Metabolic Advantage of Reduced Protein Formula

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Infants fed 'classical' casein- or whey-predominant formulas have higher levels of some amino acids and consistently elevated urea levels in their blood when compared to BF infants [17]. The short-term effects of these differences on infant growth and health have been carefully assessed and considered as safe. Nevertheless, the impact of both the quantity and quality of protein intake during early life on the incidence of disease later in life is, as yet, not known.

Dehydration and Kidney Functions

Potential renal solute load refers to solutes of dietary origin that would need to be excreted in the urine if not utilized by the body. It represents the sum of dietary nitrogen, sodium, potassium, chloride and phosphorus [18] and is a suitable parameter to measure the risk of dehydration illness. When ingested in excess, proteins constitute a considerable part of the solutes that must be excreted by the kidneys. Taking this into consideration, Ziegler and Fomon [18] recommended reducing the maximum protein content of infant formula from the level of 4.5g/100kcal, specified by the Food and Drug Administration, to 3.2g/100kcal. As an adaptive response to a high solute load, glomerular filtration rate and kidney size increase. While the adverse effects of a high protein intake in patients with kidney disease have been documented, there is to date no clear evidence of such detrimental effects in healthy individuals. The effect of formula- vs. breastfeeding on kidney growth was recently investigated in a cohort study of 631 healthy children examined at 3 and 18 months of age [19]. The results showed that kidney size and serum urea nitrogen were greater in the FF infants. Nevertheless, the differences in relative kidney size were temporary, as they were no longer apparent at 18 months of age [19]. The consequences of such increased kidney growth on kidney functions later in life are unknown.

Growth and Adiposity

Growth velocity seems to differ between BF and FF infants, especially when infants are breast fed for more than 6 months. Exclusively BF infants tend to grow more rapidly in the first 2-3 months of life, but from 6 to 12 months have a body weight, body length or body weight for length that are slightly lower than FF infants [20-23]. A significantly higher protein and/or energy intake [24-26] is associated with the faster growth rate observed in FF infants, but conflicting results exist [27, 28]. To date, the long-term impact of this moderate difference in growth on obesity risk later in life, is unknown. An association between high dietary protein intake during early childhood and subsequent adiposity has also been proposed [29]. In a longitudinal study a positive correlation was found between protein intake at the age of 2 years, but not at 10 months of age, and the body mass index and subscapular skin-fold at 8 years of

Days after birth

Fig. 4. IGF-1 levels (^g/l) in infants fed a modified sweet whey protein formula with a reduced protein content of 1.9 g protein/100 kcal (A) or a normal sweet whey formula containing 2.4 g protein/100 kcal (■).

Days after birth

Fig. 4. IGF-1 levels (^g/l) in infants fed a modified sweet whey protein formula with a reduced protein content of 1.9 g protein/100 kcal (A) or a normal sweet whey formula containing 2.4 g protein/100 kcal (■).

age [29]. Although some studies [30, 31] have described an association between protein intake at >9 months of age and adiposity in later childhood, other studies have reported an association with body size but not with body fat mass [32]. Interestingly, the influence of excess protein intake during the first year of life on weight gain in infancy and the risk of obesity later in life is now being studied in a large European Childhood Obesity Project [33].

A high protein intake is likely to have endocrine effects. It has been suggested that the higher growth velocity reported in FF vs. BF infants is due to a high protein intake early in life that promotes secretion of insulin-like growth factor-1 (IGF-1), a trophic hormone involved in longitudinal growth as well as muscle and fat mass development. Although there is limited knowledge about neonatal endocrine responses to milk feeding, there is increasing evidence that at 2 [34] and 6 months of age [35] FF infants have greater serum IGF-1 levels than BF infants. In a recent study, Savino et al. [34] observed that plasma IGF-1 levels are directly correlated with the Z score for weight, body mass index and tricipital skin-fold thickness in 2-month-old infants. Interestingly, we have observed that, during the first 4 months of life, infants fed a MSW formula (1.9 g protein/100kcal) have a different evolution of their IGF-1 plasma levels to infants fed a normal sweet whey formula (2.4g protein/100 kcal). IGF-1 levels decrease significantly (p = 0.013) between 28 and 112 days in infants fed formulas with a reduced level of protein (fig. 4).

IGF-1 levels average 79.3 ± 34.0ng/ml (mean ± SD, n = 35) at 28 days and 58.9 ± 37.8ng/ml (n = 41) at 112 days of age. On the other hand, in infants fed control formula IGF-1 levels did not decrease. IGF-1 levels average 77.5 ± 31.0ng/ml (n = 21) at 28 days and 80.8 ± 37.8ng/ml (n = 27) at 112 days of age (fig. 4). This confirms the strong influence of protein intake on IGF-1 levels. Interestingly, IGF-1 levels with a reduced protein formula are similar to those reported for BF infants [36].

Insulin acts as a growth factor during development and is considered as an anabolic factor of lean and fat mass. Moreover, protein intake is known to potentiate glucose-stimulated insulin secretion [37]. The amino acid profile of the ingested protein itself plays a role in the insulin response to feeding. In this respect, lysine, leucine, phenylalanine, valine and arginine are the amino acids which are the most potent insulin secretagogues [38]. Interestingly, FF newborns show higher postprandial plasma insulin levels than their BF counterparts [39]. Up to 6 months of age, urinary C-peptide (a marker of insulin secretion) correlates with plasma valine levels and is 2 to 3 times greater in FF infants than in BF infants [40]. Similarly, infants fed a formula containing 2.5 g protein/100 kcal between 4 and 6 months of age have higher levels of urinary C-peptide than BF infants or infants fed a formula containing 1.8 g pro-tein/100kcal [24]. In this study, weight gain is reported to correlate with C-peptide excretion, protein intake and plasma concentrations of the branched-chain amino acids, valine, leucine and isoleucine [24]. Interestingly, infants fed a modified sweet whey formula (1.8 g protein/100kcal) vs. a classical whey-predominant formula (2.2g protein/100kcal) displayed significantly lower plasma levels of a number of amino acids, such as valine, leucine and isoleucine (table 3), which are considered to be insulin secretagogues. While the arginine levels were higher with the modified formula, the phenylalanine levels were unchanged (table 3). It would be of interest to investigate whether these differences are associated with decreased insulin levels in the plasma and/or C-peptide excretion. Additional studies are also needed to determine the short- and long-term metabolic consequences of these differences.

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