Metformin is one of the first-line and widely-used drugs in patients
with T2DM due to its safety profile, clinical efficacy and cheap cost.
It is clearly that metformin has benefits on lowering hyperglycemia and
diabetes-related complications in clinical use. However, the exact
mechanisms of metformin in multiple therapies are still blurred. The
classic effect of metformin is to reduce hepatic glucose production by
inhibiting gluconeogenesis in liver and increase glucose utilization in
peripheral tissues. Metformin targets mitochondrial respiratory chain
complex I to specifically reduce reactive oxygen species generation to
protect cells against oxidative stress-induced cell apoptosis. AMPK
complex is a key factor in the action of metformin; however it is
inconclusive that metformin activate AMPK directly or indirectly.
Furthermore, the liver-centered mechanism of metformin has been
challenged by that of gut microbiota alteration and GLP-1 secretion.
Actually, more and more studies showed that metformin act on gut
microbiota to exert anti-hyperglycemia effect. In addition, new emerging
evidence showed that metformin has off-label function on bone
metabolism, cancer inhibition and lifespan extension; however the
underlying mechanism of such properties of metformin still remains
elusive. Despite most of results are from cells in vitro and model
organisms, clinical trials have been recruited by institutes around the
world to verify the therapeutic effects of metformin in anti-tumor and
anti-aging. Taken together, in this review we provide a new perspective
on metformin and repurpose its novel and promising application in the
therapy of cancer, bone fracture healing and age-related diseases.