Metformin, a well-known anti-diabetic agent, is very effective in lowering
blood glucose in patients with
type 2 diabetes with minimal side-effects.
Metformin is also being recommended in the treatment of
obesity and
polycystic ovary syndrome.
Metformin elicits its
therapeutic effects mainly via activation of
AMP-activated kinase (AMPK) pathway. Renal cells under hyperglycemic or proteinuric conditions exhibit inactivation of cell defense mechanisms such as AMPK and autophagy, and activation of pathologic pathways such as
mammalian target of rapamycin (mTOR), endoplasmic reticulum (ER) stress, epithelial-to-mesenchymal transition (EMT), oxidative stress, and
hypoxia. As these pathologic pathways are intertwined with AMPK signaling, the potential benefits of
metformin therapy in patients with
type 2 diabetes would extend beyond its anti-hyperglycemic effects. However, since
metformin is eliminated unchanged through the kidneys and some studies have shown the incidence of
lactic acidosis with its use during severe renal dysfunction, the use of
metformin was contraindicated in patients with renal disease until recently. With more studies indicating the relatively low incidence of
lactic acidosis and revealing the additional benefits with
metformin therapy, the US FDA has now approved
metformin to be administered in patients with established renal disease based on their renal function. The purpose of this review is to highlight the various mechanisms by which
metformin protects renal cells that have lost its functionality in a diabetic or non-diabetic setting and to enlighten the advantages and therapeutic potential of
metformin as a nephroprotectant for patients with
diabetic nephropathy and other non-diabetic forms of
chronic kidney disease. J. Cell. Physiol. 232: 731-742, 2017. © 2016 Wiley Periodicals, Inc.