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Perinatal Factors Disturbing MEX miR-Regulated β Cell Homeostasis: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor: Bodo C. Melnik , Gerd Schmitz
The perinatal period is a time of fast physiological changes dependent on epigenetic programming. Adverse events may lead to epigenetic changes, with implications for health and disease. Epigenetic alterations have been linked to early life environmental stressors, including mode of delivery, famine, psychosocial stress, severe institutional deprivation and childhood abuse. Recent evidence points to an intensive exosome cross-talk between pancreatic β-cells and towards β-cells by transmitted exosomes from adipocytes, skeletal muscle cells, macrophages and T-lymphcytes. It is thus conceivable that milk exosomes (MEX) of human breast milk and their microRNA (miR) cargo also affect postnatal β-cells and promote their proliferation and mass expansion. Translational evidence indicates that human MEX miRs enhance mTORC1/c-Myc-driven β-cell proliferation. It is a matter of concern that maternal obesity, gestational diabetes, caesarean delivery and especially MEX-deficient infant formula feeding disturb physiological MEX miR signalling during the postnatal period thereby increasing the risk of type 2 diabetes later in life. In all mammals, MEX miR signalling fades after weaning. However, humans, who regularly consume pasteurized cow milk are continuously exposed to bioavailable bovine MEX miRs, which are identical in nucleotide sequence with human MEX miRs. Circumstantial evidence supports the view that bovine MEX miRs promote β-cell dedifferentiation back to the mTORC1-driven neonatal immature phenotype with reduced glucose-stimulated insulin secretion. MEX miR signalling, beneficial for the immature postnatal β-cell, turns into a pathogen for the mature adult β-cell. The human consumer should not be exposed to diabetogenic MEX and their miRs after the weaning period. Thus, the elimination of bovine MEX and their bioactive miRs is a promising approach for the prevention of type 2 diabetes and other MEX-related diseases of civilization.
  • milk exosome
  • microRNA
  • beta-cell de-differentiation

1. Preterm Birth

Human MEX miR expression patterns also respond to preterm birth conditions. Kahn et al. [1] demonstrated that the expression MEX miR-22 and miR-148a are significantly upregulated in MEX of mothers giving birth to preterm infants compared to term infants. Shiff et al. [2] confirmed that the expression of miR-148a was higher in the colostrum of preterm than in full-term human milk, whereas miR-320 was more highly expressed in the colostrum of full-term than in preterm human milk.
Preterm MEX miR composition may influence early postnatal development of the pancreatic β-cells of preterm infants. Remarkably, MECP2 is a highly conserved target of miR-22, miR-148a, and miR-30 [3][4]. MECP2 is important for gene silencing and guides DNMT1 to CpG sides for DNA methylation [5], which generally suppresses gene transcription [6]. Thus, preterm MEX miR-22 and miR-148a via targeting MECP2 and DNMT1, respectively, may suppress gene promoter methylation and thus promote gene transcription, a potential mode of action accelerating β cell growth of the preterm infants. In contrast, inhibition of miR-22 in primary cultures of human subcutaneous adipocytes resulted in increased lipid oxidation, mitochondrial activity, and energy expenditure. These effects may be mediated through activation of target genes such as KDM3A, KDM6B, PPARA, PPARGC1B, and SIRT1, which are involved in lipid catabolism, thermogenesis, and glucose homeostasis [7][8]. MiR-22 reduces the expression PGC-1α, the co-transcription factor of ERRγ, synergistically promoting mitochondrial biogenesis. It has been shown in hepatocytes that inhibition of miR-22 activates AMPK [9]. In muscle cells, miR-22 inhibits AMPK/SIRT1/PGC-1α signaling [10][11]. In murine models and primary brown adipocytes, miR-22 activates mTORC1 signaling by directly suppressing TSC1 and HIF1AN, promoting glycolysis, and maintaining thermogenesis [12]. HIF1AN is also a predicted target of miR-148a [13]. The thermogenic activity of miR-22 is of critical importance for the survival of premature infants, and apparently miR-22 via suppressing AMPK and activating mTORC1 may promote β cell proliferation and glycolytic activity of the premature neonatal β cells [12]. Of note, VHL, which forms a complex with HIF1AN on the promoter of HIF-1α, represses HIF-1α transcriptional activity [14]. VHL mRNA is a direct target of miR-21 [15][16][17][18][19], a signature miR of human and bovine milk [20][21][22][23][24][25]. Deletion of VHL protein in β cells resulted in HIF-1α activation, leading to increased anaerobic glycolysis with impaired GSIS [26], the postnatal metabolic profile of proliferating and functionally immature β cells.
Furthermore, miR-22 targets TP53 [27], and thus augments p53-dependent glycolysis [28][29][30], which promotes the anabolic and biosynthesis of the critical components required for cell growth [31]. Fortified MEX miR-22- and miR-148a signaling of preterm milk may thus enhance glycolysis and proliferation of β cells to compensate for the prematurity of β cells. Moreover, MEX miR-148a/miR-22-mediated suppression of HIF1AN may attenuate postnatal HIF-1α-regulated β cell glucose sensing [26].
Whole milk collected within month 2 of lactation from mothers of preterm infants showed stable expression of miR-16 and miR-21 [32]. Notably, miR-16-5p inhibits the apoptosis of high glucose-induced pancreatic β cells via targeting of chemokine with CXC motif ligand 10 [33]. Circulating serum levels of miR-16-5p were upregulated in women with gestational diabetes [34]. Remarkably, miR-16-5p directly targets sestrin 1 (SESN1) [35], whereas miR-148a-3p converges with miR-16-5p in targeting sestrin 2 (SESN2) [36]. The p53 target genes sestrin 1 and sestrin 2 connect genotoxic stress and mTORC1 signaling [37]. Sestrin 1 and sestrin 2 activate AMPK phosphorylating TSC2 and stimulate its GAP activity, thereby inhibiting mTORC1 [37]. Furthermore, sestrins can bind the mTORC1-regulating GATOR2 protein complex, which was postulated to control the trafficking of mTORC1 to lysosomes [38]. Sestrin 2 inhibits mTORC1 activity via GATOR regulation and inhibits mTORC1 lysosomal localization via a Rag-dependent mechanism [39]. Sestrin 2-GATOR2-GATOR1-RagB signaling mediates the stress-dependent suppression of mTORC1 activity [40]. Sestrins function as guanine nucleotide dissociation inhibitors for Rag GTPases to control mTORC1 signaling [41] and regulate the localization of mTORC1 in response to amino acids [42][43].
In premature infants, plasma insulin levels are increased by amino acid administration, but glucose infusion is ineffective in stimulating insulin release [44]. Notably, protein levels in colostrum and mature human milk are increased in mothers delivering preterm infants compared to the protein content of term infants [45][46]. Apparently, adaptations of maternal milk protein content and MEX miR composition via suppression of sestrin-AMPK signaling may accelerate compensatory mTORC1-dependent β cell growth of the preterm infant.

2. Maternal Stress during Pregnancy

Maternal stress is associated with adverse child health [47]. Bozack et al. [48] studied the associations between maternal lifetime stressors and negative events in pregnancy and MEX/EV miRs. The expression level of 8 and 17 exosome/EV miRs was associated with Life Stressor Checklist-Revised Survey (LSCR) and Negative Life Event (NLE) scores, respectively. Among the primary miRs associated with LSCR scores was miR-155, whereas miR-96 was associated with increased NLE scores, respectively [48]. Notably, MAFB and PTEN are direct targets of miR-155 [49][50]. MiR-96 directly targets AKT1S1 [51], the gene encoding proline-rich AKT substrate 40-KD, which functions as a negative regulator of mTOR kinase [52][53][54][55][56].

3. Maternal Obesity

Maternal obesity is a major risk factor of T2DM of the offspring [57][58][59][60][61]. The first 1000 days of life have been postulated to be the key period for T2DM prevention [59]. Maternal obesity, the human milk metabolome, and human milk fat showed associations with infant body composition and postnatal weight gain [58][62][63]. Of note, maternal obesity modifies the concentrations of key MEX miRs [64]. In the overweight/obese group of women compared to the normal weight group at 1 month after birth, the abundance of MEX miR-148a and miR-30b was lower by 30% and 42%, respectively [64]. In addition, the levels of miR-30b, let-7a and miR-378 in colostrum were negatively correlated with maternal pre-pregnancy BMI, whereas in mature milk, let-7a was negatively correlated with maternal weight late in the pregnancy [65]. Reduced MEX miR-148a and miR-30b levels in the milk of obese mothers may thus negatively affect MEX miR-mediated β cell proliferation.

4. Gestational Diabetes Mellitus

Epidemiological and epigenetic evidence points to an increased risk of T2DM in the offspring of mothers with gestational diabetes mellitus (GDM) [66][67][68][69][70][71][72]. Suckling of normal Wista rats by a diabetic Goto-Kakizaki rat had a negative impact on metabolic programming of β cell of newborn rats associated with a reduction of β cell mass, resulting in long-term glucose intolerance [73]. GDM changes the metabolomes of human colostrum, transition milk, and mature milk [74][75]. Notably, Shah et al. [76] observed reduced levels of MEX miR-148a, miR-30b, let-7a, and let-7d in the milk from mothers with GDM.

5. Maternal Diet

The maternal diet has an influence on the levels of human milk miRs. Hicks et al. [77] reported that nearly half of abundant miRs were impacted by diet. Of interest, eicosapentaenoic acid via binding to free fatty acid receptor 4 (FFAR4) enhances the expression of miR-30b and miR-378 [78]. Remarkably, levels of miR-30b and miR-378 in the colostrum exhibit a negative relation to maternal pre-pregnancy BMI [65]. Preferential intake of n-3 PUFA may thus modify the m6A RNA methylation status of the β cell via miR-30b-mediated suppression of FTO [79]. Consumption of the “Cafeteria diet”—a standardized animal model of hypercaloric Western junk food [80]—during lactation (day 15) in rats, resulted in higher levels of miR-222 in rat milk compared to the miR-222 levels of the control animals [81][82]. Of note, serum exosomes enriched in miR-222 after bone marrow transplantation increased murine β cell proliferation in mice after STZ-induced β cell injury [83]. The cell cycle inhibitor CDKN1B is a conserved target gene of miR-148a and miR-222 [84].

6. Caesarean Delivery

Plasma oxytocin levels increase gradually during pregnancy and especially during labor [85]. Gutman-Ido et al. [86] found that oxytocin upregulates miR-148a and miR-30 in human colostrum but downregulates miR-320. Notably, miR-320 was highly expressed compared with miR-148a in the colostrum of mothers who did not receive exogenous oxytocin [86]. It has been shown in breast cancer cells and diabetic mice pancreatic tissue that miR-320 attenuates PI3K/AKT/ELF3 signaling [87][88]. E74-like factor 3 (ELF3) is a direct target of miR-320 [87] and silencing of ELF3 has been shown to promote β cell apoptosis [89]. It is thus conceivable that caesarean section, associated with deficient oxytocin signaling compared to vaginal labor, disturbs the balance of prosurvival/proapoptotic miR-148a/miR-320 signaling, compromising β cell mass expansion, which may enhance the risk of T2DM later in life. In fact, Chiba et al. [90] recently demonstrated that that miR-148a and miR-125b are significantly reduced in transition and in the mature milk of mothers giving birth via caesarean delivery compared with MEX miR levels observed with normal vaginal birth. Furthermore, caesarean section reduces the prevalence of early breastfeeding [91] and may thus negatively affect postnatal MEX miR-mediated programming of β cells.

7. Changes of miR Levels during Breastfeeding

The concentration of miRs change during the process of lactation [77][90]. The levels of miR-148a and miR-125b were lower in mature milk compared to transition milk [90]. Between the second week and the third month of lactation of healthy mothers delivering term infants, seven human milk miRs had significant stage-specific upregulation (miR-3184-3p, miR-92b-5p, let-7d-3p, miR-516a-5p, miR-187-5p, miR-3126-5p, and miR-196a-5p), whereas four had significant stage-specific downregulation (miR-125b-5p, miR-146a-5p, miR-34a-5p, and miR-1307-3p) [92].

8. Duration of Breastfeeding

Growing evidence indicates that the duration of breastfeeding plays a crucial for postnatal epigenetic imprinting and long-term clinical outcomes [93][94][95][96][97]. Breastfeeding has been related to the modification of methylation markers associated with T2DM [98]. Observational evidence suggests that breastfeeding reduces the risk of both T1DM and T2DM [99][100][101][102]. The duration of breastfeeding may thus have an impact on the exposure time and quantity of MEX miRs and their potential epigenetic signaling effects on pancreatic islets, enhancing β cell proliferation and mass expansion.

9. Human Donor Milk

Human donor milk is an important source of milk, especially for preterm infants whose mothers are unable to provide milk [103][104]. Perri et al. [105] reported that the method of human milk Holder pasteurization (HoP) of 62.5 °C, 30 min, did not alter the distribution or the expression profile of four selected miRs (miR-21, miR-181a, miR-150, and miR-223) tested in both colostrum and human milk. Smyczynska et al. [106] confirmed miR-148a in the greatest amount, accounting for almost 24% of total exosomal miRNA and about 12% in whole milk, prior to Holder pasteurization (HoP) and high pressure processing (HPP) 450 MPa for 15 min. HoP led to a 82-fold decrease in whole RNAs and a 302-fold decrease in exosomes [106]. After HPP, the percentage of miR-148a dropped to about 1/3 of its level in raw milk, whereas pasteurization affected miR-148a recovery to a much higher degree. Thus, in comparison to physiological breastfeeding, the application of HoP-processed human donor milk is associated with a critical loss of exosomal miR-148a, which may adversely affect β cell proliferation.

10. MiR-Deficient Artificial Formula Feeding

Compared to raw cow milk, significant reductions of miR levels have been measured in powdered formula [25]. Leiferman et al. [107] reported that milk miRs were not detectable in infant formulas. The levels of miR-148a and miR-125b in all recently analyzed infant formulae were lower than 1/500th and 1/100th of those in mature human milk, respectively [90]. Lectins in soy formula bind bovine MEX and prevent their absorption in healthy adults [108]. Thus, breastfeeding combined with soy-based complementary formula may impair the intestinal MEX miR uptake of the infant, which is of concern, as soy-based formula has been advocated as a substitute for infants with cow milk allergy [109][110]. Soy formula may thus interfere with MEX uptake and MEX miR signaling, which are important for allergy prevention [24][111][112]. Of note, miR-148a via suppression of DNMT1 controls the expression of FOXP3, the master transcription factor of regulatory T-cells, which are reduced in atopic infants [111]. Furthermore, miR-375 binds directly to JAK2 mRNA, reducing its expression [113][114][115][116]. Increased JAK2 signaling has been associated with the pathogenesis of atopic diseases [117][118][119][120]. Of note, JAK1/JAK2 inhibition reversed established autoimmune insulitis in NOD mice [121]. The first signs of β cell autoimmunity may be initiated during the first year of life, implying that risk factors for β cell autoimmunity and T1DM must be operative in early infancy [98][99][100][101]. An adequate miR-375 gene dosage in pancreatic β cells plays an essential role in the maintenance of β cell mass [122].
Cheshmeh et al. [123] reported that the expression levels of FTO and CPT1A genes in mononuclear blood cells of formula-fed and mix-fed infants was significantly higher compared to the exclusive breastfeeding group. MEX miR-deficient formula is unable to provide sufficient miR-30b and miR-148a to target FTO and CPT1A expression, respectively, which are critically involved in m6A-dependent β cell proliferation and CPT1A-mediated mitochondrial fatty acid oxidation. Thus, formula feeding may bear the risk of the deviated epigenetic regulation required for appropriate β cell proliferation [124][125]. Table 2 summarizes the perinatal factors that modify MEX miR expression.
Table 2. Perinatal factors modifying MEX miR signaling.
Impact Factors Effects on MEX miR Concentrations References
Maternal obesity miR−148a  ↓ miR-30b ↓ [64]
Gestational diabetes mellitus miR−148a  ↓ miR-30b ↓ [76]
Maternal stress during pregnancy miR−155  ↑ miR−96 ↑ [48]
Caesarean delivery miR−148a  ↓ miR-125b ↓ [90]
Oxytocin treatment miR−148a  ↑ miR-30 ↑ miR-320 ↓ [86]
Holder pasteurized human donor milk miR−148a ↓ [106]
Preterm birth miR−148a  ↑ miR-22 ↑ [1][2]
Infant formula miR−148a ↓↓  (below detection limit) [25][90][107]
Soy protein-based formula Impaired intestinal MEX miR uptake [108]
Raw cow milk miR−148a ↑↑ miR-21 ↑↑ [25][126]
Pasteurized cow milk miR-148a ↑ miR-21 ↑ miR-30d ↑ [126][127]
Ultraheat-treated cow milk miR−148a and others miRs ↓↓ [126][127]
One arrow up = upregualtion; two arrows up = extensive upregulation; one arrow down = downregualtion; two arrows down = extensive downregulation.

This entry is adapted from the peer-reviewed paper 10.3390/ijms231911503

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