A purinergic mechanism underlying metformin regulation of hyperglycemia.

ABSTRACT: 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 μM. Here we report metformin, at 10-30 μM, 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 P2Y₂ receptors (P2Y₂R) suppresses PIP₃ production, compromising insulin-induced AKT activation while promoting hepatic glucose production. Furthermor

SUBMITTER: Senfeld J 

PROVIDER: S-EPMC10291329 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature