Figure 2. Metformin actions in metabolically relevant cell types.

Metformin's primary target in hepatocytes, adipocytes, and myocytes is the mitochondrion. In the liver, metformin inhibits respiratory chain complex I and mGPDH, both located in the inner mitochondrial membrane. Inhibition of complex I increases the AMP/ATP ratio, thereby activating AMPK, a central regulator of anabolic and catabolic pathways and of mitochondrial biogenesis. Inhibition of mGPDH causes elevated NADH concentrations that shift the equilibrium of the lactate dehydrogenase reaction to lactate, resulting in elevated lactate production and reduced gluconeogenic substrate pyruvate levels. In adipocytes and myocytes, AMPK activation leads to inactivation of TBC1D1/D4 proteins. This promotes insulin-independent translocation of GLUT4-containing vesicles from intracellular depots to the plasma membrane, thereby increasing GLUT4 concentration in the plasma membrane. Abbreviations: ACC – acetyl-coenzyme A carboxylase; AMPK – AMP-activated protein kinase; GLUT4 – glucose transporter 4; mGPDH – mitochondrial glycerophosphate dehydrogenase; PFKFP – 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase; PGC1α – peroxisome proliferator-activated receptor γ coactivator 1α; SREBP1c – sterol-regulatory element-binding protein 1c; STK11 – serine/threonine kinase 11; TBC1D1/D4 – TBC1 domain family members D1 and D4.