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.Method:The main aim of this review is to explore the recent implications of metformin in hepatic
gluconeogenesis, AMPKs, and SHIP2 and subsequently to elucidate the metformin action across
intestine and gut microbiota. We have searched PubMed, google scholar, Medline, eMedicine, National
Library of Medicine (NLM), clinicaltrials.gov (registry), and ReleMed for the implications
of metformin with its updated role in AMPKs, SHIP2, and hepatic gluoconeogenesis, and gut microbiota.
In this review, we have described the efficacy of metformin as a drug repurposing strategy
in modulating the role of AMPKs and lysosomal-AMPKs, and controversies associated with
metformin.Result: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 doses, 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.Conclusion:In addition, new exciting mechanisms suggest the role of metformin in promoting
beneficial gut microbiome and gut health; metformin regulates duodenal AMPK activation, incretin
hormone secretion, and bile acid homeostasis to improve intestinal glucose absorption and
utilization.
