Figure 2 Intracellular actions of metformin

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Figure 2 Intracellular actions of metformin Figure 2 | Intracellular actions of metformin. Metformin alters nutrient metabolism through insulin-dependent and insulin-independent effects that vary with the amount of drug exposure and the activity of insulin within different tissues. The intestine is exposed to high levels of metformin, which have insulin-independent effects, whereas liver and muscle are exposed to lower concentrations of metformin that influence the metabolic effects of insulin. Metformin can improve insulin sensitivity via effects on insulin-receptor signalling and post-receptor signalling pathways of insulin action. Metformin can alter cellular nutrient metabolism and energy production independently of insulin via suppression of the mitochondrial respiratory chain and activation of 5′ AMP-activated protein kinase (AMPK). ACC, acetyl-CoA carboxylase; FBPase, fructose-1,6-bisphosphatase; G6Pase, glucose-6-phosphatase; GLUT, glucose transporter isoform; hOCT1, organic cation transporter 1; IRS, insulin receptor substrate; LKB1, serine/threonine–protein kinase STK11; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PDK, 3-phosphoinositide-dependent protein kinase; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol-3,4-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PKB, protein kinase B; GPD-M, glycerol-3-phosphate dehydrogenase, mitochondrial. Tahrani, A. A. et al. (2016) Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus Nat. Rev. Endocrinol. doi:10.1038/nrendo.2016.86