Title:The Pathogenic Role of Persistent Milk Signaling in mTORC1- and Milk- MicroRNA-Driven Type 2 Diabetes Mellitus
Volume: 11
Issue: 1
Author(s): Bodo C. Melnik
Affiliation:
Keywords:
Branched-chain amino acid dysmetabolism, β-cell apoptosis, endoplasmic reticulum stress, diabetogenic milkderived
microRNAs, mTORC1, 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.
