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.
Highlights
Type 2 diabetes mellitus (T2DM) will affect 500 million people worldwide by 2030 [1]
The use of MTF progressively expanded from diabetes to obesity, liver disease, and, cancer therapy
MTF is an example of hormesis, the dose–response phenomenon characterized by a low dose stimulation and high dose inhibition, resulting in an adaptive response to cellular metabolism variations
Summary
Type 2 diabetes mellitus (T2DM) will affect 500 million people worldwide by 2030 [1]. FXR is involved in ileal absorption of bile acids; its inhibition results in reduced bile acid absorption and consequent increased excretion in T2DM patients treated with MTF [58] It has been shown that MTF may increase the level of bile acids by decreasing the abundance of Bacteroides fragilis and of its bile salt hydrolase activity [94] Another mechanism through which MTF might improve glucose metabolism through the modulation of gut microbiota is by maintaining the intestinal barrier functionality. Metastatic colorectal cancer with reduced expression of MATE1 are more responsive to MTF [99] These findings suggest that MTF needs to reach high concentrations in cells to exert protective effects from colorectal cancer, and that inhibition of Complex I activity may have a role in mediating MTF’s benefits
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