Melnik Bodo C
Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Am Finkenhügel 7A, D-49076 Osnabrück, Germany.
Nutr Metab (Lond). 2019 Dec 6;16:85. doi: 10.1186/s12986-019-0412-1. eCollection 2019.
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 -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 -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. -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 -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 -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.
自20世纪50年代以来，2型糖尿病（T2DM）的患病率稳步上升，这一时期冷藏巴氏杀菌牛奶广泛普及。母乳喂养可预防晚年T2DM的发生，而越来越多的流行病学证据强调了饮用牛奶在T2DM中的作用。最近在啮齿动物模型中的研究表明，在母乳喂养期间，胰腺β细胞代谢不成熟，通过激活雷帕霉素复合物1（mTORC1）的机制靶点和抑制AMP激活的蛋白激酶（AMPK）而优先增殖。断奶决定了β细胞的代谢转变，从具有低胰岛素分泌的增殖性、未成熟表型转变为具有葡萄糖刺激胰岛素分泌、较少增殖、mTORC1活性降低但AMPK活性增加的分化成熟表型。从这个角度提出的转化证据首次表明，牛奶miRNA转移的终止是这种代谢转变的驱动因素。miRNA-148a是AMPK以及磷酸酶和张力蛋白同源物的关键抑制剂，而磷酸酶和张力蛋白同源物是mTORC1的关键抑制剂。糖尿病患者的β细胞恢复到出生后的表型，mTORC1活性高而AMPK活性低，这可以解释为牛乳miRNA持续转移到饮用母乳的人身上。牛乳miRNA-148a显然促进β细胞去分化为未成熟的mTORC1高/AMPK低表型，导致胰岛素分泌功能受损、mTORC1驱动的内质网应激增加、自噬减少和早期β细胞凋亡。与巴氏杀菌牛奶不同，牛奶中的miRNA会被细菌发酵、煮沸和超高温处理灭活，目前的婴儿配方奶粉中也没有。持续的牛奶miRNA信号为T2DM的发病机制增添了新的视角，并解释了母乳喂养的保护作用，但持续饮用巴氏杀菌牛奶导致的牛奶miRNA持续信号具有致糖尿病作用。
