REVIEW article
Front. Nutr.
Sec. Nutrition and Metabolism
Volume 12 - 2025 | doi: 10.3389/fnut.2025.1652297
This article is part of the Research TopicHuman Milk, Nutrition and Infant Development, Volume IIView all 11 articles
Diabetes-preventive molecular mechanisms of breast versus formula feeding: New insights into the impact of milk on stem cell Wnt signaling
Provisionally accepted
Bodo Melnik1
Ralf Weiskirchen2*
Sabine Weiskirchen2
WOLFGANG RICHARD STREMMEL3
Swen M John1
Claus - Leitzmann4
Gerd Schmitz5- 1University of Osnabrück, Osnabrück, Germany
- 2RWTH Aachen University, Aachen, NRW, Germany
- 3Praxis for Internal Medicine, Baden-Baden, Germany
- 4Justus-Liebig-Universitat Giessen, Giessen, Germany
- 5Universitat Regensburg, Regensburg, Germany
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Human milk serves as a transmitter for epigenetic programming involved in postnatal tissue development and organ maturation of the infant. In contrast to formula feeding (FF), prolonged breastfeeding (BF) has been associated with diabetes-preventive effects. Polymorphisms of the transcription factor 7-like 2 (TCF7L2), the key downstream effector of Wingless (Wnt) signaling, increase the risk of diabetes mellitus. Wnt signaling is crucial for β-cell development and proliferation. However, there is limited information regarding Wnt/β-catenin/TCF7L2-dependent effects of BF versus FF on postnatal β-cell progenitor cell development, β-cell proliferation and βcell mass expansion. The objective of our literature review is to collect and analyze data to provide translational evidence that different components of human milk promote Wnt signaling. We will specifically focus on the variations in Wnt signaling in enteroendocrine L-cells and pancreatic β-cells in response to either FF or BF. FF-induced overstimulation of mTORC1 may suppress Wnt gene expression through S6K1-mediated histone H3K27 trimethylation (H3K27me3). Moreover, the absence of milk exosomal miRNAs in formula that target mRNAs of crucial Wnt inhibitors, as well as reduced levels of eicosapentaenoic acid and glutamine in formula, may further hinder appropriate Wnt signaling, negatively impacting intestinal stem cells, enteroendocrine L-cells and potentially βcell progenitor cells. Overall, the evidence presented supports the conclusion that FF has a detrimental impact on the Wnt/β-catenin/TCF7L2-regulated enteroendocrine-islet axis, disrupting proper β-cell maturation and proliferation. We propose that human milk, compared to formula, offers optimized conditions for physiological Wnt signaling promoting adequate neonatal β-cell mass expansion, which could explain the early diabetes-preventive effects of prolonged BF.
Keywords: breastfeeding, Diabetes Mellitus, milk exosome, microRNA, formula feeding, Wingless signaling, β-cell, Diabetes Prevention
Received: 23 Jun 2025; Accepted: 11 Jul 2025.
Copyright: © 2025 Melnik, Weiskirchen, Weiskirchen, STREMMEL, John, Leitzmann and Schmitz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ralf Weiskirchen, RWTH Aachen University, Aachen, 52074, NRW, Germany
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