Metformin inhibits basal secretion from the pituitary gland of growth hormone, adrenocorticotropic hormone, follicle stimulating hormone, and expression of proopiomelanocortin, which in part accounts for its insulin-sensitizing effect with multiple actions on tissues including the liver, skeletal muscle, endothelium, adipose tissue, and the ovaries. The average patient with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one-third.Activation of AMPK was required for metformins inhibitory effect on liver glucose production. AMPK is an enzyme that plays an important role in insulin signalling, whole-body energy balance, and the metabolism of glucose and fats. AMPK activation was required for an increase in the expression of small heterodimer partner, which in turn inhibited the expression of the hepatic gluconeogenic genes phosphoenolpyruvate carboxykinase and glucose 6-phosphatase. Metformin is frequently used in research along with AICA ribonucleotide as an AMPK agonist. The mechanism by which biguanides increase the activity of AMPK remains uncertain: metformin increases the concentration of cytosolic adenosine monophosphate (AMP) (as opposed to a change in total AMP or total AMP/adenosine triphosphate) which could activate AMPK allosterically at high levels; a newer theory involves binding to PEN-2. Metformin inhibits cyclic AMP production, blocking the action of glucagon, and thereby reducing fasting glucose levels.
Interactions
The H2-receptor antagonist cimetidine causes an increase in the plasma concentration of metformin by reducing clearance of metformin by the kidneys; both metformin and cimetidine are cleared from the body by tubular secretion, and both, particularly the cationic (positively charged) form of cimetidine, may compete for the same transport mechanism. A small double-blind, randomized study found the antibiotic cephalexin to also increase metformin concentrations by a similar mechanism; theoretically, other cationic medications may produce the same effect.Metformin also interacts with anticholinergic medications, due to their effect on gastric motility. Anticholinergic drugs reduce gastric motility, prolonging the time drugs spend in the gastrointestinal tract. This impairment may lead to more metformin being absorbed than without the presence of an anticholinergic drug, thereby increasing the concentration of metformin in the plasma and increasing the risk for adverse effects. Pharmacology
Mechanism of action
The molecular mechanism of metformin is not completely understood. Multiple potential mechanisms of action have been proposed: inhibition of the mitochondrial respiratory chain (complex I), activation of AMP-activated protein kinase (AMPK), inhibition of glucagon-induced elevation of cyclic adenosine monophosphate (cAMP) with reduced activation of protein kinase A (PKA), complex IV–mediated inhibition of the GPD2 variant of mitochondrial glycerol-3-phosphate dehydrogenase (thereby reducing glycerol-derived hepatic gluconeogenesis), and an effect on gut microbiota. Metformin also exerts an anorexiant effect in most people, decreasing caloric intake. Metformin decreases gluconeogenesis (glucose production) in the liver.