PIK3R4 and metabolic syndrome: Interference with the expression of the regulatory subunit in the class III PI3K complex, Vps15, results in three novel and yet unreported outcomes: (i) defects of IR degradation and increased Akt signalling accompanied by profound perturbations in endocytic trafficking; (ii) blunted gluconeogenesis concomitant with nuclear exclusion of FoxO1 transcription factor and defects in FoxO1-dependent gene expression; and (iii) amelioration of metabolic syndromes in genetic and diet-induced animal models.