Metformin triggers PYY secretion in human gut mucosa

Abstract

Context:The anti-diabetic drug Metformin causes weight loss, but the underlying mechanisms are unclear. Recent clinical studies show that metformin increases plasma levels of the anorectic gut hormone, PYY, but whether this is through a direct effect on the gut is unknown. Objective:We hypothesised that exposure of human gut mucosal tissue to metformin would acutely trigger PYY secretion. Design, Setting, Participants, and Interventions:Mucosal tissue was prepared from 46 human colonic and 9 ileal samples obtained after surgical resection and ex vivo secretion assays performed. Tissue was exposed to metformin, as well as a series of other compounds as part of our mechanistic studies, in static incubations. Supernatant was sampled after 15 minutes. Main Outcome Measures:PYY levels in supernatant, measured using ELISA. Results:Metformin increased PYY secretion from both ileal (P < 0.05) and colonic (P < 0.001) epithelia. Both basal and metformin-induced PYY secretion were unchanged across BMI or in tissues obtained from individuals with type 2 diabetes. Metformin-dependent PYY secretion was blocked by inhibitors of the plasma membrane monoamine transporter (PMAT) and the serotonin transporter (SERT), as well as by an inhibitor of AMP kinase (AMPK). Conclusions:This is the first report of a direct action of metformin on the gut epithelium to trigger PYY secretion in humans, occurring via cell internalisation through PMAT and SERT and intracellular activation of AMP kinase. Our results provide further support that the role of metformin in the treatment of metabolic syndrome has a gut-based component.