1, GLP-1) secretion with increased glucose utilization. In the nervous system, metformin reduces amyloid plaque formation and decline of cognitive function. In the circulatory systems, metformin improves dyslipidemia and endothelial dysfunction with reduced cardiovascular–renal events. Metformin reduces site-specific cancer events, including prostate and liver, in part due to amelioration of insulin resistance with reduced activation of insulin/insulin-like growth factor (IGF-1). Metformin is eliminated by the kidney. Metformin alleviates podocyte loss, mesangial cells apoptosis, and tubular cells senescence through AMPK-mediated signaling pathways. In chronic kidney disease, renal fibrosis is ameliorated by metformin, mainly via AMPK activation. Reduced glomerular filtration and tubular secretion may lead to accumulation of metformin and increased risk of lactic acidosis, especially in stress situations [17] (adapted from reference [13]).

Figure 3

Summary of clinical effects of metformin in different disease conditions. NAFLD, Non-alcoholic fatty liver disease (NAFLD); NASH, non-alcoholic steatohepatitis; CKD, chronic kidney disease; and UKPDS, United Kingdom Prospective Diabetes Study.

Figure 4

The action of metformin on cancer. Metformin activates adenosine monophosphate activated protein kinase (AMPK), an immediate downstream effector of the tumor suppressor liver kinase B1 (LKB1), resulting in inhibition of tumor growth. The various downstream effects of metformin-mediated AMPK activation in tumor growth inhibition include: (1) activation of the tuberous sclerosis complex (TSC) with inhibition of mammalian target of rapamycin (mTOR) activity, resulting in inhibition of protein synthesis and cell growth; (2) activation of p53 and p21 along with inhibition of cyclins, resulting in cell-cycle arrest; (3) inhibition of lipid and sterol biosynthetic pathways; (4) inhibition of sterol regulatory element-binding protein-1c (SREBP-1) by regulating its expression and phosphorylation, leading to down-regulation of fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC); (5) direct phosphorylation and inhibition of ACC; and (6) systemic effects on multiple organs such as reducing diabetes-associated cancers by improving glucose balance with reduced levels of growth factors such as insulin, insulin-like growth factor 1 (IGF-1) and leptin which can initiate and promote cancer growth with progression. Metformin had also been shown to reduce cancer events via AMPK-independent mechanisms [113,114] (adapted from reference [115,116]).