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 branched-chain 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 anti-apoptotic 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 sig-naling 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.

Milk MicroRNAs in Health and Disease

“…Milk microRNAs are found in all milk fractions and other dairy preparations and are ingested by infants or adult consumers on a daily basis (Melnik, ; Oh et al., ). Without protection, milk microRNAs would be degraded during digestion or by the high levels of RNAse found in milk (Gupta et al., ; Ramaswamy et al., ) resulting in a very poor bioaccessibility.…”

“…Because EVs are the main carrier of microRNAs, such models for milk microRNA bioavailability studies are very limited. Other studies experimented deficiencies in sample conservation (for example, dry ice loss), thus limiting the interpretations of the negative results (Laubier et al., ; Melnik, ; Melnik & Schmitz, ; Melnik et al., , ; Title et al., ).…”

Potential relevance of microRNAs in inter-species epigenetic communication, and implications for disease pathogenesis

“…Moreover bovine milk exosomal miR-21 and miR-29b could be relevant in obesity, insulin resistance and type 2 diabetes mellitus via the nutrient sensitive mechanistic target of rapamycin complex 1 (mTORC1) 69,70 and other pathways such as the 71 miR-29b might activate mTORC1 by increasing the amount of intracellular branched-chain amino acids via inhibiting the enzyme responsible for their catabolism. 72 (Fig.…”

Milk consumption does not prevent but induces type 2 diabetes

“…Furthermore, it is noteworthy to mention that pasteurized milk provides bioavailable exosomal microRNAs including the diabetogenic microRNA‐29b . MicroRNA‐29b serum levels significantly increase after consumption of commercial pasteurized milk .…”

“…Furthermore, it is noteworthy to mention that pasteurized milk provides bioavailable exosomal microRNAs including the diabetogenic microRNA‐29b . MicroRNA‐29b serum levels significantly increase after consumption of commercial pasteurized milk . MicroRNA‐29b targets and suppresses the expression of dihydrolipoamide branched‐chain transacylase (DBT), the functionally important core protein of branched‐chain α ‐ketoacid dehydrogenase (BCKD), and the key enzyme of BCAA catabolism.…”