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National Institutes of Health (U.S.). Nutrition Co.

Annual report : National Institutes of Health. Program in Biomedical and Behavioral Nutrition Research and Training (Volume 1983) online

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tion of glucose transporters rapidly cycling in an exocytic/endo-
cytic-like fashion; insulin acts at a step whereby glucose trans-
porters associated with the plasma membrane become functional, and
cAMP-mediated counter- regulation of insulin-stimulated glucose trans-
port by catecholamines comprises both the regulation of the subcellu-
lar distribution of glucose transporters and the modulation of the
activity of those glucose transporters present in the plasma mem-
brane. Insulin also appears to stimulate glucose transport in iso-
lated guinea pigs and human adipose cells and rat diaphragm through
this same translocation mechanism. Basic research investigations
under way have also shown that the adipocytes of guinea pigs are in-
sulin resistant due to a reduced number of glucose carrier proteins.

Studies have also examined the effects of overnutrition on the devel-
opment of insulin resistance in subjects with normal glucose toler-
ance. The results thus far indicate that acute overnutrition does
play a role in the development of insulin resistance, and that chang-
es in glucose disposal rates are related to in vivo measurements of
non-oxidative glucose disposal rates as determined by indirect calor-
imetry.

Other studies have suggested that muscle glycogen depletion follow-
ing exercise in animals is associated with increased insulin sensi-
tivity. Studies in man have shown that after exercise, muscle glyco-
gen decreases significantly while muscle glycogen synthase activity

66



increases significantly, basal and insulin stimulated carbohydrate
oxidation rates decrease, and carbohydrate storage rates increase.
These results suggest that muscle glycogen synthase activity may be
rate limiting for carbohydrate storage rates and therefore for total
glucose disposal rates in glycogen depleted men.

Studies continue to attempt to learn more about the mechanisms of
action for various hormones and enzymes necessary for metabolism.
Gastrin, secretin, chol ecystokinin, and bombesin are being studied
through in vitro systems while the action of dihydrofol ate reductase
and its unique molecular biology are being examined in various ani-
mal studies.

Clinical research is under way to examine the relationship of nutri-
tional factors to the etiology, morbidity and mortality of metabolic
and other diseases or conditions, such as diabetes mellitus, perio-
dontal disease, cystic fibrosis, obesity, hypochloremic metabolic
alkalosis, and cystinosis. Clinical studies of the Pima Indians
have shown them to have the highest known prevalence and incidence
of noninsul in-dependent diabetes mellitus in the wrld. They also
have a high prevalence of obesity, low plasma cholesterol levels,
reduced low density lipoprotein (LDL) synthesis, and a decreased
incidence of cardiovascular disease. This population appears to be
insulin resistant as well as hyperinsul inemic; the hyperinsul inemia
found in Pima children is thought to contribute to the development of
obesity and diabetes in adulthood. Recently, a study to examine the
possible relationship of periodontal and other oral diseases to
diabetes in this population has begun. Lipoprotein metabolism in
Pima Indians is being investigated in order to further understand
the control of lipoprotein metabolism and how lipid metabolism is
influenced by obesity and diabetes. Preliminary studies have shown
that a large proportion of VLDL is metabolized without conversion to
LDL and therefore this alternate pathway might be a mechanism for
maintenance of the low LDL levels in this population. Obesity was
also associated with an increased flux of free fatty acids without
increasing plasma concentrations, which could account for increased
VLDL production in these individuals. Total plasma cholesterol and
VLDL levels increased with increasing obesity whereas high density
lipoprotein (HDL) cholesterol decreased.

It has also been proposed that the high incidence of obesity in the
Pima Indians may be due to a thrifty gene, one that would predispose
them to store energy more efficiently. It appears that in the obese
Pimas, although their basal plasma concentrations of norepinephrine
is similar to that of Caucasians, plasma levels are higher following
norepinephrine infusions. Thus, they appear to suffer from a clear-
ance defect for norepinephrine as well as a decreased thermogenic re-
sponse to the homione following overfeeding. The studies suggest a
large flux of substrates and regulators (i.e., insulin) which causes
the overproduction of lipoproteins; however, compensatory mechanisms
are operative that result in the maintenance of low plasma concen-
trations.



67



Two South Pacific popu1ations - the Polynesians of Rarotonga and
Melanesians of New Hebrides - are also being studied in terms of
differences in lipoprotein metabolism. Data indicate that cholester-
ol and triglyceride levels in the Rarotongas were higher than those
in the Melanesians, and that the Rarotongas have a higher incidence
of cardiovascular disease.

In clinical studies of cystic fibrosis (CF), attempts are being made
to define more precisely the abnormalities that contribute to the
pulmonary and gastrointestinal symptoms of this disease. Lingual
lipase activity is being studied in order to further clarify its role
in fat absorption in these patients, while serum amylase and its
isoenzymes are also being analyzed for diagnostic purposes. The
altered fatty acid composition found in the blood and tissue lipids
of patients with CF is more often found in those patients with malab-
sorption problems than in those with normal pancreatic function.
Recent studies suggest that the lower caloric intake of the CF pa-
tient relative to their caloric requirement may lead to an increased
utilization of absorbed essential fatty acids (i.e., linoleic acid).

From studies on the pathogenesis of cystinosis, an inherited disorder
characterized by excessive intralysosomal accumulations of the amino
acid cystine, it appears that the disorder is due to a defective
carrier mechanism required for the escape of L-cystine from the
intralysosomal space; this explains the large accumulation of cystine
found in this disease.

The evaluation of hypersensitivity reactions after the ingestion of
foods continues to be an important research area supported by NIAID.
The clinical management of food hypersensitivity (allergy) is compli-
cated by the need for extensive differential diagnosis, the absence
of definitive diagnostic procedures, and the lack of satisfactory
prophylactic therapy. In general, the approach to the management of
food allergy is the same as the approach to the management of aller-
gic diseases of the skin and of the upper and lower respiratory
tracts: identification of the offending agent and the treatment of
adverse reactions. Results from one study of 45 patients with a
history of immediate adverse reactions to foods showed that the
majority of the reactions involved the gastrointestinal tract alone
or in combination with the skin or respiratory tract, and that the
foods most frequently involved were shellfish, peanuts, eggs, fish,
tomatoes, and walnuts. The data suggest that an immediate adverse
reaction to food may initially present itself in adulthood. These
individuals tend to be atopic, usually three or fewer foods are
implicated, and sensitivities may persist for years.

Investigations are also under way on the effects of other agents,
such as sulfites added to foods as preservatives, on severe asthmat-
ics and individuals with recurrent idiopathic anaphylaxis and system-
ic mastocytosis. Preliminary data on patients with these diseases
who are given increasing amounts of the sulfites suggest that the
majority of patients with idiopathic anaphylaxis and systemic masto-
cytosis are not sensitive to sulfites. However, a subset of severe
asthmatics do react adversely to sulfites with increased difficulty
in breathing.

68



studies carried out as part of the NICHD intramural nutrition program
range from research on molecular genetics, inborn errors of metabo-
lism, and endocrinological and reproductive research, to epidemiolog-
ical research on breast versus bottle feeding. Studies on genetic
expression with nutritional deficiencies have shown that with a
nutrient imbalance, guanosine 3,5'bipyrophosphate (ppGpp) is in-
volved in the expression of approximately one-half of the _E. col i
genes, but has no regulatory effects during normal growth. Lethal
consequences of the £el_ S mutation, which abolished ppGpp accumula-
tion during energy starvation, have been observed. The rel A and rel
S double mutant is markedly defective in its ability to curtail
cellular functions when adapting from luxuriant growth to nutritional
impoverishment.

Research continues on various inborn errors of metabolism, including
cystinosis, glutathione synthase deficiency, gl utathionuria, gamma
glutamyl cysteine synthase deficiency, homocystinuria, glucose-6-
phosphate dehydrogenase deficiency, phenylketonuria, galactosemia,
and adrenal leukodystrophy; investigators are particularly interested
in developing nutritional therapy and new diagnostic techniques in
these conditions. The etiology of cystinosis has been discovered and
the first transmembrane lysosomal transport system for amino acids
has been identified. The investigator plans to determine which small
molecules are carried across the lysosanal membrane and what is the
basic defect in lysosomal diseases that involve the storage of free
compounds. Currently, treatments of such diseases that are being
investigated include using pantethine for cystinosis, betaine for
homocystinuria, and cysteamine for type III hyperli pidemia. A clini-
cal trial is examining the safety and efficacy of cysteamine for the
treatment of children with nephropathic cystinosis, a metabolic
disease that leads to end-stage renal disease before 10 years of age.
Cysteamine' s effectiveness will be evaluated by determining the
creatinine clearance values of the treated children.

The study of obesity in children with Prader-Willi syndrome attempts
to detect the anatomic and physiological causes for the lack of the
sense of satiety, to establish whether the mechanism involved is the
same as in patients with exogenous obesity, to identify any special
biochemical or physiological features in these patients, and to
determine the pattern of absorption and metabolism of carbohydrates
in Prader-Willi patients and those children with exogenous obesity.

Children being treated for glycogen storage disease (GSD) have shown
significant improvanents in maintaining normal blood glucose levels
with the administration of corn starch every 6 hours. These studies
also investigate the possible therapeutic effects of glucose, poly-
cose, rice starch, potato starch, cooked corn, cooked potato and
cooked rice containing equivalent amounts of complex carbohydrates in
maintaining normal blood glucose levels in these patients. The
usefulness of starch administration in mollifying and preventing the
myopathy of Type III GSD is also being examined.



69



The use of magnesium in infants with apnea and bradycardia is being
investigated since animals deficient in magnesium often develop
these symptoms. Magnesium deficiency in animals appears also to
manifest itself with retention of magnesium by the kidney. Since rat
dams fed 150 mg of magnesium (MgCO^) appear to suffer high fetal
wastage, investigators are looking into the effects of feeding dolo-
mite [CaMg (CO^)^] in these animals. Investigators also are examin-
ing the effects of prolonged furosemide administration on magnesium
metabolism; changes of bone magnesium and calcium in very young
nursing rats with congenital magnesium deficiency; histopathological
changes in the lungs of rats with acute magnesium deficiency using
light and electron microscopy; the distribution of neurotransmitters
by fluorescence microscopy studies; the pathogenesis of the shock-
like episode of magnesium deficiency through studies of neurotrans-
mitters release; and differences between congenital and acquired
magnesium deficiency in young animals.

Other studies examine the trace elements of sodium and calcium, as
well as the use of vitamin supplements. These studies look at the
physiological and pathological aspects of the renin angiotensin
system with emphasis on the regulation of aldosterone secretion.
Specific issues include the regulation of adrenal sensitivity to
angiotensin II during altered sodium intake and the mechanisms of
steroidogenesis in the adrenal glomerulosa cell. Changes in the
kinetics of calcium metabolism in normal children at various stages
of growth from infancy to puberty are also under investigation.
Another study is examining whether there is a link between vitamin
supplements taken in the periconceptional period and the risk of
neural tube defects in the infant.

Research on the effects of ethanol on the mother and fetus and on the
possible manifestation of fetal alcohol syndrome (FAS) is an impor-
tant area of nutrition research. Studies that are under way attempt
to identify and characterize the biochemical markers in children
that may predispose them to alcoholism and/or alcohol -induced demen-
tia in adulthood; to explore the biochemical mechanisms of fetal
alcohol syndrome; to develop new methods to treat borderline FAS
children in order to improve their postnatal growth and central
nervous system retardation; to delineate the effects of a thiamine
deficient diet and ethanol on fetal development using an animal
model; and to determine the effects of ethanol on various neuro-
peptides.

Investigators have also shown that changes in thyroid hormones during
hypocaloric feeding in humans can now be demonstrated with the use of
the pulse wave arrival time (QKd) . Data have shown that with pro-
longed hypocaloric feeding, the QKd is prolonged, and therefore,
suggests hypothyroidism at the target organ level. Oral supplementa-
tion with T^ rather than T- prevents these changes in QKd. Changes
observed in peripheral thyroid hormone levels during hypocaloric
feeding appear to be due to adaptive mechanisms that result in hypo-
metabol ism.



70



Results from the study on trends in breast and bottle feeding in Pima
women of the Gila River reservation have shown that parity had a
positive association with bottle feeding. The highest proportion of
bottle feeders occurred among women with small families before 1963
and with large families after 1963. Prenatal and postnatal care had
a limited influence on the determinants of breast and bottle feeding.
The study shows that mother and infant-oriented reasons dominated in
the selection of breast or bottle feeding the first infant; while
work-related reasons had a stronger influence on the decisionmaking
process for feeding the last child. This study will now determine
whether breast feeding or bottle feeding is associated with reduced
infections in children.

Another study of 1,275 American mothers, 800 of whom are breast
feeders and 475 are bottle feeders, includes examination of independ-
ent and joint effects of various factors on the frequency and dura-
tion of breast and bottle feeding. These factors include prenatal
and postnatal medical services; the mother's perception of support
from peers, family and medical environments; confidence, enthusiasm
and attitude of the mother toward breast feeding; sociodemographic
factors; physiological conditions; and the initial feeding pattern,
as well as changes over time.

NEI investigators are examining associations between specific nutri-
ents and normal ocular health and function, as well as various ocular
diseases. A new intracellular binding protein for retinoids has been
identified in the subretinal space; research continues to elucidate
the protein's role in ocular vitamin A metabolism and document its
appearance at progressive stages of embryonic and newborn develop-
ment.

Concentrations of vitamins A and E in the pigmented rat retina and
retinal pignent epithelium are known to affect the formation and
accumulation of lipofuscin pigment. It was found that the amount of
lipofuscin in the retinal pigment epithelium (RPE) is a linear func-
tion of the logarithm of dietary vitamin A levels whereas vitamin E
deficiency accelerates the accumulation of lipofuscin in RPE, which
is identical to the pigment that accumulates with aging. Vitamin A
deficiency in rats results in a striking decrease in the amounts of
lipofuscin that accumulates in RPE as a result of normal aging or
vitamin E deficiency. Scientists are also studying independent
changes in lipofuscin associated only with the aging process.

Investigators examine the distribution of calcium, copper and zinc
concentrations in the retina, pigmented epithelium, choroid, and
biological fluids in animal models of human retinal degeneration and
in human retinal diseases. The effects of nutrition and genetic
background on the progress of chorioretinal degeneration in the
retinal dystrophic pigmented RCS rat are under investigation as well
as the etiologies of cataracts and gyrate atrophy. The various
etiologies of cataracts being examined include: the distribution of
inorganic elements such as copper, zinc, selenium, and calcium in
cataracts associated with retinal degeneration; the role of exogenous
or endogenous oxidative stress in the formation of cataracts; and



71



changes in the composition and metabolism of lipids in the plasma
membranes and lenses. Inhibitors to the formation of cataracts
through the limitation of aldose reductase activity are also being
explored. The potential role of aldose reductase and pyrrol ine-5-
carboxylate reductase in cataractogenesis is being investigated. The
latter enzyme is involved in the metabolic conversion of ornithine
and glutamine to proline, and therefore, may regulate the cellular
redox potentials and increase ATP levels through the pentose shunt.
Studies of gyrate atrophy attempt to determine how dietary manipula-
tions of pyridoxine administration modify ornithine levels and, in
fact, arrest or improve conditions associated with the disease. A
study of senile macular degeneration investigates whether the admini-
stration of vitamin E and vitamin C protects against vision loss in
the good eye of persons suffering from senile macular degeneration in
the other eye.

Nutrition as it relates to the aging process is being studied by
NIA's intramural scientists in both animal models and human subjects.
One area of interest is the mechanism(s) by which undernutrition
affects various physiological functions with aging. In one study of
male Wistar rats subjected to dietary restriction by alternate days
of feeding and fasting, the normal age-associated loss of striatal
dopamine receptors in the brain was substantially retarded. For
example, the dopamine receptor concentrations in the striata of 24-
month-old rats that had been on the restricted diet since weaning
were 50 percent greater than those of the control animals of the same
age given free access to food. Data collected on the rate of activi-
ty of specific enzymes with age support the concept that the rate of
aging of most biochemical variables is decreased in those animals
with dietary restrictions. However, dietary restriction did not
significantly increase the life span of the animals. In fact, in
animals aged 17 to 19.5 months a diet providing 50 percent of the RDA
for vitamins decreased their life expectancy. Longevity in these
animals therefore may be increased by ensuring the ingestion of the
RDA for vitamins daily.

Dietary restriction is also being studied in experiments using the
monkey Macaca mulatta , in terms of its effects on age-related behav-
ioral changes such as motor performance, thermoregulation, learning,
and memory.

Another study is examining the relationship of age to the biological
responsiveness of hormones and hormone sensitive tissues. Age-relat-
ed alterations of beta-adrenergic mediated lipolysis in the rat
indicate that the amount and type of fat in the diet affect the
hormone sensitive lipolytic response. Dietary fat was shown to have
a profound effect on the lipid composition of cell membranes, which
in turn controls the activity of numerous cell membrane enzymes
including the hormone sensitive adenylate cyclase system.

Dietary fat, however, does not affect every tissue in the same way
within the same animal, e.g., a diet high in unsaturated fat has
little or no effect on fat cell membranes but greatly affects liver
cells, which exhibit an increased hormone responsiveness to both



72



catecholamines (epinephrine) and the polypeptide hormones (glucagon).
In addition, a high fat diet inhibits to a large degree lipolytic
responsiveness. The control of lipolysis with age is a complex area
of nutrition research and will require further research on the inter-
relationships of diet and aging.

An important aspect of the NIA intramural program involves human
studies under way as part of the Baltimore Longitudinal Study of
Aging (BLSA), initiated in 1958 to observe the same subjects over a
long period of time in order to quantify true age changes and eluci-
date the mechanisms underlying these changes. The study group in-
cludes 1,000 male and female subjects, ranging from 20 to 96 years of
age, who return every 2 years for reevaluation and are enrolled in
the study for life. Cohorts from this study population are being ex-
amined for changes in bone and skeleton, oral health status, salivary
gland function, taste thresholds, plasma lipids, and nutrient intake.

Osteoarthritis, a degenerative joint disease, and bone loss are the
two principal age-related changes to the human skeleton. Advanced
cases of the former produce severe restrictions of movement associat-
ed with pain, while advanced bone loss is likely to result in osteo-
porosis and frequent bone fractures. Dietary, genetic, and epidemio-
logical factors are being examined in terms of their effects on three
skeletal sites - hand-wrist, ulna and radius, and vertebral column - of
three different populations, i.e., the participants of the Baltimore
Longitudinal Study, a sample of Guamanians (Chamorros), and among
patients afflicted with amyotrophic lateral sclerosis/parkinsonism
dementia complex of Guam.

Demographic, socioeconomic and dental characteristics are being
determined in 254 BLSA participants, who will serve as a basic study
population for future cross-sectional and longitudinal investigations
of aging and oral health status and function. One study of salivary
gland function in BLSA subjects has shown a linear decrease in sodium
secretion into the stimulated parotid salivary gland function with
age. Males showed a greater decrease than females.

Studies on quality-specific variation in taste thresholds with aging
include the detection of taste thresholds for the four basic taste
qualities in 81 adults between 23 and 88 years of age. Data indicate
that sodium chloride thresholds have a small but significant increase
with age; quinine sulfate thresholds have a similar increase but are
less significantly related to age; sucrose and citric acid thresholds
are not significantly related to age; and citric acid thresholds
appear to be different in males and females. Thus, the detection
thresholds for the four taste qualities undergo different changes
with age.

An analysis of plasma cholesterol values in BLSA participants show
that levels increase in early adult life and decrease in late life.
All age cohorts showed a significant decline in plasma cholesterol
levels between the 1950' s and 1970' s. The change in body weight,
polyunsaturated/saturated fatty acid ratio in the diet, and dietary
cholesterol explains only a small percentage of this secular effect.



73



In order to gain insight on the nutrient intake across the adult age
span, 180 BLSA male participants recorded 7-day dietary diaries
during three time periods: 1961 to 1965, 1966 to 1970, and 1971 to
1975. At the time of the first dietary diary, their ages ranged from
35 to 74 years. The analysis of the effects of aging, cohort, and
time on diet utilized three research designs concurrent1y - cross-
sectional , longitudinal, and time series. The nutrients considered
were calories, protein, carbohydrate, fat, saturated fatty acids,
polyunsaturated fatty acids, and cholesterol. The data indicate that
the intake of calories, fat, saturated fatty acids, and cholesterol
decrease with age, while polyunsaturated fatty acid intake increased.
Cohort effects were not observed for any of the nutrients.


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Online LibraryNational Institutes of Health (U.S.). Nutrition CoAnnual report : National Institutes of Health. Program in Biomedical and Behavioral Nutrition Research and Training (Volume 1983) → online text (page 9 of 21)