Fig. 6

Dairy milk exosomes and type 2 diabetes mellitus. In peripheral tissues (muscle and adipose tissue), miR-29b promotes insulin resistance via inhibiting the core protein dihydrolipoamide branched-chain acyltransferase (DBT) of branched-chain alpha-ketoacid dehydrogenase (BCKD), the rate limiting enzyme of branched-chain amino acid (BCAA) degradation. Resulting increases in intracellular BCAA levels enhance mTORC1-S6K1 activity. Overstimulated S6K1 phosphorylates and inhibits insulin-receptor substrate 1 (IRS-1) thereby decreasing insulin signaling and glucose transporter 1 (GLUT1) translocation to the cell membrane. In addition, miR-29b-mediated suppression of secreted protein acidic and rich in cysteine (SPARC) reduces GLUT4 activity. miR-29b-mediated attenuation of BCAA degradation increases BCAA-mTORC1-mediated insulin synthesis. miR-29b-mediated suppression of SPARC reduces insulin secretion. In addition, miR-148a-mediated suppression of V-Maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) in the β-cell reduces glucose-dependent insulin secretion. Continued miR-29b-mediated overstimulation of insulin synthesis and miR148a- and miR-29b-mediated impairment of insulin secretion enhances endoplasmic reticulum (ER) stress promoting β-cell apoptosis, the hallmark of type 2 diabetes mellitus