A purinergic mechanism underlying metformin regulation of hyperglycemia

Metformin, created in 1922, has been the first-line therapy for treating type 2 diabetes mellitus for almost 70 years; however, its mechanism of action remains controversial, partly because most prior studies used supratherapeutic concentrations exceeding 1 mM despite therapeutical blood concentrations of metformin being less than 40 mu M. Here we report metformin, at 10-30 mu M, blocks high glucose-stimulated ATP secretion from hepatocytes mediating its antihyperglycemic action. Following glucose administration, mice demonstrate increased circulating ATP, which is prevented by metformin. Extracellular ATP through P2Y(2) receptors (P2Y(2)R) suppresses PIP3 production, compromising insulin-induced AKT activation while promoting hepatic glucose production. Furthermore, metformin-dependent improvements in glucose tolerance are abolished in P2Y(2)R-null mice. Thus, removing the target of extracellular ATP, P2Y(2)R, mimics the effects of metformin, revealing a new purinergic antidiabetic mechanism for metformin. Besides unraveling long-standing questions in purinergic control of glucose homeostasis, our findings provide new insights into the pleiotropic actions of metformin.

Automated summary

Metformin, which has been the first-line therapy for diabetes for almost 70 years, has a controversial mechanism of action. A new study found that metformin blocks high glucose-stimulated ATP secretion, thus exerting its antihyperglycemic effect. The study also revealed that the purinergic antidiabetic mechanism of metformin involves the inhibition of P2Y(2) receptors, which is similar to the effects observed when these receptors are removed.