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INTRODUCTION: Infant formula-feeding is associated with reduced insulin sensitivity. In rodents and healthy humans, advanced glycation end product (AGE)-rich diets exert diabetogenic effects. In comparison with human breast-milk, infant formulas contain high amounts of AGEs. We assessed the role of AGEs in infant-formula-consumption-associated insulin resistance. METHODS: Total plasma levels of N(ε)-(carboxymethyl)lysine (CML), AGEs-associated fluorescence (λ(ex) = 370 nm/λ(em) = 445 nm), soluble adhesion molecules, markers of micro- binflammation (hsCRP), oxidative stress (malondialdehyde, 8-isoprostanes) and leptinemia were determined, and correlated with insulin sensitivity in a cross-sectional study in 166 healthy term infants aged 3-to-14 months, subdivided according to feeding regimen (breast-milk- vs. infant formula-fed) and age (3-to-6-month-olds, 7-to-10-month-olds, and 11-to-14-month-old infants). Effects of the consumption of low- vs. high-CML-containing formulas were assessed. 36 infants aged 5.8±0.3 months were followed-up 7.5±0.3 months later. RESULTS: Cross-sectional study: 3-to-6-month-olds and 7-to-10-month-old formula-fed infants presented higher total plasma CML levels and AGEs-associated fluorescence (p<0.01, both), while only the 3-to-6-month-olds displayed lower insulin sensitivity (p<0.01) than their breast-milk-fed counterparts. 3-to-6-month-olds fed low-CML-containing formulas presented lower total plasma CML levels (p<0.01), but similar insulin sensitivity compared to those on high-CML-containing formulas. Markers of oxidative stress and inflammation, levels of leptin and adhesion molecules did not differ significantly between the groups. Follow-up study: at initial investigation, the breast-milk-consuming infants displayed lower total plasma CML levels (p<0.01) and AGEs-associated fluorescence (p<0.05), but higher insulin sensitivity (p<0.05) than the formulas-consuming infants. At follow-up, the groups did not differ significantly in either determined parameter. CONCLUSIONS: In healthy term infants, high dietary load with CML does not play a pathophysiological role in the induction of infant formula-associated insulin resistance. Whether a high load of AGEs in early childhood affects postnatal programming remains to be elucidated

Total plasma N^ε-(carboxymethyl)lysine (CML) levels and insulin sensitivity in breast-milk- and formula-fed infants included in the cross-sectional study.

<p>2A/Plasma total CML concentration in relation to feeding regimen and age. Box-plots represent median, interquartile range and 5^th–95^th percentile; 2B/Age-dependence of plasma total CML concentration in the breast-milk-fed infants (BM) and those consuming high-CML-containing infant formulas (IF); 2C/Relationship between plasma total CML concentration and age in the low-CML-containing infant formulas fed healthy infants; 2D/Insulin sensitivity assessed by Quantitative insulin-sensitivity check index (QUICKI) in the breast-milk- (BM) and infant formula-fed (IF) infants, low-CML-containing formulas (Low-CML IF) and high-CML-containing formulas (High-CML IF) consuming infants aged 3-to-6-months (m.), 7-to-10-months, and 11-to-14-months. Box-plots represent median, interquartile range and 5^th–95^th percentile.</p

Characteristics of the mothers of included infants.

<p>BM: mothers of exclusively breast-fed infants; IF: mothers of infant formulas recieving infants; BMI: body mass index.</p

Cohort characteristics and blood chemistry data – cross-sectional study.

<p>Infants were allocated according to their age and feeding regimen. From among 69 infants 3-to-6-month-olds, 33 were exclusively breast-fed (BM) and 36 received infant formula (IF): 17 consumed formulas with high- and 14 with low-CML-content. Fourty-one 7-to-10-month-old infants were weaned from breast-milk, while 37 from formulas: 18 infants consumed low-CML- and 19 high-CML-containing formulas. Six older infants aged 11-to-14 months still received breast-milk as a supplement to diversified diet, while 13 drunk formula (5 consumed low-CML- and 8 high-CML-containing formulas). AGE-Fl: plasma advanced glycation end-products specific fluorescence; AU: arbitrary units; sRAGE: soluble receptor for advanced glycation end products; hsCRP: high-sensitive C-reactive protein; sICAM-1: soluble intercellular adhesion molecule-1; sVCAM-1: soluble vascular adhesion molecule-1; sVAP-1: soluble vascular adhesion protein-1;</p>*<p>: p<0.05 vs. the corresponding age-group consuming breast-milk;</p>**<p>: p<0.01 vs. the corresponding age-group consuming BM;</p>***<p>: p<0.001 vs. the corresponding age-group consuming BM;</p><p>+: p<0.05 vs. the corresponding age-group consuming infant formula with low-CML content;</p><p>#: p<0.05 vs. the 3-to-6-month-old infants on the same feeding regimen;</p><p>##: p<0.01 vs. the 3-to-6-month-old infants on the same feeding regimen; results are given as mean±sem or median and interquartile range;</p><p>ND: not determined.</p

Recruitment and allocation of the infants according to age and feeding regimen.

<p>IF: infant formula; CML: N^ε-(carboxymethyl)lysine; *: Five infants could not be uneuquivocally assigned to any group (four due to concurrent administration or just recent switch from low- to high-CML-containing formula, one child consumed formula not analyzed for CML content).</p

Characteristics of the followed-up infants.

<p>Thirty-six infants aged 5.8±0.3 (Basal data) months were followed-up 7.5±0.3 months later (Follow-up). BM: 11 infants exclusively breast-fed at basal sampling and receiving breast-milk as a supplement to infants’ mixed diet at follow-up; IF: 25 infants consuming infant formulas at basal investigation as well as at follow-up; QUICKI: Quantitative insulin-sensitivity check index; CML: plasma N^ε-(carboxymethyl)lysine; AGE-fl: plasma advanced glycation end products specific fluorescence; sRAGE: soluble receptor for advanced glycation end products; hsCRP: high-sensitive C-reactive protein; sICAM-1: soluble intercellular adhesion molecule-1; sVCAM-1: soluble vascular adhesion molecule-1; sVAP-1: soluble vascular adhesion protein-1;</p>*<p>: p<0.05 vs. the breast-milk consuming group at corresponding time interval;</p>**<p>: p<0.01 vs. the breast-milk consuming group at corresponding time interval;</p><p>+: p<0.05 vs. the basal sampling in the same feeding regimen group;</p><p>++: p<0.001 vs. the basal sampling in the same feeding regimen group; results are given as mean±sem or median and interquartile range;</p><p>–: not applicable.</p

Comprehensive assessment of nephrotoxicity of intravenously administered sodium-oleate-coated ultra-small superparamagnetic iron oxide (USPIO) and titanium dioxide (TiO2) nanoparticles in rats

As a main excretory organ, kidney is predisposed to direct/indirect injury. We addressed the potential nephrotoxic effects following expositions of healthy rats to nanoparticle (NP) loads relevant to humans in a situation of 100% bioavailability. Up to 4 weeks after administration, a single iv bolus of oleate-coated ultra-small superparamagnetic iron oxide NPs (in dose of 0.1%, 1.0% and 10.0% of LD50) or TiO2 NPs (1.0% of LD50) did not elicit decline in renal function, damage to proximal tubules, alterations in: renal histology or expression of pro-inflammatory/ pro-fibrotic genes, markers of systemic or local renal micro-inflammation or oxidative damage. Antioxidant enzyme activities in renal cortex, mildly elevated at 24 h, completely restored at later time points. Data obtained by multifaceted approach enable the prediction of human nephrotoxicity during preclinical studies, and may serve as comparison for alternative testing strategies using in vitro and in silico methods essential for the NP-nephrotoxicity risk assessment

Advanced Glycation End Products in Infant Formulas Do Not Contribute to Insulin Resistance Associated with Their Consumption

Introduction: Infant formula-feeding is associated with reduced insulin sensitivity. In rodents and healthy humans, advanced glycation end product (AGE)-rich diets exert diabetogenic effects. In comparison with human breast-milk, infant formulas contain high amounts of AGEs. We assessed the role of AGEs in infant-formula-consumption-associated insulin resistance. Methods: Total plasma levels of Nε-(carboxymethyl)lysine (CML), AGEs-associated fluorescence (λex = 370 nm/λem = 445 nm), soluble adhesion molecules, markers of micro- binflammation (hsCRP), oxidative stress (malondialdehyde, 8-isoprostanes) and leptinemia were determined, and correlated with insulin sensitivity in a cross-sectional study in 166 healthy term infants aged 3-to-14 months, subdivided according to feeding regimen (breast-milk- vs. infant formula-fed) and age (3-to-6-month-olds, 7-to-10-month-olds, and 11-to-14-month-old infants). Effects of the consumption of low- vs. high-CML-containing formulas were assessed. 36 infants aged 5.8±0.3 months were followed-up 7.5±0.3 months later. Results: Cross-sectional study: 3-to-6-month-olds and 7-to-10-month-old formula-fed infants presented higher total plasma CML levels and AGEs-associated fluorescence (p<0.01, both), while only the 3-to-6-month-olds displayed lower insulin sensitivity (p<0.01) than their breast-milk-fed counterparts. 3-to-6-month-olds fed low-CML-containing formulas presented lower total plasma CML levels (p<0.01), but similar insulin sensitivity compared to those on high-CML-containing formulas. Markers of oxidative stress and inflammation, levels of leptin and adhesion molecules did not differ significantly between the groups. Follow-up study: at initial investigation, the breast-milk-consuming infants displayed lower total plasma CML levels (p<0.01) and AGEs-associated fluorescence (p<0.05), but higher insulin sensitivity (p<0.05) than the formulas-consuming infants. At follow-up, the groups did not differ significantly in either determined parameter. Conclusions: In healthy term infants, high dietary load with CML does not play a pathophysiological role in the induction of infant formula-associated insulin resistance. Whether a high load of AGEs in early childhood affects postnatal programming remains to be elucidated