Molecular Mechanisms of Metformin for Diabetes and Cancer Treatment

Abstract

Metformin has been the first-line drug treatment for hyperglycemia and insulin resistance for over 50 years. However, the molecular basis of its therapeutic role remained incompletely understood. Recent advances demonstrate that metformin could exert its glucose-lowering effect by multiple mechanisms, including activation of 5′-AMP-activated protein kinase, decreasing production of cyclic AMP, suppressing mitochondrial complex I of the electron transport chain, targeting glycerophosphate dehydrogenase, and altering the gut microbiome. In addition, epidemiological and clinical observation studies suggest that metformin reduced cancer risk in patients with type 2 diabetes and improved survival outcome of human cancers. Experimental studies have shown that this drug can inhibit cancer cell viability, growth, and proliferation through inhibiting mTORC1 signaling and mitochondrial complex I, suggesting that it may be a promising drug candidate for malignancy. Here, we summarize recent progress in studies of metformin in type 2 diabetes and tumorigenesis, which provides novel insight on the therapeutic development of human diseases.

Mitochondrial targets of metformin—Are they physiologically relevant?

“…Since upstream AMPK activator liver kinase B1 (LKB1) is known to act as potent tumor suppressor, possible link between metformin administration and reduced cancer incidence has been suggested and indeed proven by the first epidemiological study . Since then, anticancer effect of metformin has been demonstrated in various models in vivo as well as in vitro …”

“…5 Since then, anticancer effect of metformin has been demonstrated in various models in vivo as well as in vitro. 6,7 Although metformin belongs to widely prescribed drugs, its mechanism of action in both type II diabetes and cancer is still under investigation. Based on epidemiological studies, association between adiposity and increased risk of cancer has been proposed via deregulation of key pathways including insulin resistance, but the direct connection is missing.…”

Impact of metformin use on the outcomes of newly diagnosed diffuse large B‐cell lymphoma and follicular lymphoma

“…It exerts its antidiabetic effects by decreasing hepatic glucose production, increasing glucose use by peripheral tissues, and enhancing insulin sensitivity (Ikhlas & Ahmad, 2017). The primary molecular targets of metformin include Complex I of the mitochondrial electron transport chain (ETC) and the adenosine monophosphate (AMP)-activated protein kinase (AMPK) (Li et al, 2018a;Mallik & Chowdhury, 2018;Vancura et al, 2018). AMPK is a heterotrimeric serine/threonine protein kinase that plays a central role in metabolism and energy regulation by restricting anabolic processes while promoting catabolic processes (Ikhlas & Ahmad, 2017;Vancura et al, 2018).…”

“…Activation of AMPK and inhibition of mechanistic/ mammalian target of rapamycin complex 1 (mTORC1) are the main mechanisms underlying the potential antineoplastic effects of metformin (Li et al, 2018a;Mallik & Chowdhury, 2018;Vancura et al, 2018). The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/mTOR pathway is important for cell proliferation and survival in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), two of the most common types of non-Hodgkin lymphoma (NHL) (Majchrzak et al, 2014;Pongas & Cheson, 2016).…”

Metformin paradoxically worsens insulin resistance in SHORT syndrome

“…In contrast, mutation in insulin signalling causing the SHORT syndrome (PI3K) affects very immediate post-receptor steps of insulin signalling [3]. Recent evidence suggests that metformin might also exert an anti-cancer effects [10], that may also involve at least some partial blockade of PI3K/MAPK signaling pathway, that is also implicated in cell growth [11]. If metformin indeed partially inhibits PI3K, then we speculate that further inhibition of this already mutated enzyme might have prevented any beneficial effects of metformin, as these generally affect further i.e.…”