Early programming of the IGF-I axis: Negative association between IGF-I in infancy and late adolescence in a 17-year longitudinal follow-up study of healthy subjects

doi:10.1016/j.ghir.2008.06.003

Growth Hormone & IGF Research

Volume 19, Issue 1, February 2009, Pages 82-86

https://doi.org/10.1016/j.ghir.2008.06.003 Get rights and content

Abstract

Background: IGF-I is a major regulator of growth, influenced primarily by diet in infancy and primarily by GH in childhood. Breastfed infants have lower IGF-I levels compared to formula fed and tend to be shorter. The higher protein content of infant formula has a stimulatory effect on IGF-I production. Conversely, studies suggest that later in childhood, those breastfed are taller and have higher IGF-I levels. Therefore, it has been suggested that the IGF-I axis may be programmed by diet during infancy. The association between IGF-I in infancy and later life is not known.

Objective: To examine the association between IGF-I in infancy and adolescence.

Design: Infants (109) from the observational Copenhagen cohort study.

Methods: Serum-IGF-I was measured during infancy (2, 6, and 9 months) and at follow-up at 17 years. Associations were examined by correlation tests and linear regression controlling for gender, breastfeeding, and other covariates. Likelihood ratio test based on residual log likelihood was applied for analysis including all measurements during infancy.

Results: There was an inverse association between IGF-I at 9 months and 17 years (r = −0.39, P = 0.014, and n = 40). A 1 ng/ml higher IGF-I concentration at 9 months corresponded to 0.95 ng/ml lower IGF-I concentration at 17 years. IGF-I levels at 2 and 6 months were not significantly associated with IGF-I at 17 years, but the estimated directions were negative. These associations were not changed when adjusted for breastfeeding and other covariates except IGF-I at 2 months which was significantly negatively associated with IGF-I at 17 years (P = 0.030) corresponding to a 0.96 ng/ml lower IGF-I concentration at 17 years per ng/ml IGF-I at 2 months. Inclusion of all measurements during infancy showed a negative association with 17-year values (r = −0.26, P = 0.043, and n = 109).

Conclusion: The results support the hypothesis that the IGF-I axis can be programmed early in life.

Introduction

IGF-I mediates the growth-promoting effects of growth hormone (GH) and plays an important role in the regulation of postnatal growth. In childhood, the synthesis of IGF-I is mainly regulated by GH but nutrition plays also an important role as concentrations of IGF-I can be influenced by protein intake and certain micronutrients. During infancy nutrition seems to play a major role in the regulation of growth. Several studies have reported lower IGF-I levels of breastfed infants compared to formula fed infants [1], [2] and in accordance with this breastfed infants tend to be shorter [3]. Conversely, other studies have shown that breastfed infants have higher IGF-I levels later in childhood and are taller as adults [4], [5]. It has been suggested that the differences between breastfed and formula fed infants in IGF-I levels and growth velocity could be explained by differences in protein content in breast milk and infant formula. This is supported by a study in which, higher IGF-I levels were found in infants getting a high protein infant formula, compared to a formula with a lower protein content [6]. Based on such data showing lower IGF-I and lower growth velocity during infancy and higher IGF-I values and higher growth velocities later in childhood among breastfed infants, it has been suggested that nutrition during infancy can have a programming effect on the IGF-I axis [7]. In accordance with this hypothesis the aim of the present study was to examine the association between IGF-I levels in infancy and in late adolescence in the Copenhagen cohort study on infant nutrition and growth.

Section snippets

Subjects

Healthy term (142) infants (boys = 63) participated in the Copenhagen cohort study on infant nutrition and growth, a prospective observational study. The inclusion criteria were: parents of Danish origin, singleton birth, gestational age between 37 and 42 weeks, birth weight for gestational age between 10th and 90th percentiles, no neonatal disease or malformation as described elsewhere [3]. Children were examined during infancy at 2, 6, and 9 months and followed up at 17 years where 109 subjects

Results

During infancy the IGF-I concentration decreased significantly from 2 to 6 months (P ⩽ 0.001) but did not change from 6 to 9 months (Table 1). The estimated mean IGF-I levels in infancy were higher for the girls than for the boys but not statistically significant. On contrary in adolescence the girls had significant lower IGF-I levels than the boys (P = 0.029). IGF-I at 17 years was not correlated with birth weight or current height even after adjustment for gender and weight at 17 years (data not

Discussion

In this 17-year longitudinal follow-up study of 109 healthy children who were followed from birth to adolescence, we found a negative association between IGF-I levels during infancy and in late adolescence, which to our knowledge has not been reported previously.

In otherwise healthy adults a high serum IGF-I concentration is associated with increased risk of some cancers, and a low IGF-I concentration is associated with increased risk of ischemic heart disease and diabetes [11], [12].

Acknowledgments

The research was financially supported by the LUNDBECK foundation, the Danish Heart Association, and Ville Heises foundation.

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Bovine milk fat globule membrane (MFGM) added in infant formula supports typical growth and safety through 24 mo of age in term infants.
To assess micronutrient (zinc, iron, ferritin, transferrin receptor), metabolic [glucose, insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), insulin-like growth factor-1 (IGF-1), triglycerides (TGs), total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C)], and inflammatory (leptin, adiponectin, high sensitivity C-reactive protein) secondary outcomes through 24 mo of age in infants who received standard cow’s milk-based infant formula (SF), similar formula with added bovine MFGM (EF), or human milk (HM) through 1 y.
Infants whose parents agreed to a blood draw at baseline (<120 d of age) (SF = 80; EF = 80; HM = 83) were included. Subsequent collections (2–4 h fasting) occurred at D180, D365, and D730. Biomarker concentrations were analyzed and group changes tested using generalized estimating equations models.
Only serum iron (+22.1 μg/dL) and HDL-C (+2.5 mg/dL) were significantly higher for EF compared with SF at D730. Prevalence of zinc deficiency for EF (-17.4%) and SF (-16.6%) at D180 and depleted iron stores for SF (+21.4%) at D180 and EF (-34.6%) and SF (-28.0%) at D365 were significantly different compared with HM. IGF-1 (ng/mL) for EF and SF was significantly higher at D180 (+8.9) and for EF (+8.8) at D365, and (+14.5) at D730 compared with HM. Insulin (μUI/mL) for EF (+2.5) and SF (+5.8) and HOMA-IR for EF (+0.5) and SF (+0.6) were significantly higher compared with HM at D180. TGs (mg/dL) for SF (+23.9) at D180, for EF (+19.0) and SF (+17.8) at D365, and EF (+17.3) and SF (+14.5) at D730 were significantly higher compared with HM. Zinc, ferritin, glucose, LDL-C and total cholesterol changes were higher in formula groups compared with HM between various time points.
Micronutrient, metabolic, and inflammatory biomarkers were generally similar through 2 y in infants who received infant formula with or without added bovine MFGM. Over the 2 y, differences were observed between infant formulas and HM reference group. This trial was registered at clinicaltrials.gov as NTC02626143.
The effect of milk and rapeseed protein on growth factors in 7–8 year-old healthy children – A randomized controlled trial
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Citation Excerpt :
Some sex interactions were observed in the Milk and Blend2 groups as IGF-1, the molar ratio IGF-1/IGFBP-3 and insulin in the Milk group and insulin in the Blend2 group increased less in boys than in girls from baseline to week 4. Although sex differences have often been reported in relation to intake of milk or milk-based infant formula and growth factors [24,26,33,34], we have no clear interpretation of these findings. Children in the Milk group grew approximately 0.3 cm in height whereas children in the groups receiving rapeseed blends groups grew 0.6 and 0.8 cm during the 4 week intervention.
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Design: An exploratory 3-armed randomized, double-blind, controlled trial was conducted in 129 healthy 7–8 year-old Danish children. Children received 35 g milk and rapeseed protein (ratio 54:46 or 30:70) or 35 g milk protein per day for 4 weeks. The primary outcome was difference in IGF-1 changes between intervention groups after 4 weeks. Secondary outcomes included changes in IGF-1 after 1 week and changes in insulin-like growth factor binding protein-3 (IGFBP-3), IGF-1/IGFBP-3, insulin, height, weight and body composition after 1 and 4 weeks. Results were analysed by multiple linear mixed-effect models.
Results: There were no differences in changes of plasma IGF-1, insulin-like growth factor binding protein-3 (IGFBP-3), IGF-1/IGFBP-3 ratio or insulin between groups after 1 or 4 weeks based on 89 complete cases (P > 0.10). IGF-1 increased by 13.7 (95% CI 9.7;17.7) ng/mL and 18.0 (14.0;22.0) ng/mL from baseline to week 1 and 4, respectively, a 16% increase during the intervention. Similarly, insulin increased by 31% (14; 50) and 33% (16; 53) from baseline to week 1 and 4. Fat-free mass index (FFMI) increments were higher with milk alone than rapeseed blends (P < 0.05), coinciding with a trend towards a lower height increment. Body mass index increased within all groups (P < 0.05), mainly due to an increase in FFMI (P < 0.01).
Conclusion: There were no differences in changes of growth factors between the combinations of milk and rapeseed protein and milk protein alone in healthy, well-nourished children with a habitual intake of milk. Within groups, growth factors increased considerably. Future studies are needed to investigate how intakes of plant and animal proteins affect childhood growth.
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Impulsivity is a multifaceted construct associated with poor planning skills, difficulty in maintaining attention, and behavioral disinhibition—especially in conditions of highly activated affective states. Impulsivity plays a prominent role in adolescents, in whom high levels of impulsivity expose them to a greater risk of exhibiting risky behaviors or developing pathological conditions. Currently, one of the most popular frameworks to explain and assess impulsivity is the UPPS-P, which distinguishes between five impulsivity components, and from which the UPPS-P Scale and its short form are derived. In light of the relatively low number of psychometric analyses of the scale in adolescents, this study aimed to verify the psychometric properties of the Short UPPS-P Scale among Italian adolescents. The participants were 647 adolescents (68% males, mean age = 16.9, SD = 1.1 years). Confirmatory factor analysis supported the five-factor model of the scale, which was found to be invariant across gender and age and to have had good internal consistency values. Gender and age differences were also investigated. Evidence for validity was provided by supporting relationships between specific UPPS dimensions, gambling frequency, problem gambling, and problematic use of social networks. Overall, the findings showed that the Short UPPS-P Scale is a promising instrument to assess the multidimensional construct of impulsivity in adolescents in both research and clinical practice.
Associations of protein intake in early childhood with body composition, height, and insulin-like growth factor i in mid-childhood and early adolescence
2019, American Journal of Clinical Nutrition
Early protein intake may program later body composition and height growth, perhaps mediated by insulin-like growth factor I (IGF-I). In infancy, higher protein intake is consistently associated with higher IGF-I concentrations and more rapid growth, but associations of protein intake after infancy with later growth and IGF-I are less clear.
Our objective was to examine associations of protein intake in early childhood (median 3.2 y) with height, IGF-I, and measures of adiposity and lean mass in mid-childhood (median 7.7 y) and early adolescence (median 13.0 y), and with changes in these outcomes over time. We hypothesized that early childhood protein intake programs later growth.
We studied 1165 children in the Boston-area Project Viva cohort. Mothers reported children's diet using food-frequency questionnaires. We stratified by child sex and examined associations of early childhood protein intake with mid-childhood and early adolescent BMI z score, skinfold thicknesses, dual-energy X-ray absorptiometry (DXA) fat mass, DXA lean mass, height z score, and IGF-I concentration. We adjusted linear regression models for race/ethnicity, family sociodemographics, parental and birth anthropometrics, breastfeeding status, physical activity, and fast food intake.
Mean protein intake in early childhood was 58.3 g/d. There were no associations of protein intake in early childhood with any of the mid-childhood outcomes. Among boys, however, each 10-g increase in early childhood total protein intake was associated with several markers of early adolescent size, namely BMI z score (0.12 higher; 95% CI: 0.01, 0.23), DXA lean mass index (1.34% higher; 95% CI: −0.07%, 2.78%), and circulating IGF-I (5.67% higher; 95% CI: 0.30%, 11.3%). There were no associations with fat mass and no associations with any adolescent outcomes among girls.
Early childhood protein intake may contribute to programming lean mass and IGF-I around the time of puberty in boys, but not to adiposity development. This study was registered at clinicaltrials.gov as NCT02820402.
Higher maternal protein intake during pregnancy is associated with lower cord blood concentrations of insulin-like growth factor (IGF)-II, IGF binding protein 3, and insulin, but not IGF-I, in a cohort of women with high protein intake
2017, Journal of Nutrition
Background: Prenatal exposure to dietary protein may program growth-regulating hormones, consequently influencing early-life growth patterns and later risk of associated chronic diseases. The insulin-like growth factor (IGF) axis is of particular interest in this context given its influence on pre- and postnatal growth and its sensitivity to the early nutritional environment. Objective: Our objective was to examine associations of maternal protein intake during pregnancy with cord blood concentrations of IGF-I, IGF-II, IGF binding protein-3 (IGFBP-3), and insulin. Methods: We studied 938 mother-child pairs from early pregnancy through delivery in the Project Viva cohort. Using multivariable linear regression models adjusted for maternal race/ethnicity, education, income, smoking, parity, height, and gestational weight gain and for child sex, we examined associations of second-trimester maternal protein intake [grams per kilogram (weight before pregnancy) per day], as reported on a food frequency questionnaire, with IGF-I, IGF-II, IGFBP-3, and insulin concentrations in cord blood. We also examined how these associations may differ by child sex and parity. Results: Mothers were predominantly white (71%), college-educated (64%), and nonsmokers (67%). Mean ± SD protein intake was 1.35 ± 0.35 g · kg⁻¹ · d⁻¹. Each 1-SD increment in second-trimester protein intake corresponded to a change of −0.50 ng/mL (95% CI: −2.26, 1.26 ng/mL) in IGF-I and −0.91 μU/mL (95% CI: −1.45, −0.37 μU/mL) in insulin. Child sex and parity modified associations of maternal protein intake with IGF-II and IGFBP-3: protein intake was inversely associated with IGF-II in girls (P-interaction = 0.04) and multiparous mothers (P-interaction = 0.05), and with IGFBP-3 in multiparous mothers (P-interaction = 0.04). Conclusions: In a cohort of pregnant women with relatively high mean protein intakes, higher intake was associated with lower concentrations of growth-promoting hormones in cord blood, suggesting a pathway that may link higher protein intake to lower fetal growth. This trial was registered at clinicaltrials.gov as NCT02820402.
Maternal protein intake during pregnancy and linear growth in the offspring
2016, American Journal of Clinical Nutrition
Background: Observational and experimental evidence demonstrates that protein intake in infancy programs linear growth. To our knowledge, few studies have examined prenatal maternal protein intake.
Objective: Our objective was to examine associations of maternal protein intake during pregnancy with offspring linear growth.
Design: We analyzed data from 1961 mother–child pairs in Project Viva. We assessed first- and second-trimester diet with the use of food-frequency questionnaires and analyzed protein intake as grams per kilogram prepregnancy weight per day. We used research measures of offspring length at birth and in infancy (∼6 mo), early childhood (∼3 y), and midchildhood (∼7 y), as well as clinical growth measures obtained from after birth through midchildhood. We calculated sex-specific birth length z scores for gestational age with the use of international reference data. We used mixed models with repeated length measures to predict individual length gain velocities for birth to <6 mo and 6 mo to 7 y of age, then used these velocities as outcomes in adjusted linear regression models with maternal protein intake as the main predictor.
Results: Mean (range) second-trimester protein intake was 1.4 g · kg⁻¹ · d⁻¹ (0.3–3.1 g · kg⁻¹ · d⁻¹). After adjusting for maternal sociodemographics, gestational weight gain, maternal and paternal height, and (for postdelivery outcomes) child sex, gestational age, and breastfeeding duration, each 1-SD (0.36 g · kg⁻¹ · d⁻¹) increment in second-trimester protein intake corresponded to a −0.10 (95% CI: −0.18, −0.03) change in birth length z score, a −0.03 cm/mo (95% CI: −0.05, −0.01 cm/mo) change in slope of length growth from birth to <6mo, and a −0.09 cm/y (95% CI: −0.14, −0.05 cm/y) change in slope of length growth from 6 mo to midchildhood. Results were similar for first-trimester intake.
Conclusions: In a population with relatively high protein intake during pregnancy, higher protein intake was associated with shorter offspring birth length and slower linear growth into midchildhood. Results suggest that higher protein intake during pregnancy does not increase fetal and child growth and may even reduce early length growth. Project Viva was registered at clinicaltrials.gov as NCT02820402.

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Early programming of the IGF-I axis: Negative association between IGF-I in infancy and late adolescence in a 17-year longitudinal follow-up study of healthy subjects

Abstract

Introduction

Section snippets

Subjects

Results

Discussion

Acknowledgments

J. Nutr.

Am. J. Clin. Nutr.

Am. J. Clin. Nutr.

Int. J. Gynaecol. Obstet.

A prospective study of serum insulin-like growth factor I (IGF-I) and IGF-binding protein-3 in 942 healthy infants: associations with birth weight, gender, growth velocity, and breastfeeding

J. Clin. Endocrinol. Metab.

Ghrelin, leptin and IGF-I levels in breast-fed and formula-fed infants in the first years of life

Acta Paediatr.

Weight, length, head circumference, and growth velocity in a longitudinal study of Danish infants

Dan. Med. Bull.

Anthropometry and body composition of 18-year old men according to duration of breast feeding: birth cohort study from Brazil

BMJ

Association between breast feeding and growth: the Boyd-Orr cohort study

Arch. Dis. Child Fetal Neonatal Ed.

Growth of breast-fed and formula-fed infants

Nestle. Nutr. Workshop Ser. Pediatr. Program.