The Hormetic Effect of Metformin: “Less Is More”?

Abstract

Metformin (MTF) is the first-line therapy for type 2 diabetes (T2DM). The euglycemic effect of MTF is due to the inhibition of hepatic glucose production. Literature reports that the principal molecular mechanism of MTF is the activation of 5′-AMP-activated protein kinase (AMPK) due to the decrement of ATP intracellular content consequent to the inhibition of Complex I, although this effect is obtained only at millimolar concentrations. Conversely, micromolar MTF seems to activate the mitochondrial electron transport chain, increasing ATP production and limiting oxidative stress. This evidence sustains the idea that MTF exerts a hormetic effect based on its concentration in the target tissue. Therefore, in this review we describe the effects of MTF on T2DM on the principal target organs, such as liver, gut, adipose tissue, endothelium, heart, and skeletal muscle. In particular, data indicate that all organs, except the gut, accumulate MTF in the micromolar range when administered in therapeutic doses, unmasking molecular mechanisms that do not depend on Complex I inhibition.

A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan

“…Collectively these data cast doubt as to the contribution of inhibition of complex 1 as the primary target and explanation for the therapeutic effects of metformin both as an anti-diabetic and as an anti-aging drug. This conclusion is also supported in reviews (133,142), and by clinical data from T2DM patients treated with metformin that show normal mitochondrial complex 1 respiration in skeletal muscle biopsies (143). As discussed below, it is important to consider the pharmacokinetic properties of metformin when extrapolating data from in vitro studies to potential benefits when used clinically.…”

Metformin: Is it a drug for all reasons and diseases?

“…has a short plasma half-life of approximately 4 h (h) (2-6 h) (Table 2) implying that cellular levels are rapidly lowered [92]. In contrast, low μM concentrations of metformin enhance complex 1 activity [52,79,81,84,86,[92][93][94][95][96]. Finally, concentrations of metformin as low as 5 μM inhibit gluconeogenesis in primary hepatocytes from mice without altering the ATP/AMP ratio [97].…”

Low-Dose Metformin as a Monotherapy Does Not Reduce Non-Small-Cell Lung Cancer Tumor Burden in Mice

“…Indeed, metformin has a relatively short half-life, a high rate of absorption in the small intestine, and a nearly complete clearance via the kidneys, supporting that in our conditions the bioavailability of metformin is limited and delivery to the tumor site is inadequate [ 39 , 40 ]. Furthermore, it is important to acknowledge that metformin has a hormetic response such that the concentration of metformin within a target tissue influences the mechanism of action, which was elegantly reviewed by Panfoli et al [ 41 ]. Therefore, the tissue concentration supporting the classical effects of metformin as an anti-diabetic drug, may differ from that necessary to alter the cellular and molecular signaling within a tumor.…”