Molecular Mechanism of Metformin in DM2- A New Hypothesis

Metformin, the antihyperglycaemic drug, though in use since 1957 eluded as to its mechanism of
action till date. There is some truth but not the whole truth, in even the much-favoured mechanisms of
AMP-stimulated protein kinase (AMPK) stimulation and inhibition of complex 1
of Electron Transport Chain (ETC), as there are objections, unresolved, as yet. Subsequent
innovative mechanisms, like gut- mediated responses-involving glucagon-like peptide {GLP 1 ) and
sodium-glucose transporter protein ( SGLT 1) or signalling pathways involving transcription factors
like a mammalian target of repamycine (mTOR C2), sirtuin 1 (SIRT 1) etc., and the recently proposed
brain-gut- liver axis fared no better. The obvious truth to be accepted is that probably no single
mechanism can explain all the observed phenomena. An attempt is made to rope in all mechanisms
into one, invoking the glucagon signalling pathway, by a non-AMPK, non-Complex1 inhibitory
mechanism by the proposed hypothesis. To this extent, new concepts like gate control concept and
Warburg- like effect in diabetes mellitus type2 (DM2) are proposed. It is conceptualised that deranged
glycolysis is at the root cause of the disturbed energy metabolism in DM 2 and the answer to restore
the same lies in a reversal of the factors that lead to derailed glycolysis. Besides, a brief recapitulation
of what is known is attempted, with emphasis on the bottlenecks of each of these mechanisms