Metabolic Action of Metformin

Abstract

Metformin, a cheap and safe biguanide derivative, due to its ability to influence metabolism, is widely used as a first-line drug for type 2 diabetes (T2DM) treatment. Therefore, the aim of this review was to present the updated biochemical and molecular effects exerted by the drug. It has been well explored that metformin suppresses hepatic glucose production in both AMPK-independent and AMPK-dependent manners. Substantial scientific evidence also revealed that its action is related to decreased secretion of lipids from intestinal epithelial cells, as well as strengthened oxidation of fatty acids in adipose tissue and muscles. It was recognized that metformin's supra-therapeutic doses suppress mitochondrial respiration in intestinal epithelial cells, whereas its therapeutic doses elevate cellular respiration in the liver. The drug is also suggested to improve systemic insulin sensitivity as a result of alteration in gut microbiota composition, maintenance of intestinal barrier integrity, and alleviation of low-grade inflammation.

Keywords: glucose metabolism; hepatic gluconeogenesis; lipid metabolism; metformin.

Figure 1

The fate of metformin in the human body. After oral ingestion, 50% of metformin is absorbed by passive diffusion, and the rest of the drug is transported by facilitated diffusion via PMAT and OCT1 transporters in intestinal enterocytes. Then, the drug leaves enterocytes via OCT1 and is transported to the liver via the portal vein where it reaches concentrations of 40–70 µM. Metformin enters the liver via OCT1 and OCT3 where it inhibits gluconeogenesis. The drug is not metabolized by the liver, but MATE1 expressed in hepatocytes participates in elimination of unchanged drug with the bile or in its transport with the blood to kidney. Then, metformin enters renal epithelial cells via OCT2. Next, the drug is secreted by renal MATE1 and MATE2 in unchanged form and eliminated with urine. Abbreviations: M, metformin; PMAT, plasma membrane monoamine transporter; OCT1, organic cation transporter 1; OCT2, organic cation transporter 2; OCT3, organic cation transporter 3; MATE 1, multidrug and toxin extrusion protein 1; MATE2, multidrug and toxin extrusion protein 2.

Figure 2

Metformin regulates the metabolism of lipids in enterocytes, L-cells, hepatocytes, and adipocytes. In the intestine, the drug initiates the expression of GLP-1 and its secretion via AMPK-independent and -dependent pathways in L cells. In enterocytes, metformin suppresses chylomicron storage and production via decreasing the levels of Apo-IV and Apo-48, as well as the synthesis of TG. In turn, in hepatocytes, metformin-dependent activated AMPK phosphorylates ACC and SREBP-1, leading to suppression of DNL and restoring CPT-1 activity. The drug also promotes the process of mitochondrial fission, leading to an increase in mitochondrial number and elevation of FA oxidation. The action of metformin in adipocytes contributes to increased uptake of FA and HSL activity, involving lipolysis. The drug also strengthens mitochondrial biogenesis via inducing PGC-1 signaling. Additionally, metformin activates AMPK, which also promotes mitochondrial fission. Lastly, the drug enhances oxidation of FA in adipocytes. Abbreviations: M, metformin; MAG, myelin-associated glycoprotein precursor; DAG, diacylglycerol; TG, triglycerides; ApoA-IV, apolipoprotein A-IV; ApoB-48, apolipoprotein B-48; MGAT, monoacylglycerol acyltransferase; DGAT, diglyceride acyltransferase; AMPK, 5’ adenosine monophosphate-activated protein kinase; PKA, protein kinase A; GLP-1, glucagon-like peptide-1; CAMPii, Ca²⁺/calmodulin-dependent protein kinase II; GSK-3β, glycogen synthase kinase-3 β; TCF7, transcription factor 7; MFF, mitochondrial fission factor; ACC, acetyl-CoA carboxylase; CPT1, carnitine palmitoyltransferase I; FA, fatty acid; FAS; DNL, de novo lipogenesis; SREBP1, sterol regulatory element-binding protein 1; malony-CoA, malonyl-coenzyme A; VLDL-TG, high-plasma very-low-density lipoprotein triglyceride; PGC1, peroxisome proliferation-activated receptor-gamma coactivator-1; HSL, hormone-sensitive lipase.

Figure 3

The improvement of systemic insulin sensitivity is a result of metformin-evoked microbiota alteration. In the intestine, the drug alters the microbiota composition, leading to reduced production of LPS and increased secretion of SCFAs. In turn, SCFAs and metformin-driven AMPK activation contribute to an improvement of the intestinal barrier, reducing the production of chylomicron, which in turn triggers a decreased level of LPS in circulation. In insulin-sensitive cells, the decreased level of LPS and low-grade inflammation lead to strengthening insulin signaling via decreased acetylation of IRS and phosphorylation of threonine and serine, as well as elevated PIP₃ levels. Abbreviations: M, metformin; SCFAs, short-chain fatty acids; LPS, lipopolysaccharides; TG, triglyceride; TJ, tight junction; AMPK, 5’ adenosine monophosphate-activated protein kinase; TLR4, Toll-like receptor 4; CD14, cluster of differentiation 14; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; IKKB, inhibitor of nuclear factor kappa-B kinase subunit beta; SHIP2, SH2 domain-containing inositol 5-phosphatase 2; PIP3, phosphatidylinositol(3,4,5)triphosphate; PTEN, phosphatase and tensin homolog; ER, endoplasmic reticulum; JNK, c-Jun N-terminal kinase; IRS, insulin receptor.