What is Metformin?

Abstract

Metformin is a medication used to treat type 2 diabetes. It is also used to prevent diabetes in people who are at high risk for the disease. Metformin works by affecting liver metabolism in several ways. First, it is taken up into hepatocytes by a protein called OCT1. Once inside cells, metformin accumulates in the mitochondria because of the difference in electric potential between the inside and outside of cells. Second, metformin inhibits a protein called Complex I, which is needed for making energy in the mitochondria. This inhibition decreases the amount of energy available to the cell, which activates a protein called AMPK. Third, AMPK also can be activated by a process that happens in lysosomes, which are organelles in cells that break down molecules. Fourth, when AMPK is activated, it decreases the production of fat in the liver and increases the breakdown of fat. This leads to a decrease in the amount of fat stored in the liver and an increase in the liver’s sensitivity to insulin. Fifth, AMPK also activates a protein called PDE4B, which decreases the level of a molecule called cAMP. Sixth, when cAMP levels are decreased, the activity of a protein called PKA is also decreased. PKA normally activates the genes that make enzymes needed for gluconeogenesis, but when its activity is decreased, these genes are not activated and gluconeogenesis does not occur. Finally, metformin also decreases the activity of the enzyme fructose-1,6-bisphosphatase, which is needed for gluconeogenesis.

Metformin way to act

Metformin is a medication used to treat type 2 diabetes. It is also used to prevent diabetes in people who are at high risk for the disease. Metformin works by affecting liver metabolism in several ways. First, it is taken up into hepatocytes by a protein called OCT1. Once inside cells, metformin accumulates in the mitochondria because of the difference in electric potential between the inside and outside of cells. Second, metformin inhibits a protein called Complex I, which is needed for making energy in the mitochondria. This inhibition decreases the amount of energy available to the cell, which activates a protein called AMPK. Third, AMPK also can be activated by a process that happens in lysosomes, which are organelles in cells that break down molecules. Fourth, when AMPK is activated, it decreases the production of fat in the liver and increases the breakdown of fat. This leads to a decrease in the amount of fat stored in the liver and an increase in the liver’s sensitivity to insulin. Fifth, AMPK also activates a protein called PDE4B, which decreases the level of a molecule called cAMP. Sixth, when cAMP levels are decreased, the activity of a protein called PKA is also decreased. PKA normally activates the genes that make enzymes needed for gluconeogenesis, but when its activity is decreased, these genes are not activated and gluconeogenesis does not occur. Finally, metformin also decreases the activity of the enzyme fructose-1,6-bisphosphatase, which is needed for gluconeogenesis.

Metformin affects liver metabolism in several ways. First, it is taken up into hepatocytes by a protein called OCT1. Once inside cells, metformin accumulates in the mitochondria because of the difference in electric potential between the inside and outside of cells. Second, metformin inhibits a protein called Complex I, which is needed for making energy in the mitochondria. This inhibition decreases the amount of energy available to the cell, which activates a protein called AMPK. Third, AMPK also can be activated by a process that happens in lysosomes, which are organelles in cells that break down molecules. Fourth, when AMPK is activated, it decreases the production of fat in the liver and increases the breakdown of fat. This leads to a decrease in the amount of fat stored in the liver and an increase in the liver’s sensitivity to insulin. Fifth, AMPK also activates a protein called PDE4B, which decreases the level of a molecule called cAMP. Sixth, when cAMP levels are decreased, the activity of a protein called PKA is also decreased. PKA normally activates the genes that make enzymes needed for gluconeogenesis, but when its activity is decreased, these genes are not activated and gluconeogenesis does not occur. Finally, metformin also decreases the activity of the enzyme fructose-1,6-bisphosphatase, which is needed for gluconeogenesis.

Detailed description from the science article:

The multiple mechanism via which metformin affects liver metabolism. Note that the possible effect of metformin on mitochondrial glycerophosphate dehydrogenase [7] has not been included. (1) Uptake of metformin into hepatocytes is catalysed by the organic cation transporter-1 (OCT1) [11]. Being positively charged, the drug accumulates in cells and, further, in the mitochondria because of the membrane potentials across the plasma membrane and the mitochondrial inner membrane [14]. (2) Metformin inhibits Complex I, preventing mitochondrial ATP production and, thus, increasing cytoplasmic ADP:ATP and AMP:ATP ratios (the latter by displacement of the adenylate kinase reaction); these changes activate AMPK [17]. (3) Alternatively, AMPK may be activated by a lysosomal mechanism, not shown in detail here but requiring Axin and late endosomal/lysosomal adaptor, MAPK and mTOR activator 1 (LAMTOR1) [27]. (4) Increases in AMP:ATP ratio also inhibit fructose-1,6-bisphosphatase (FBPase), resulting in the acute inhibition of gluconeogenesis [30], while also inhibiting adenylate cyclase and lowering cAMP production [32]. (5) Activated AMPK phosphorylates the ACC1 and ACC2 isoforms of ACC, inhibiting fat synthesis and promoting fat oxidation instead, thus reducing hepatic lipid stores and enhancing hepatic insulin sensitivity [34]. (6) AMPK also phosphorylates and activates the cAMP-specific 3′,5′-cyclic phosphodiesterase 4B (PDE4B), thus lowering cAMP by another mechanism [33]. (7) Glucagon-induced increases in cAMP activate cAMP-dependent protein kinase A (PKA), causing a switch from glycolysis to gluconeogenesis via phosphorylation and inactivation of PFKFB1, causing a decrease in fructose-2,6-bisphosphate (F2,6BP), an allosteric activator of phosphofructokinase (PFK) and inhibitor of fructose-1,6-bisphosphatase (FBPase). (8) PKA also phosphorylates and inactivates the liver isoform of the glycolytic enzyme pyruvate kinase (Pyr K) and (9) phosphorylates the transcription factor cAMP response element binding protein (CREB), thus inducing transcription of the genes encoding the gluconeogenic enzymes PEPCK and G6Pase. (10) Phosphorylation of CREB-regulated transcriptional co-activator-2 (CRTC2) by AMPK, or by AMPK-related kinases such as salt-inducible kinase 2 (SIK2), causes CRTC2 to be retained in the cytoplasm, antagonising the effects of PKA on the transcription of PEPCK and G6Pase [61, 62]. PKA inhibits SIK2 by direct phosphorylation at multiple sites [62]. Ac-CoA, acetyl-CoA; BPG, 1,3-bisphosphoglycerate; DHAP, dihydroxyacetone phosphate; FBP, fructose 1,6-bisphosphate; F6P, fructose 6-phosphate; G3P, glyceraldehyde 3-phosphate; G6P, glucose 6-phosphate; Ma-CoA, malonyl-CoA; OAA, oxaloacetate; PEP, phosphoenolpyruvate; 3PG, 3-phosphoglycerate

Metformin is a medication used to treat type 2 diabetes. It works by affecting the way the liver metabolizes sugar and fat, which leads to a decrease in the amount of sugar and fat stored in the liver. This in turn increases the liver’s sensitivity to insulin and decreases the amount of sugar produced by the liver.