Introduction:Metformin, a biguanide on the WHO’s list of essential medicines has a
long history of 50 years or more in treating hyperglycemia, and its therapeutic saga continues beyond
diabetes treatment. Glucoregulatory actions are central to the physiological effects of metformin;
surprisingly, the precise mechanism with which metformin regulates glucose metabolism is
not thoroughly understood yet.Methods:Research suggests that biguanide exhibits hormetic effects depending on the concentrations
used (micromolar to millimolar). The primary mechanism attributed to metformin action is
the inhibition of mitochondrial complex I, and subsequent reduction of cellular energy state, as observed
with increased AMP or ADP ratio, thereby metformin can also activate the cellular energy
sensor AMPK to inhibit hepatic gluconeogenesis. However, new mechanistic models have been
proposed lately to explain the pleiotropic actions of metformin; at low dose, metformin can activate
lysosomal-AMPK via the AXIN-LKB1 pathway. Conversely, in an AMPK-independent
mechanism, metformin-induced elevation of AMP suppresses adenylate cyclase and glucagon-activated
cAMP production to inhibit hepatic glucose output by glucagon. Metformin inhibits mitochondrial
glycerophosphate dehydrogenase; mGPDH, and increases the cytosolic NADH/NAD+,
affecting the availability of lactate and glycerol for gluconeogenesis. Metformin can inhibit Src homology
2 domain-containing inositol 5-phosphatase 2; SHIP2 to increase the insulin sensitivity
and glucose uptake by peripheral tissues. In addition, new exciting mechanisms suggest the role of
metformin in promoting beneficial gut microbiome and gut health. Metformin regulates duodenal
AMPK activation, incretin harmone secretion and bile acid homeostasis to improve intestinal glucose
absorption and utilization.Results:Research suggests that biguanide exhibits hormetic effects depending on the concentrations
used (micromolar to millimolar). The primary mechanism attributed to metformin action is
the inhibition of mitochondrial complex I, and subsequent reduction of cellular energy state, as observed
with increased AMP or ADP ratio, thereby metformin can also activate the cellular energy
sensor AMPK to inhibit hepatic gluconeogenesis. However, new mechanistic models have been
proposed lately to explain the pleiotropic actions of metformin; at low dose, metformin can activate
lysosomal-AMPK via the AXIN-LKB1 pathway. Conversely, in an AMPK-independent
mechanism, metformin-induced elevation of AMP suppresses adenylate cyclase and glucagon-activated
cAMP production to inhibit hepatic glucose output by glucagon. Metformin inhibits mitochondrial
glycerophosphate dehydrogenase; mGPDH, and increases the cytosolic NADH/NAD+,
affecting the availability of lactate and glycerol for gluconeogenesis. Metformin can inhibit Src homology
2 domain-containing inositol 5-phosphatase 2; SHIP2 to increase the insulin sensitivity
and glucose uptake by peripheral tissues. In addition, new exciting mechanisms suggest the role of
metformin in promoting beneficial gut microbiome and gut health. Metformin regulates duodenal
AMPK activation, incretin harmone secretion and bile acid homeostasis to improve intestinal glucose
absorption and utilization.Conclusion:The proper understanding of the key regulators of metformin actions is of utmost importance
to enhance its pleotropic benefits on diabetes and beyond.
