Schematic diagram of the proposed new mechanism by which metformin inhibits hepatic gluconeogenesis (42). Up or down arrows next to a metabolite or enzyme show the direction the concentration or activity changes in response to
metformin. Metformin (whose uptake into hepatocytes is promoted by the organic cation transporter [OCT1]) accumulates in mitochondria
where it inhibits Complex 1 of the respiratory chain, lowering cytoplasmic ATP and increasing ADP and AMP. AMP activates AMPK
but also inhibits adenylate cyclase, reducing effects of glucagon on cAMP and PKA and thus reducing the ability of PKA to
promote gluconeogenesis by phosphorylation of PFK2 and other targets regulating transcription of gluconeogenic genes. F16BP,
fructose-1,6-bisphosphate; F16BPase, fructose-1,6-bisphosphatase; F26BP, fructose-2,6-bisphosphate; G6Pase, glucose-6-phosphatase;
PFK1, 6-phosphofructo-1-kinase; PFK2, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase.