The pathogenic role of persistent milk signaling in mTORC1- and milk-microRNA-driven type 2 diabetes mellitus

Abstract

Milk, the secretory product of the lactation genome, promotes growth of the newborn mammal. Milk delivers insulinotropic amino acids, thus maintains a molecular crosstalk with the pancreatic β-cell of the milk recipient. Homeostasis of β-cells and insulin production depend on the appropriate magnitude of mTORC1 signaling. mTORC1 is activated by branched-chain amino acids (BCAAs), glutamine, and palmitic acid, abundant nutrient signals of cow´s milk. Furthermore, milk delivers bioactive exosomal microRNAs. After milk consumption, bovine microRNA-29b, a member of the diabetogenic microRNA-29- family, reaches the systemic circulation and the cells of the milk consumer. MicroRNA-29b downregulates branchedchain α-ketoacid dehydrogenase, a potential explanation for increased BCAA serum levels, the metabolic signature of insulin resistance and type 2 diabetes mellitus (T2DM). In non-obese diabetic mice, microRNA-29b downregulates the antiapoptotic protein Mcl-1, which leads to early β-cell death. In all mammals except Neolithic humans, milk-driven mTORC1 signaling is physiologically restricted to the postnatal period. In contrast, chronic hyperactivated mTORC1 signaling has been associated with the development of age-related diseases of civilization including T2DM. Notably, chronic hyperactivation of mTORC1 enhances endoplasmic reticulum stress that promotes apoptosis. In fact, hyperactivated β-cell mTORC1 signaling induced early β-cell apoptosis in a mouse model. The EPIC-InterAct Study demonstrated an association between milk consumption and T2DM in France, Italy, United Kingdom, Germany, and Sweden. In contrast, fermented milk products and cheese exhibit an inverse correlation. Since the early 1950´s, refrigeration technology allowed widespread consumption of fresh pasteurized milk, which facilitates daily intake of bioactive bovine microRNAs. Persistent uptake of cow´s milk-derived microRNAs apparently transfers an overlooked epigenetic diabetogenic program that should not reach the human food chain.

Fig. (1)

Schematic working model representing the potential crosstalk bewteen milk signaling and persistent β-cell mTORC1 hyperactivation promoting endoplasmic reticulum (ER)-stress and early β-cell apoptosis. Milk is a rich source of branched-chain amino acids (BCAAs). Leucine (Leu) and glutamine (Gln) synergistically activate β-cell mTORC1. mTORC1 activation is important for insulin synthesis. Insulin synthesis is further promoted by whey-stimulated secretion of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1(GLP-1). Milk-derived exosomal microRNA-29b (miR29b) may represent a shutoff mechanism of mitochondrial BCAA catabolism that increases BCAA plasma levels enhancing BCAA-driven β-cell mTORC1 activation. Persistent milk-mediated β-cell mTORC1 activation promotes ER-stress leading to early β-cell apoptosis. ER-clearance is impaired by mTORC1-mediated inhibition of autophagy further promoting β-cell apoptosis. ER-stress in a vicious cycle via activating transcription factor 4 (ATF4)-mediated upregulation of L-type amino acid transporter (LAT) aug-ments leucine-mTORC1 signaling. Further enhancement of β-cell apoptosis may result from milk miR29b-mediated inhibition of anti-apoptotic Mcl-1. Milk miR-21-mediated inhibition of FoxO1 may increase β-cell proliferation and may increase oxidative stress further promoting β-cell apoptosis. See list of abbreviations.

Fig. (2)

Hazard ratios (HRs) (and 95% CIs) for the association of milk consumption with diabetes risk (highest compared with lowest quintile) per Eu-ropean country of the EPIC-InterAct Study (n=340,234) according to the Sluijs et al. [242] with permission the American Society of Nutrition. Notably, 80.3% of the EU population (France, Italy, UK, Germany, Sweden) exhibited an increased diabetes risk in relation to milk consump-tion, whereas 6.4% (Netherlands, Denmark) showed no correlation and 13.3% (Spain) exhibited an inverse association

Fig. (3)

Schematic representation of milk-mediated disturbances of β-cell homeostasis. Persistent milk signaling overactivates β-cell mTORC1 promot-ing endoplasmic reticulum (ER)-stress resulting in early β-cell apoptosis leading to type 2 diabetes. Metformin treatment attenuates nutrient (milk)-driven overstimulation of mTORC1. Rapamycin treatment inhibits mTORC1 resulting in β-cell suppression and diabetes. Long-term β-cell survial and optimized β-cell homeostasis requires an appropriate well balanced magnitude of β-cell mTORC1 signaling