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Original Research |
Central Wisconsin Center (N.R.G., M.H.F., W.N.A.), University of Wisconsin-Madison, Madison, Wisconsin
Department of Pediatrics (N.R.G., W.N.A.), University of Wisconsin-Madison, Madison, Wisconsin
Department of Rehabilitation Medicine (N.R.G.), University of Wisconsin-Madison, Madison, Wisconsin
Address correspondence to: Norris R. Glick, M.D., Central Wisconsin Center, 317 Knutson Drive, Madison, WI 53704. E-mail: nrglick{at}facstaff.wisc.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Methods: Serum IGF-1, albumin, pre-albumin, creatinine, zinc (Zn) and plasma amino acids were measured before and after a four-week 25% increase in formula in 25 individuals, divided into those fed by day (Group A) or by night (Group B).
Results: Circulating IGF-1 was low in nine of the 22 subjects (40.9%) included in the analysis. Mean IGF-1 increased 10.4% (p=0.004). Despite high intakes of essential amino acids and Zn, initial mean plasma tryptophan and phenylalanine were low, and serum Zn was low in 40.9% of subjects. Plasma tryptophan was low at both samplings and correlated with circulating IGF-1 concentrations (p=0.02) at the beginning of the study. Serum IGF-1 and Zn also correlated (p=0.02) initially.
Conclusions: IGF-1 is commonly low in this population and is associated with low plasma amino acid and Zn concentrations, despite high intakes of these nutrients. The causes and clinical implications of these abnormalities need further study.
Key words: insulin-like growth factor-I, plasma amino acids, profoundly retarded, tryptophan, zinc
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Low circulating IGF-1 concentrations are associated with adverse health effects, including cognitive function [3], adolescent bone mass acquisition and adult bone integrity [4]. In a hospitalized elderly population, circulating IGF-1 predicted life-threatening infectious and non-infectious complications with 76% accuracy [5].
There are approximately 135,000 people in the U.S. with severe or profound mental retardation [6]. They are prone to a variety of health problems apart from their cognitive limitations, including osteoporosis [7] and premature death [8], the latter often associated with complications of infectious disease. A subset of people with profound mental retardation requires long-term gas-trostomy tube feedings, thereby making it feasible to determine nutrient intake accurately and optimize nutritional status. It may be possible, by manipulating nutritional intake such that IGF-1 concentrations rise, to realize improvements in those areas where IGF-1 have been shown to affect health.
IGF-1 abnormalities among people with severe disabilities have been described in only one report [9]. In this study seven of ten children with short stature and cerebral palsy had low IGF-1 concentrations. To our knowledge, IGF-1 has not been measured in nonambulant adults with profound mental retardation. We conducted a four-week study to measure circulating IGF-1 concentrations and to evaluate the effects of increased formula intake on IGF-1, Zn, albumin, prealbumin and plasma amino acids. The relationship between the intakes of amino acids and Zn and their blood concentrations was also examined.
Clinical application of the information obtained from this study may permit nutritional manipulations aimed at improving cognition, bone integrity and immune function via optimization of IGF-1 in this population.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Subjects were fed either Osmolite HN® or Jevity® (Ross Laboratories, Columbus, Ohio) during this study. These formulas are identical, except for largely insoluble (94%) fiber and additional calcium, phosphorus and chloride found in Jevity. Those who routinely received Osmolite HN or Jevity prior to the study continued on these products while the remaining subjects were switched to these products from similar commercial formulas at least one week prior to the study. Each individual had unique neurological deficits and individualized medication requirements, making it necessary for each subject to act as his or her own control. All formula, water, and medications had been provided exclusively by gastrostomy tube at least one year. All subjects had stable weights. Each received quantities of formula that were consistent with accepted recommendations for optimizing weight, yet were just below intakes empirically found to cause excessive weight gain, based upon ongoing individualized evaluations by staff dietitians.
Children and adolescents were excluded in order to avoid the hormonal and nutritional factors involving growth that may complicate interpretation of IGF-1 and amino acid patterns. In addition, individuals with the following conditions were excluded from the study: known gut absorptive defects (such as gluten-sensitive enteropathy and inflammatory bowel disease), diabetes mellitus, compromised renal function, liver disease, steroid therapy, HIV infection, cancer or identified inborn errors of metabolism.
During the week prior to blood sampling, all subjects received Osmolite HN or Jevity at their customary volumes. A 25% increase in the volume of formula was then introduced in two steps, first by increasing the daily volume by 15% for one week and then by an additional 10% for the final three weeks. (These incremental changes were used to minimize the risk of inducing gastroesophageal reflux.) As the volume of formula was increased, the volume of water was correspondingly decreased. All fluid volumes were carefully recorded by 10 mL increments. In order to meet minimum protein requirements, three subjects received additional protein supplementation with Promod® (Ross Laboratories, Columbus, Ohio). Body lengths (taking into account hip and knee contractures, but not scoliosis) and weights were obtained at the start of the project, and weights were measured weekly.
Subjects were divided into two Groups (Table 1), based solely on their pre-existing feeding schedules: Group A routinely received feedings several times during the day. Group B routinely received formula between 1800 hours and 0600 hours in order to accommodate daytime activity schedules, with the majority given between midnight and 0400 hours (Table 1). Blood specimens were drawn after ten-hour fasts just prior to the first increase in formula and on the last day of the 25% increase in formula intake. The ten-hour fast required that Group A samples be drawn at 0700 hours; Group B samples were collected at 1400 hours.
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Statistical Analysis
The plasma amino acid data were summarized statistically by Ross Laboratories. Descriptive statistics, t tests, and Pearson correlations were performed using Systat software (Systat, Inc., Evanston, IL). In order to reduce the risk of Type I errors in the context of multiple comparisons, the level of statistical significance was reduced to 0.02. All tests were two-tailed.
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RESULTS |
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Plasma concentrations of several amino acids (Table 3) were low compared to a group of normal people receiving similar amounts of protein, i.e., graduate students ingesting one gram/kg body weight/day. (Ross Laboratories, unpublished data) Most noteworthy were the initial low concentrations of tryptophan and phenylalanine in our study group. Following the supplemental formula, valine and phenylalanine increased, glutamine, glycine and threonine decreased, and tryptophan did not change. Although our standard for statistical significance was not reached, plasma tryptophan concentrations were marginally higher for Group A (day-fed) than Group B (night-fed) in both pre-supplementation (50.0±2.6 vs. 40.4±3.5 µmol/L, mean±SEM, p=0.05) and end-supplementation samplings (49.4±2.5 vs. 41.2±2.6, p=0.04). There were no differences in the other amino acid concentrations between Groups A and B.
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Nine subjects (40.9%), two of whom received valproic acid routinely, had serum Zn concentrations below the normal range (10.7–18.4 µmol/L) at the start of the study, and seven subjects had low concentrations at the conclusion of the study. However, there was no overall change after receiving the additional formula.
Prealbumin, although normal in both samplings, showed a significant increase at the end of the project (p<0.001).
Serum albumin concentrations were normal in both samplings, did not change during the study and initially correlated with plasma tryptophan (r=0.65, p=0.001) and serum Zn (r=0.62, p=0.002). At the conclusion of the study the correlation of albumin with tryptophan (r=0.51, p=0.01) and Zn persisted (r=0.76, p<0.001).
Slightly elevated C-reactive protein concentrations were noted in two subjects initially, one of whom had low IGF-1 that improved following the additional formula. A third individual had slightly elevated C-reactive protein at the end of the study. Although eight subjects received antibiotics for minor infections, these findings show that neither infection nor inflammation appeared to complicate interpretation of the data. Since all thyroid-stimulating hormone values were normal, none of the IGF-1 or amino acid abnormalities could be attributed to abnormal thyroid status.
Two subjects did not complete the study. One experienced vomiting believed to be due to severe constipation and required intravenous fluids. The other developed a severe urinary tract infection near the end of the study. Each of these individuals required temporary changes in intake judged likely to make analyses unreliable. Based upon extremely low initial and undetectable final IGF-1 concentrations, an abnormal sella turcica, and suspected hypopituitarism, the data from a third individual were excluded from analysis. No changes in routine medications were made except for minor alterations in those used to relieve constipation. Nineteen of the 22 people included in the analysis received anticonvulsants, with two receiving valproic acid. Circumstantially, 11 individuals received Osmolite HN, and 11 received Jevity.
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DISCUSSION |
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The importance of the availability of amino acids for the synthesis of IGF-1 has been documented by in vitro hepatocyte studies. Tryptophan is particularly crucial for protein synthesis, as observed by Harp et al. [11], who found significant declines in hepatic IGF-1 mRNA levels and IGF-1 release in culture media that are devoid of tryptophan or lysine. Supplementation with tryptophan to half-normal plasma concentrations raised IGF-1 concentrations to 78% of those from cells in complete media. Similarly, Brameld, et al. [12], using a pig hepatocyte culture system, showed dramatic dose-dependent reductions in IGF-1 mRNA synthesis involving arginine, proline, threonine, tryptophan and valine. An amino acid-responsive element that is particularly tryptophan-sensitive has been identified in the rat IGF-1 gene [12].
Plasma tryptophan is especially noteworthy in our study because it was low at both samplings and it correlated with circulating IGF-1 concentrations at the beginning of the study. Low plasma tryptophan was also found in a large sample of institutionalized, severely and profoundly retarded adults [13].
The plasma amino acid picture in our study was otherwise mixed, with features of both malnutrition and adequate intake. On one hand, the low concentrations of most essential amino acids (isoleucine, leucine, methionine, phenylalanine, tryptophan and valine) are consistent with malnutrition [14]. The improvement in the ratios of cystine/glycine, tyrosine/glycine and valine/glycine was also consistent with some degree of malnutrition [15]. On the other hand, normal albumin, prealbumin and glycine and low alanine concentrations were not typical of malnutrition [14]. Our results are consistent with a degree of hypoaminoacidemia, whether due to malabsorption or abnormal flux, despite normal total protein and high essential amino acid intakes. Except for tryptophan, the plasma amino acid pattern we observed is similar to that of formula-fed elderly men receiving similar quantities of protein (0.8–1.2 g/kg) that provided essential amino acids 1.0 to 2.9 times higher than the RDA [16]. Protein intake has a complicated effect on plasma amino acid patterns, depending upon a number of factors. In contrast to our findings, Forslund et al. [17] demonstrated a prominent inverse relationship between protein intake and plasma amino acids in healthy men ingesting T1 g/kg vs. 2.5 g/kg.
It is important to emphasize that the plasma essential amino acid concentrations observed in this study were neither due to inadequate intake of these nutrients (Table 4) nor the result of circadian change [18]. Even prior to receiving the supplemental formula, essential amino acids intakes were up to eight times the recommended intakes of the 1985 FAO/WHO/UNU Expert Consultation and more than twice the recent recommendations of Young and El-Khoury [19].
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Zn status alone may explain our observations regarding IGF-1. Roth and Kirchgebner found that the administration of a Zn-deficient diet to rats by gastric tube causes IGF-1 to fall [22]. Others reported that serum growth hormone-binding protein is regulated by dietary Zn, a deficiency of which causes parallel reductions in both growth hormone and serum IGF-1 [23]. In Zn-deficient children with short stature, Zn supplementation increased circulating IGF-1 and induced growth [24]. In a study of postmenopausal women, Zn intake was the major determinant of IGF-1 concentrations among age, body weight and 25 nutrient variables [25].
Based upon a Zn turnover model [26], a longer period of increased Zn intake may be required to observe changes in serum Zn concentrations and to optimize Zn pools. It is acknowledged that serum Zn is imprecise in determining Zn status. Although alternate methods are being investigated [27], serum Zn is the most commonly used and most readily available method of estimating Zn status. Anticonvulsants, especially sodium valproate, may also modify Zn status [26].
Caloric intake, another determinant of IGF-1, is lower than normal in people with severe developmental disabilities. It is therefore necessary to balance the risks of providing inadequate calories with the risks of obesity. Formulas for determining caloric requirements are imprecise when applied to individuals, and adjustments, based upon weight responses, are the primary way of optimizing intake [28]. It is uncertain whether a longer period of increased formula intake for our subjects would have resulted in further biochemical improvements, but excessive weight gain, based upon the trends observed in this study, would likely have occurred.
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CONCLUSION |
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ACKNOWLEDGMENTS |
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Received May 31, 2000. Accepted December 15, 2000.
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
