The impact of persistent milk consumption in the pathogenesis of type 2 diabetes mellitus

Bodo C. Melnik and Gerd Schmitz

Background: Milk and sugar are excessively consumed in a Western diet. There is increasing epidemiological evidence that the intake of unfermented pasteurized cow´s milk is associated with an increased risk of type 2 diabetes mellitus (T2D). It is the intention of this review to provide translational biochemical evidence for milk´s diabetogenic mode of action. Milk proteins provide the highest amounts of branched-chain amino acids (BCAAs) and thus contribute to total BCAA intake, which enhances BCAA plasma levels associated with increased risk of T2D. The consumption of pasteurized milk raises plasma levels of miRNA-29b, which is a diabetogenic miRNA promoting insulin resistance (IR). miRNA29b inhibits the activity of branched-chain α-keta acid dehydrogenase, the rate limiting enzyme of BCAA catabolism, which is impaired in patients with IR and T2D. Milk consumption stimulates mTORC1 activity and increases insulin synthesis. β-cell mTORC1 is overactivated in T2D patients resulting in impaired autophagy which enhances endoplasmic reticulum (ER) stress associated with a greater risk of early β-cell apoptosis,

the pathogenic hallmark of T2D. Chronic insulinotropic action of milk-derived BCAAs, IR-

promoting mTORC1 overactivity, and miRNA-29b signaling combined with excessive glucose-mediated insulin secretion overburden β-cell insulin homeostasis. Epidemiological and translational evidence identifies continued milk intake as a promoter of T2D, the most common metabolic disease of Western civilization.

Keywords: Branched-chain amino acids, branched-chain 𝛼-keto acid dehydrogenase, diabetes, mellitus type 2, insulin resistance, milk, miRNA-29b, mechanistic target of rapamycin complex 1.

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Milk Exosomal microRNAs: Postnatal Promoters of β Cell Proliferation but Potential Inducers of β Cell De-Differentiation in Adult Life

Bodo C. Melnik and Gerd Schmitz

Pancreatic β cell expansion and functional maturation during the birth-to-weaning period is driven by epigenetic programs primarily triggered by growth factors, hormones, and nutrients provided by human milk. As shown recently, exosomes derived from various origins interact with β cells. This review elucidates the potential role of milk-derived exosomes (MEX) and their microRNAs (miRs) on pancreatic β cell programming during the postnatal period of lactation as well as during continuous cow milk exposure of adult humans to bovine MEX. Mechanistic evidence suggests that MEX miRs stimulate mTORC1/c-MYC-dependent postnatal β cell proliferation and glycolysis, but attenuate β cell differentiation, mitochondrial function, and insulin synthesis and secretion. MEX

miR content is negatively affected by maternal obesity, gestational diabetes, psychological stress, caesarean delivery, and is completely absent in infant formula. Weaning-related disappearance of MEX miRs may be the critical event switching β cells from proliferation to TGF-β/AMPK-mediated cell differentiation, whereas continued exposure of adult humans to bovine MEX miRs via intake of pasteurized cow milk may reverse β cell differentiation, promoting β cell de-differentiation. Whereas MEX miR signaling supports postnatal β cell proliferation (diabetes prevention), persistent bovine MEX exposure after the lactation period may de-differentiate β cells back to the postnatal phenotype (diabetes induction).

Keywords: beta-cell; diabetes mellitus; milk exosome; microRNA; beta-cell de-differentiation; beta-cell, identity; proliferation

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Milk exosomal miRNAs: potential drivers ofAMPK-to-mTORC1 switching in β-cell de-differentiation of type 2 diabetes mellitus

Bodo C. Melnik

Type 2 diabetes mellitus (T2DM) steadily increases in prevalence since the 1950’s, the period of widespread distribution of refrigerated pasteurized cow’s milk. Whereas breastfeeding protects against the development of T2DM in later life, accumulating epidemiological evidence underlines the role of cow’s milk consumption in T2DM. Recent studies in rodent models demonstrate that during the breastfeeding period pancreatic β-cells are metabolically immature and preferentially proliferate by activation of mechanistic target of rapamycin complex 1 (mTORC1) and suppression of AMP-activated

protein kinase (AMPK). Weaning determines a metabolic switch of β-cells from a proliferating, immature phenotype with low insulin secretion to a differentiated mature phenotype with glucose-stimulated insulin secretion, less proliferation, reduced mTORC1- but increased AMPK activity. Translational evidence presented in this perspective implies for the first time that termination of milk miRNA transfer is the driver of this metabolic switch. miRNA-148a is a key inhibitor of AMPK and phosphatase and tensin homolog, crucial suppressors of mTORC1. β-Cells of diabetic patients return to the postnatal phenotype with high mTORC1 and low AMPK activity, explained by continuous transfer of bovine milk miRNAs to the human milk consumer. Bovine milk miRNA-148a apparently promotes β-cell de-differentiation to the immature mTORC1-high/AMPK-low phenotype with functional impairments in insulin secretion, increased mTORC1-driven endoplasmic reticulum stress, reduced autophagy and early β-cell apoptosis. In contrast to pasteurized cow’s milk, milk’s miRNAs are inactivated by bacterial fermentation, boiling and ultra-heat treatment and are missing in current infant formula. Persistent milk miRNA signaling adds a new perspective to the pathogenesis of T2DM and explains the protective role of breastfeeding but the diabetogenic effect of continued milk miRNA signaling by persistent consumption of pasteurized cow’s milk.

Keywords: AMP-activated protein kinase, Beta-cell de-differentiation, Beta-cell metabolic switch, Diabetes mellitus type 2, Estrogen-related receptor gamma, Exosome, miRNA-148a, Mechanistic target of rapamycin complex 1, Pasteurized milk, Weaning

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