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Original Studies |
Department of Medicine (N.S.L.), Medical Research Council/University of Cape Town Bioenergetics of Exercise Research Unit (E.V.L.), and Department of Pediatrics and Child Health (D.W.), University of Cape Town Medical School, Cape Town 7925, South Africa; Department of Clinical Biochemistry, University of Cambridge (C.N.H.), Cambridge CB2 2QR, United Kingdom; and Molecular Medicine Center, University of Edinburgh (R.A., J.R.S.), Edinburgh EH4 2XU, Scotland
Address all correspondence and requests for reprints to: Prof. Naomi S. Levitt, Department of Medicine, University of Cape Town, Faculty of Health Sciences, Observatory 7925, Cape Town, South Africa. E-mail: dinky{at}uctgsh1.uct.ac.za
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Abstract |
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Twenty-year-old, historically disadvantaged, urbanized South Africans (n = 137) with birth weights either below the 10th percentile [underweight for age (UFA)] or between the 25th and 75th percentiles [appropriate for gestational age (AFA)] had anthropometry, blood pressure, lipid levels, and glucose tolerance measured. In a subset (n = 62), 0900 h plasma cortisol concentrations, cortisol responses to 1 µg ACTH, and urinary glucocorticoid metabolites were measured.
The mothers of UFA infants were themselves lighter and had a lower body mass index (P = 0.0016). At age 20 yr, although the UFA group was still smaller and lighter, with a lower body mass index, they had higher fasting plasma glucose levels (P = 0.047), and a greater proportion demonstrated glucose intolerance (11.9% vs. 0%; P < 0.01). The UFA group also had higher systolic [UFA, 126.0 ± 13.3 (±SD); AFA, 122.0 ± 11.7 mm Hg; P = 0.007] and diastolic (72.3 ± 8.4 vs. 69.5 ± 8.7 mm Hg; P = 0.02) blood pressures, after covarying for current weight and gender. Plasma cortisol levels determined at 0900 h were higher in the UFA group (484.9 ± 166.3 vs. 418.6 ± 160.6 nmol/L) and showed a greater plasma cortisol response to low dose ACTH stimulation (area under the curve for cortisol: UFA, 77,238 ± 19,511; AFA, 66,597 ± 16,064 nmol/L·min; P = 0.04). In conclusion, the link between low birth weight and adult glucose intolerance and blood pressure elevation occurs in young adults in a high risk, disadvantaged population despite a lack of full catch-up growth. Moreover, cortisol axis activation is an early feature in the process linking low birth weight with adult cardiovascular and metabolic disease and is not dependent upon adult obesity or full catch-up growth, at least in this population undergoing the health transition.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Two major mechanistic hypotheses have been proposed to explain fetal programming: maternal malnutrition and prenatal glucocorticoid exposure (3, 10, 11, 12). Both are supported by animal experiments with limited human data. In rats, dietary restriction of protein during pregnancy lowers birth weight and produces subsequent glucose intolerance and hypertension in adulthood (13, 14). Women starved in the last trimester of pregnancy during the 1944/1945 Dutch famine produced lower birth weight babies who, in adulthood, showed reduced glucose tolerance, although no effects on blood pressure were reported (15). In rats, prenatal exposure to excess exogenous (dexamethasone) or endogenous glucocorticoids (inhibition of the feto-placental enzymatic barrier to maternal glucocorticoids, 11ß-hydroxysteroid dehydrogenase type 2) also results in lower birth weight and permanently elevates blood pressure and glucose and insulin levels in the adult offspring (16, 17, 18). Both mechanisms have been postulated to reset neuroendocrine pathways that may induce and maintain the adult sequelae (11, 12). Indeed, in both rats and humans, low birth weight is associated with higher glucocorticoid concentrations in later life, which might contribute to the adult phenotype (19, 20). Whether this is a cause or a consequence of the adult phenotype following low birth weight is unclear. In particular, in humans, the key observations of elevated plasma cortisol levels in those who had low birth weights has been shown in adults in their seventh decade, many of whom already have other manifestations of the "fetal origins" phenotype (20) that per se might contribute to hypothalamic-pituitary-adrenal (HPA) axis dysregulation. Moreover, it is unclear whether higher morning cortisol levels in adults from low birth weight cohorts are a reproducible finding and whether they are accompanied by altered responses of the HPA axis to stimulation.
There has been a paucity of epidemiological studies examining the association between birth weight and subsequent elevated blood pressure, glucose intolerance, and dyslipidemia from developing countries undergoing the epidemiological health transition from a predominance of infectious diseases to an increasing incidence of age-related degenerative cardiovascular and metabolic disorders (21, 22, 23, 24, 25, 26). Little work has been directed at potential underlying mechanisms in these settings. In South Africa, the community of mixed ancestry, derived from Koi San (original hunter-gatherer inhabitants of South Africa), European, East Indian, Malaysian, and Bantu-speaking black Africans is typically a low income working class group that has only recently become urbanized. This group has the highest rate of low birth weight among the South African communities and also has a so-called triple mortality pattern, reflecting high rates of death due to infectious disease, trauma, and chronic degenerative disease, in particular stroke and ischemic heart disease (27). In addition, this community has a diabetes prevalence of 10% and a hypertension prevalence of 25% (28, 29). Dissection of adult risk factors (notably obesity) from any effects of early life is critical in such populations at high risk of adult cardiovascular and metabolic disorders. Therefore, in a cohort of young, nonobese adults from this disadvantaged community, we investigated 1) the relationship between birth weight and glucose intolerance, blood pressure, and dyslipidemia; and 2) whether there was any association between birth weight and dysregulation of the HPA axis as assessed by plasma cortisol at 0900 h and under ACTH-stimulated conditions as well as glucocorticoid metabolism.
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Subjects and Methods |
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In 1975 and 1976 the maternal and neonatal characteristics of primigravid women of mixed ancestry were studied at the Groote Schuur Hospital Maternity Center. In the original cohort there were 1077 singleton infants born at full term (37–41 weeks) whose birth weight fell on or below the 10th percentile [underweight for gestational age (UFA)] or between the 25th and 75th percentiles for gestational age [appropriate weight for gestational age (AFA)]. As part of the study protocol, each child was gestationally scored using the Dubowitz method on the day after birth. Birth weight, length, head circumference, placental weight, ponderal index, maternal age, height, and in most cases maternal postdelivery weight were recorded. From this cohort a random sample of 133 AFA boys and 146 AFA girls was drawn from the 846 AFA births, and all 231 UFA children were included in the current sample. Tracing of these individuals was attempted using maternal hospital records, children’s hospital records, and the voters roll. Those found were invited to participate in the study. For the current study, 25 AFA boys, 39 AFA girls, 38 UFA boys, and 35 UFA girls were traced; this comprised 23% of the AFA and 32% of the UFA children. This low recovery rate may be attributed to socio-political factors, in particular the forced dislocation of entire neighborhoods, combined with the difficulty of tracing, in many cases, the offspring of single mothers.
Protocol
At the age of 20 yr, each subject’s primary caregiver, usually the mother, was interviewed to obtain data on maternal health and socio-economic status at the time of pregnancy and the health status of the subject as a child. The participant was interviewed to obtain socio-demographic and health-related data, including current socio-economic status. Socio-economic status was characterized on the basis of parental education and housing density.
Oral glucose tolerance testing
The subjects were invited to attend the clinical center in the morning after an overnight fast, and the following investigations were carried out: anthropometry, blood pressure, fasting serum lipid profile, and glucose tolerance tests. Each subject had an indwelling cannula inserted into an antecubital vein and underwent a standard 75-g oral glucose tolerance test (OGTT; 75 g glucose monohydrate in 250 mL water). Blood samples were drawn fasting and at 30, 60, 90, and 120 min after glucose ingestion; glucose concentrations were measured at all time points; insulin was measured at 0, 30, and 120 min; and proinsulin, 32/33 split proinsulin, and lipid concentrations were measured in the fasting samples. Blood for glucose estimations was collected in tubes containing fluoride. All samples were kept on ice and centrifuged, and the plasma was stored at -20 C until assayed.
Anthropometric measurements
Height was measured using a stadiometer with subjects standing upright, without shoes to the nearest 0.5 cm. Weight was measured on a calibrated SECA beam balance (Hamburg, Germany), without shoes and in lightweight clothing to the nearest 0.1 kg. Waist circumference was measured with the individual standing in the upright position, in a horizontal plane midway between the superior iliac crest and the rib cage in the midaxillary line, at the end of normal expiration, to the nearest 0.1 cm. Hip circumference was measured as the largest horizontal circumference at the maximum protrusion of the buttocks with the feet together. Four skinfold sites were measured, i.e. triceps, biceps, subscapular, and suprailiac, using a Harpenden caliper (Holtain, London, UK). The sum of the skinfold measurements was used as a proxy for body fatness. Head circumference was also measured to the nearest 0.1 cm.
Blood pressure
Blood pressure was measured three times at 1-min intervals in each subject using an appropriately sized cuff and a Space Labs 90207 ambulatory blood pressure monitor (Spacelabs Inc., Redmond, WA). These measurements were taken after at least 20 min of seated rest. An average of the last two readings was used in the analyses.
HPA
A representative subsample of the original participants was approached for HPA testing, of whom 68 subjects agreed to participate. These comprised 36 UFA subjects (20 men and 16 women) and 32 AFA subjects (15 men and 17 women). There were no significant differences in any anthropometric variables in the participants between the original sample and the subsample.
Low dose ACTH test
Each subject attended the clinical center in the morning after fasting for 10 h. On arrival, an indwelling cannula was inserted into an antecubital vein. Fifteen minutes later, at 0830–0900 h, two basal blood samples were drawn at 15-min intervals. Thereafter, a 1-µg bolus iv injection of synthetic ACTH (Cortrosyn) was given (30). Additional blood samples were drawn 15, 20, 30, 60, and 120 min after the injection. All samples were centrifuged, and the plasma was stored at -20 C until assayed for cortisol.
Urinary glucocorticoid metabolites
On the night before the test subjects collected their urine over a timed, 12-h period. In the morning, aliquots were taken and stored at -20 C.
Anthropometry, blood pressure, and heart rate
These measurements were all repeated using the methods described earlier. Heart rate was also measured using the Space Labs blood pressure and heart rate monitor.
Both studies were approved by the University of Cape Town ethics and research committee, and the participants provided signed consent.
Definitions
Diabetes and impaired glucose tolerance were diagnosed using the 1985 WHO criteria (31). Insulin resistance was examined using the Homeostasis (HOMA) model (32): fasting insulin, proinsulin, and 32–33 split proinsulin concentrations (33). Insulin secretion was assessed using the 30-min insulin increment to the 30-min glucose increment (33) and HOMA ß-cell model (32). Fasting total immunoreactive insulin (sum of specific serum insulin, proinsulin, and 32–33 split proinsulin) was used in the HOMA model.
Laboratory methods
Plasma glucose was measured using the glucose oxidase method on a Beckman Coulter, Inc., autoanalyzer (Palo Alto, CA). Plasma total cholesterol, high density lipoprotein cholesterol, and triglyceride concentrations were measured enzymatically using standard methods (Hitachi 911 autoanalyzer, Roche Molecular Biochemicals, Mannheim, Germany). Low density lipoprotein cholesterol was calculated from cholesterol, high density lipoprotein cholesterol, and tri-glycerides using the Friedewald equation. Serum insulin, proinsulin, and split proinsulin were measured by specific immunometric assays in Cambridge, UK (34). Plasma cortisol was measured using an ACS autoanalyzer (Chiron Diagnostics Corp., East Walpole, MA). Cortisol and its metabolites were measured in urine using electron impact, gas chromatography-mass spectrometry after Sep-Pak C18 extraction, as previously described (35). Total glucocorticoid metabolite excretion was determined as the sum of the cortisol and cortisone metabolites.
Statistics
The results are expressed as the mean ± SD.
Plasma glucose, serum insulin, proinsulin, split proinsulin, and
urinary cortisol metabolite concentrations were not normally
distributed and were log transformed before analysis. The area under
the curve calculations were completed using GraphPad-Prism, version 3.0
for Windows (GraphPad Software, Inc., Berkeley, CA). The
significance of differences between groups was examined using
ANOVA, covarying for weight and gender where appropriate. Repeated
measures ANOVAs were used for the OGTT and the ACTH stimulation
test, also covarying for weight and gender. Where significant time
differences were found, Scheffe’s post-hoc analysis was
performed. 
2 tests were used to assess
intergroup differences in proportions or prevalences. Pearson
correlation coefficients were used for simple correlation analyses. A
P level of 0.05 was considered statistically
significant.
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Results |
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Maternal and birth characteristics
Birth weight, length, ponderal index, and placental weight were
significantly lower in the UFA group (Table 1
), but gestational ages were similar in
UFA and AFA groups, suggesting that the UFA infants were both stunted
and wasted. Mothers with UFA infants were shorter and over 9 kg lighter
immediately postdelivery than those of AFA infants. There were no
differences in the frequency of alcohol use or smoking during
pregnancy, nor were there differences between groups in the proportion
of mothers with either gestational diabetes or hypertension. A smaller
proportion of mothers of UFA infants had education beyond primary
school (P < 0.015).
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There were significant effects of both gender and birth weight on
adult height, weight, body mass index, sum of skinfolds, and head
circumference (Table 2). Allowing for sex
differences, the UFA babies grew up to be lighter, shorter, and
thinner, with less sc fat and a smaller head circumference at age 20
yr, compared with those who were AFA.
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After covarying for body weight, fasting plasma glucose levels
were higher in the UFA group (P = 0.047), but the
glucose responses to the OGTT did not differ significantly in the two
groups (Table 3). There were also no
differences in fasting or glucose-stimulated serum insulin, fasting
proinsulin, or split proinsulin concentrations or in the ratio of the
30-min increment in insulin over the increment in plasma glucose
concentrations, HOMA insulin resistance (IR), and HOMA ß-cell
between the two groups. Seven of the UFA subjects (11.9%) had either
impaired glucose tolerance (n = 6) or type 2 diabetes (n = 1)
compared with none of the AFA subjects (P < 0.01).
These seven subjects did not differ from the AFA subjects in weight,
waist circumference, or sum of skinfolds. However, HOMA IR (3.37
± 1.86 vs. 1.91 ± 1.24; P = 0.004)
and HOMA ß-cell (494.3 ± 573.7 vs. 167.5 ±
131.2; P = 0.0001) were higher in the seven subjects
with impaired glucose tolerance or type 2 diabetes, than in the AFA
subjects. Compared with the other UFA subjects, the seven with impaired
glucose tolerance/type 2 diabetes had significantly higher HOMA IR
(3.37 ± 1.86 vs. 1.76 ± 0.89; P
= 0.004) and HOMA ß-cell (494.3 ± 573.7 vs.
128.2 ± 84.6; P = 0.0001), but did not differ in
weight, waist circumference, or sum of skinfolds. Even after these
seven subjects were excluded, fasting glucose levels remained
significantly higher (P = 0.05) in the UFA group.
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After covarying for body weight and gender, systolic and diastolic
blood pressures were significantly higher in the UFA group (Table 4). When the subjects with altered
glucose homeostasis were excluded, blood pressures were no longer
significantly higher in the UFA group. The seven UFA subjects with
impaired glucose tolerance/diabetes had higher systolic blood pressures
than the remainder of the UFA group [systolic blood pressure,
136.8 ± 13.0 vs. 123.5 ± 12.5 mm Hg
(P = 0.02); diastolic blood pressure, 76.0 ± 8.2
vs. 71.4 ± 8.7 mm Hg (P = NS)] and
the AFA group [136.8 + 13.0 vs. 121.1 ± 11.2 mm Hg
(P = 0.0005); diastolic blood pressure, 76.0 ±
8.2 vs. 69.2 ± 9.0 mm Hg (P = NS)].
There were no significant differences in plasma triglyceride and
cholesterol concentrations and cholesterol subfractions between groups.
Other proposed indexes of an adverse intrauterine environment, such as
ponderal index, placental weight, placental to birth weight ratio, head
circumference, and birth weight or length to head circumference ratios,
were not associated with differences in blood pressure or glucose
tolerance. This may be due in part to incomplete data for placental
weight and head circumference.
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In the subset having glucocorticoid analyses, 0900 h plasma
cortisol concentrations were significantly higher in the UFA than the
AFA group (Fig. 1). Moreover, in response
to ACTH stimulation, there were main effects of birth weight group and
time on plasma cortisol levels; however, there was no group x
time interaction effect. Plasma cortisol levels in both groups were
significantly higher at 15–60 min compared with 0900 h plasma
cortisol concentrations (P < 0.001; Fig. 1). However,
plasma cortisol levels were significantly higher in the UFA group
across all time points from 0–60 min (P = 0.04).
Similarly, the area under the plasma cortisol curve from 0–60 min was
greater in the UFA group (P = 0.04; Fig. 1). These
differences in plasma cortisol persisted after covarying for current
weight and gender and also persisted when subjects with altered glucose
tolerance were excluded from the UFA group. There were no significant
differences in any specific urinary glucocorticoid metabolites between
the UFA and AFA groups (data not shown), although the variance was
large.
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Overall, systolic blood pressure correlated significantly with
current adult weight (r = 0.32; P = 0.011), waist
(r = 0.39; P = 0.001), height (r = 0.40;
P = 0.001), basal plasma cortisol (r = 0.34;
P = 0.006), post-ACTH cortisol (r = 0.28–0.30),
urinary 5ß-tetrahydrocortisol (r = 0.30;
P = 0.003) and 5
-tetrahydrocortisol (r =
0.31; P = 0.02), urinary free cortisol (r = 0.36;
P = 0.009), and total glucocorticoid metabolite
concentrations (r = 0.32; P = 0.02). Diastolic
blood pressure showed similar relationships.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Low birth weight at term, as estimated using the recognized Dubowitz method, was associated with glucose intolerance and increased blood pressure, but not dyslipidemia in 20-yr-old adults. These data are in accord with the few studies in subjects of similar age as well as the numerous reports in older adults (2, 4, 5, 6, 7, 8, 9, 26, 36). However, the current findings are particularly pertinent as they occurred in the context of a socio-economically disadvantaged community undergoing the health transition, in which low birth weight is common (15%) and the age-standardized adult prevalences of diabetes and hypertension are substantial (10% and 25%, respectively) (28, 29). Moreover, these relationships were found despite lack of full catch-up growth, adult obesity, or abdominal fat accumulation, known risk factors for insulin resistance, glucose intolerance, hypertension, and ischemic heart disease. In this study low birth weight could not be explained by higher rates of maternal smoking or alcohol intake. Interestingly, however, low birth weight occurred in offspring of mothers who were smaller, weighed less, and attained a lower level of education than the mothers of the AFA group. Low maternal socio-economic status, as measured by lesser level of education, could be implicated in the low birth weights observed. This may be a manifestation of an intergenerational effect, an idea supported by evidence that short mothers have an increased risk of small babies (37). Moreover, recent data show potent intergenerational environmental effects on HPA axis programming in inbred rats (38) Alternatively, it may be that genetic influences play a role in the association between low maternal weight, low birth weight, and subsequent adult glucose intolerance. Indeed, Hattersley et al. described mutations in the fetal glucokinase gene that cosegregate with lower birth weight (39) and result in adult hyperglycemia, although apparently not in hypertension or cortisol axis dysregulation.
The majority of the UFA subjects had a persistently low growth trajectory, yet as a group demonstrated altered glucose homeostasis and higher blood pressures. A significant number of UFA subjects exhibited an accentuated phenotype of glucose intolerance and increased blood pressure together with insulin resistance and ß-cell hyperfunction relative to the remainder of the UFA group as well as the AFA group. These seven subjects were not obese and did not have excessive abdominal fat accumulation, but demonstrated more catch-up growth in terms of body weight percentiles than the nonimpaired glucose tolerance/diabetic UFA offspring. However, they did not differ from the AFA control group in weight or waist circumference at this stage. A number of studies have previously described the association between low birth weight and insulin resistance, as measured by a variety of methods (9, 36, 40, 41). However, the reported relationship between insulin secretion and birth weight has not been consistent (36, 42), possibly as a result of different methodologies for the determination of insulin secretion, and the differing populations in terms of age, socio-economic status, and ethnicity. The frequency of abnormal glucose tolerance noted in the UFA group was surprising, as it is otherwise rare at this age in this population (28) and was indeed absent in the AFA group. Amplification of the association between low birth weight and adult hypertension, impaired glucose tolerance, and insulin resistance with subsequent obesity or increased adult height has been described (7, 8, 9). However, our data suggest that obesity or abdominal fat accumulation, known risk factors for insulin resistance, glucose intolerance, hypertension, and ischemic heart disease, are not necessary for low birth weight to link with elevations of blood pressure, glucose tolerance, or cortisol in adult life in this transitional population.
A pivotal question relates to the potential mechanisms underlying these observations. We have shown that being underweight for gestational age in the absence of current obesity and indeed independent of current weight was associated with increased HPA activity and responsiveness. This altered responsiveness was evident in the higher 0900 h plasma cortisol concentrations, confirming a previous finding in 64-yr-old Englishmen (20). We have extended this observation by demonstrating that UFA was associated with enhanced responsiveness to stimulation by physiological levels of ACTH. These findings in young adults support the suggestion (12, 20) that intrauterine programming of the HPA axis may be a fundamental mechanism underlying the association among low birth weight, the insulin resistance syndrome, and adult hypertension in humans in the absence of frank disease. Indeed, in rat models of prenatal programming of hypertension, either by dietary restriction or fetal exposure to exogenous or endogenous glucocorticoids, HPA abnormalities are a consistent feature (19, 43, 44). Moreover, reduction of elevated glucocorticoid levels reverses the increased blood pressure (45). It is tempting to speculate that the association between systolic blood pressure and both 0900 h and ACTH-stimulated plasma cortisol concentrations in young adults in this study may be of analogous significance.
The mechanisms of elevated 0900 h and ACTH-stimulated cortisol in low birth weight adults are not addressed here. The exaggerated cortisol responses to exogenous ACTH are compatible with several potential loci of effects on the HPA axis, including increased adrenal responses, increased central forward drive upon the axis, and attenuated glucocorticoid feedback upon the brain. Elevated basal cortisol levels suggest that increased adrenal responses to ACTH alone are an inadequate explanation, as otherwise intact HPA feedback would be anticipated to adjust the ACTH drive to maintain control cortisol levels. Data in the rat suggest that that adverse prenatal events (glucocorticoid exposure or stress) permanently alter the density of glucocorticoid and mineralocorticoid receptors in central nervous system HPA axis feedback sites, notably in the hippocampus (19, 46). Such receptors are also highly expressed in the human hippocampus (47), but are inaccessible for study in vivo. It is also possible that the increased HPA axis drive is consequent upon altered tissue metabolism, as has been suggested in simple obesity (35). Our data do not suggest that programming of such processes is an early manifestation of the low birth weight phenotype, although the glucocorticoid metabolite data showed considerable variance, and greater numbers may be required to fully dissect the effects.
The findings should be considered in light of the relatively small proportion of the original sample studied and that more UFA than AFA adults were traced, introducing the potential for bias. However, there is no reason to believe that the relation between birth weight and blood pressure, glucose intolerance, measures of HPA axis activity, and cortisol metabolism would differ between those studied at 20 yr of age and those not studied. The developing society from which these participants were drawn is characterized by high levels of obesity (body mass index, >25; 56% in women and 34% in men) (28). Consequently, the potentially synergistic effects of obesity and low birth weight on the prevalence of impaired glucose tolerance, hypertension, and ischemic heart disease in this community may be profound. That this may also relate to other communities undergoing transition is supported by evidence from a cohort of black South African children (5 yr olds) in whom there was an independent association among birth weight, current weight, and systolic blood pressure (23). Prevention of these cardiovascular and metabolic risk factors is complex, because there is incomplete understanding of the etiological factors associated with low birth weight or the mechanisms that link this to adult disease. Furthermore, prevention of adult obesity is difficult and may be confounded by the possible association between the adverse intrauterine environment and a "thrifty phenotype." In sum, we show the low birth weight effect on later cardiovascular and metabolic risk factors in young, nonobese South Africans from a population undergoing epidemiological transition toward a high prevalence of degenerative cardiovascular and metabolic disorders. Programming of plasma cortisol and its response to stimulation appears to be a robust and early event in the fetal origins effect and may be in part causal.
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Acknowledgments |
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Footnotes |
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Received March 1, 2000.
Revised July 10, 2000.
Revised August 25, 2000.
Accepted September 3, 2000.
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References |
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