The Effects of Low Infant Birth Weight on Metabolic Diseases

Low infant birth weight can be associated with immediate, as well as long-term, effects for the infant that will carry on, and most likely worsen, with adulthood. Both the thrifty phenotype and the fetal origins hypotheses connect low birth weight to insulin resistance, type 2 diabetes, hypertension, obesity, and other metabolic complications (1, 2). Infants are characterized as being of low birth weight if they are born weighing less than five pounds and eight ounces (3), and this cutoff is also used to identify intrauterine growth restriction(IUGR) in babies born at term (4). Infants born at a low birth weight, and therefore likely IUGR, almost certainly have experienced some sort of growth or development deficiencies as a fetus and will make necessary adjustments to adapt to these deficiencies. The discussion lies within the effects, both long-term and immediate, on metabolic diseases or their precursors in infants of low birth weight. Considering that diabetes and obesity are national concerns, studies regarding the possible causes of, or at least predispositions to, these diseases may offer insight to their prevention or to cautionary measures to be taken. A study examined twenty-five year old subjects who were either born appropriate for gestational age or IUGR-born to evaluate decreased insulin sensitivity (5). In the study’s subjects, “body fat was significantly higher in the IUGR group,” even though both groups had comparable body mass indexes, and the results revealed decreased insulin sensitivity in IUGR subjects(5). As with the former test, glucose concentration in the blood is tested to determine insulin resistance and will be seen in higher concentrations in people experiencing insulin insensitivity. Observed above in young adults, other studies observed insulin resistance in mid and late childhood (6), while still

another cited incidence of insulin sensitivity reduction as early as age one in infants born at a low birth weight (7). Insulin plays an important role in the body’s metabolic processes. The importance of examining insulin insensitivity is in its progression to, or association with, hypertension, obesity, type 2 diabetes, the metabolic syndrome/syndrome X, and cardiovascular disease which could eventually be lifethreatening (1,7). So what factors associated with low birth weight would cause insulin resistance? After being born at a low birth weight, most children experience a catch-up growth period that occurs largely between birth and age two, and it is this speedy weight gain period that is often associated with the insulin resistance and related complications (7). In a study of low birth weight infants of age one, a marked reduction in insulin sensitivity was already observed (8). These findings suggest that the catch-up growth period after birth is a crucial time period in the infant’s development of insulin resistance and future complications. After the catch up period between birth and two years, a group of infants were studied and compared during ages two to four years: “the gains in abdominal fat and body adiposity were strikingly higher in small for gestational age(SGA) than appropriate for gestational age children(AGA)” (7). Also in this study, the already increased insulin resistance in SGA infants showed a further increase in the next years, contrasting the lack of change in the AGA infants (7). The disturbing observation here is that despite the fact the SGA infants had already experienced their catch-up growth period, they still continued to add extra fat tissue while their insulin sensitivity further reduced. Perhaps the early relation of insulin resistance and fat gains continues to be the trend in adulthood.

In progression into childhood, school-aged children between ages five and fifteen were studied (6) and may help provide a link between the early insulin resistance and adult metabolic diseases. In this study, a significant difference was seen between children born SGA versus those born AGA: SGA children had higher fasting glucose, insulin levels, and insulin resistance. In addition, “the greatest insulin resistance was observed in those with low birth weight and high current weight” (6). To relate a previous study, a connection may be made between the overcompensation of catch-up growth between birth and age two and the increased insulin levels and weight gain. So, at this stage, regardless of obesity, insulin resistance is still present, with no indication of lessening with age, despite catch-up growth. These findings would then advance into young adulthood where, as earlier mentioned, insulin resistance and body fat are still significantly higher in those born as infants small for gestational age. Syndrome X, also metabolic syndrome or metabolic syndrome X, is a condition that relates hypertension, obesity, and type 2 diabetes; one researcher “was able to demonstrate that the smaller the birth weight or the weight at one year, the greater was the prevalence of this syndrome X in adult life (9). An additional study was able to quantify the risk: “the odds increased 1.72 times for each tertile decrease in birth weight” (10). Additionally, a study was conducted to research the factors involved in the development of the metabolic syndrome, specifically low birth weight and current overweight status (1). Here researchers discovered that birth weight was markedly lower in the group of children with metabolic syndrome, while the ratio of current weight compared with birth weight was high. “These findings indicate that in individuals with a

similar level of obesity, subjects with a lower birth weight and subsequent greater weight gain tend to be at a higher risk of developing the MS”(1). At increasingly smaller birth weights, the infant requires an even quicker rate of catch up growth to reach the appropriate size by approximately age two, and therefore an even greater alteration to the infant’s metabolic processes. A study using pre-term infants attempted to evaluate whether the insulin resistance was actually due to the SGA/AGA status, or the need for catch up growth after birth (11). The study of the very low birth weight preterm infants concluded “the adverse metabolic pattern of pre-school VLBW children seems related to post-natal events (rapid weight growth) independently of their being born small- or appropriate-for gestational age” (11). This study still supports the evidence that low birth weight is a definite risk factor for insulin resistance, and also adds that an even greater risk may be connected to those low birth weight infants who experience a faster catch-up growth during their early years. However, catch-up growth is ultimately the result of either low birth weight or IUGR. This restriction has proved to have a substantial effect on insulin sensitivity (12); but is the effect due to catch-up growth or to other factors of incomplete development in the fetus? In a study of ninety children with nonalcoholic fatty liver disease (NAFLD), “a highly prevalent and potentially progressive condition in adults, now considered the hepatic [liver] expression of the metabolic syndrome,” 39.9% of the children were born SGA, which was about four times greater than the general pediatric population of the hospital (12). This study shows that the liver disease is more prevalent in SGA children and says that the related insulin resistance will begin to appear even during the catch up growth period, not as a result of (12). Additionally, in a study differentiating between

SGA children who did achieve catch up growth in height within two years and those who did not, a difference in insulin sensitivity was not found. This particular study then concluded that childhood catch up growth was not the risk factor for future onset of type 2 diabetes (13), which somewhat contradicts the findings of the more current study involving pre-term infants and even more recent studies using catch up growth between zero and twenty-four months as an indicator (11). Most likely, the catch up growth is best viewed not as a determinant, but as an indicator for future metabolic complications. In which case, the catch up growth does not necessarily lead to diabetes or obesity, but rather is a phase in the development of such diseases. So then, the studies would indicate that events leading up to birth are responsible for the negative chain of events that occurs after birth. Fetal development is a very complicated process. Many maternal/environmental factors can affect fetal growth, especially when the nutrient supply to the fetus is compromised. The limited supply will cause the fetus to adapt structurally and functionally in order to survive through a process called “programming” (1). During this critical stage of development, the fetus makes these changes to itself for survival, but the programming “also results in permanent damage to the metabolic status of the fetus” (1). Essentially, in the programming adjustment, an immediate need is met and therefore proves the programming beneficial at that time. However, remaining in this “adjusted” state will be detrimental to the infant once the proper or sufficient nutrients are present. The unfavorable conditions may cause adjustment by affecting growth and proper use of pancreatic beta-cells, which are related to insulin secretion, and, when coupled with insulin resistance, provide the defects leading to type 2 diabetes later in life (11,13). However, specifically targeting beta-cells

as a primary defect is difficult, and better is the conclusion that beta-cell deterioration in combination with increasing insulin resistance can be a cause of later type 2 diabetes (13). Fetal malnutrition and subsequent programming are can also be contributors to the artery-related problems hypertension and high blood pressure and additionally may predispose the fetus to the development of insulin resistance by regulating the types of muscle fibers formed (1). Linking the beta-cell defects with those of the muscle type may help explain the additional fat distribution: developing hyperinsulinemia as a result of beta-cell compensation to muscle-specific insulin resistance could possibly promote further peripheral and central fat deposition (7). This would explain the significantly higher gains in abdominal and total body fat in SGA infants compared with AGA infants during the growth period of two to four years of age (7). The gains between the two groups in this study were actually similar in weight, height, and BMI with prominent differences in body composition. The fetal environment and infant are then predisposed to, or at-risk of, developing metabolic diseases, but what, beyond childhood, are the outcomes of low birth weight? In a study of Chinese adults, obesity, hypertension, type 2 diabetes, and birth weight were all examined and associations between birth weight and other data were assessed (2). Birth weight proved to be a predictor for future complications, especially low birth weight: low birth weights showed the highest incidences of type 2 diabetes and abdominal obesity, while the effects of birth weight combined with abdominal obesity showed a significant increase in the prevalence of type 2 diabetes (2). These findings indicate that low birth weight is an independent risk factor for both type 2 diabetes and abdominal obesity. Considering that low birth weight is a risk factor for both insulin

resistance and obesity and that obesity itself is related to insulin resistance, taking specific measures to reduce obesity would be almost imperative for persons born at a low birth weight who do not wish to develop type 2 diabetes. Experimental studies have been/are being conducted to develop treatment for babies born at a low birth weight, or SGA (7, 9). “Approximately ten percent of children born SGA fail catch-up growth and remain short” (14). Growth hormone treatment has been approved and is now a treatment for patients born short and SGA (14), but certain risk factors do raise concern: growth hormone has previously been linked to increased insulin levels and insulin resistance (14). Since SGA infants are already considered to be predisposed to insulin resistance, research should be focused on the lasting effects of growth hormone (GH) on treated SGA patients. One study compared GH treated short SGA children with non GH treated children to evaluate this concern and found that while insulin resistance was increased during GH treatment, baseline was recovered after discontinuation (14). In fact, the treated short SGA children actually experienced positive effects on blood pressure and cholesterol levels that the untreated children did not and were also taller, as a result of the GH treatment (14). GH has also shown a rise in BMI due to a rise in lean body mass, which is useful in comparing the two groups: the groups had comparable BMI’s, but the treated were taller, possibly indicating that the untreated have more fat mass, though this idea needs further research (14). Metformin has also been used in treatment with low-birth-weight insulin resistant children to increase insulin sensitivity, but has shown also to reduce total and abdominal fat while helping to increase lean mass (7).

In summary, fetal malnutrition disrupts the complicated process of fetal development. Malnutrition then acts on fetal tissues, insulin-sensitive tissues. Programming helps the fetus to adapt to its circumstances (1). A malnourished fetus will mostly likely experience IUGR and be born at a low birth weight (4). In order to make up for the inadequacy, most SGA children will experience “catch-up” growth between birth and two years of age (7). This “resets the hypothalamus-pituitary axis, leading to an increase in growth factors,” and the possible, likely development of hypertension and insulin resistance (1). Insulin resistance is then linked to many other complications including obesity, type 2 diabetes, and the metabolic syndrome (2, 9). In conclusion, prevention of metabolic diseases begins in the fetal environment. If born at a low birth weight, an infant can be considered at a higher risk for insulin resistance, diabetes, obesity, hypertension, and the metabolic syndrome. If the infant experiences a rapid catch-up growth that progresses into overcompensation, then that infant is most likely at a greater risk for such problems. Knowing the relationship between low birth weight and metabolic diseases is helpful in developing preventative methods for and decreasing the prevalence of these diseases.

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