Fig. 1

a Milk exosome-mediated miRNA signaling of pancreatic β-cells during physiologic breastfeeding and persistence of bovine milk-derived miRNA signaling by continued consumption of pasteurized cow’s milk. miRNA-148a suppresses AMPK and PTEN. miRNA-29b inhibits the catabolism of branched-chain amino acids (BCAAs). Reduced AMPK- and PTEN activity combined with increased BCAA levels activate mTORC1, which promotes β-cell proliferation and mass expansion. miRNA-148a together with miRNA-130a suppress the transcription factor complex EER γ /PGC1 α, which controls multiple mitochondrial genes involved in ATP production required for glucose-stimulated insulin secretion (GSIS). miRNA-29b suppresses ONECUT2, an inhibitor of granuphilin resulting in enhanced suppression of GSIS. miRNA-29b suppresses DNMT3A increasing the expression of “forbidden” genes of mature β-cells such as HK1 and LDHA. b Weaning terminates milk miRNA signaling. The disappearance of miRNA-148a enhances the activity of AMPK and PTEN resulting in increased suppression of mTORC1, whereas AMPK-dependent gene-regulation is upregulated. EER γ /PGC1 α activates mitochondrial genes involved in ATP production which in combination with ONECUT2-mediated granuphilin suppression enhance GSIS. However, this mature β-cell phenotype de-differentiates again by persistent intake of bovine milk exosomes