Influence of gender and body composition on glucocorticoid metabolism in middle-aged humans.
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Body Composition↗
Biomedical subjects
D I Phillips
Publications and source records attributed to D I Phillips.
Alcohol consumption and insulin resistance in young adults.
BACKGROUND: Alcohol may have a cardioprotective effect. One possible mechanism is by reducing insulin resistance, a known cardiovascular risk factor. The aim of this study was to assess the relationship between alcohol consumption, insulin resistance and other parameters determining glucose tolerance in 154 young men and women. SUBJECTS AND METHODS: Subjects completed a questionnaire documenting weekly alcohol consumption. Insulin sensitivity and glucose tolerance were measured using the intravenous glucose tolerance test with minimal model analysis. Height, weight, usual level of exercise, smoking habits and socio-economic status were also recorded. RESULTS: Insulin sensitivity correlated inversely with body mass index (r = - 0.529, P < 0.001) but not with level of physical fitness. Women were significantly less insulin sensitive than men (4.19 and 5.63 104 min-1 pmol-1 L-1, respectively; P < 0.001). Insulin sensitivity correlated positively with alcohol consumption and this trend remained significant allowing for body mass index and gender (beta = 0.17, P < 0.014). First-phase insulin secretion showed a weak but non-significant trend in the opposite direction. Fasting glucose, fasting insulin and glucose tolerance showed no relationships with alcohol consumption. CONCLUSION: These data suggest a close relationship between alcohol consumption and insulin resistance in young adults. Regular alcohol consumption is associated with decreased insulin resistance and this may partly explain the cardioprotective effect of alcohol.
Adult↗
Fetal origins of adult disease: epidemiology and mechanisms.
The past 10 years have provided unequivocal evidence that there are associations between birth size measures and future development of adult diseases, such as type 2 diabetes and coronary artery disease. Despite initial concern that bias or residual confounding in the analyses had produced these rather bizarre associations, the findings have now been reproduced in different cohorts by independent investigators from many parts of the world. The challenge for the next decade must be to discover the cellular and molecular mechanisms giving rise to these associations. If this aim is accomplished, it might be possible to devise strategies to reduce the impact of these disabling, chronic, and expensive diseases. The purpose of this review is to describe some of the relevant, important, and more recent epidemiological studies, and also to discuss potential mechanisms underpinning the associations.
Adult↗
Fetal growth and the physiological control of glucose tolerance in adults: a minimal model analysis.
Although there is now substantial evidence linking low birthweight with impaired glucose tolerance and type 2 diabetes in adult life, the extent to which reduced fetal growth is associated with impaired insulin sensitivity, defective insulin secretion, or a combination of both factors is not clear. We have therefore examined the relationships between birth size and both insulin sensitivity and insulin secretion as assessed by an intravenous glucose tolerance test with minimal model analysis in 163 men and women, aged 20 yr, born at term in Adelaide, South Australia. Birth size did not correlate with body mass index or fat distribution in men or women. Men who were lighter or shorter as babies were less insulin sensitive (P = 0.03 and P = 0.01, respectively), independently of their body mass index or body fat distribution. They also had higher insulin secretion (P = 0.007 and P = 0.006) and increased glucose effectiveness (P = 0.003 and P = 0.003). Overall glucose tolerance, however, did not correlate with birth size, suggesting that the reduced insulin sensitivity was being compensated for by an increase in insulin secretion and insulin-independent glucose disposal. There were no relationships between birth size and insulin sensitivity or insulin secretion in women. These results show that small size at birth is associated with increased insulin resistance and hyperinsulinemia in young adult life but that these relationships are restricted to the male gender in this age group.
Adult↗
Low birth weight predicts elevated plasma cortisol concentrations in adults from 3 populations.
Low birth weight is linked with raised blood pressure in adult life. Recent evidence has suggested that a neuroendocrine disturbance involving the hypothalamic-pituitary-adrenal axis could mediate this link. We therefore investigated the relation between birth weight and fasting plasma cortisol concentrations and the association of cortisol with current blood pressure in population samples of 165 men and women born in Adelaide, South Australia, from 1975 to 1976, 199 men and women born in Preston, UK, from 1935 to 1943, and 306 women born in East Hertfordshire, UK, from 1923 to 1930. Fasting plasma cortisol was measured in plasma samples obtained between 8 and 10 AM. Blood pressure was measured with an automated sphygmomanometer. Low birth weight was associated with raised fasting plasma cortisol concentrations in all 3 populations. A combined analysis that allowed for differences in the gender composition, age, and body mass index between the studies showed that cortisol concentrations fell by 23.9 nmol/L per kilogram increase in birth weight (95% CI 9.6 to 38.2, P<0.001). Fasting plasma cortisol concentrations also correlated positively with the subjects' current blood pressure. However, the association between cortisol and blood pressure was most marked in subjects who were obese (P=0.038 for interaction between body mass index and cortisol, P=0.01 for interaction between waist-to-hip ratio and cortisol). These results show that low birth weight is associated with raised fasting plasma cortisol concentrations. Increased activity of the hypothalamic-pituitary-adrenal axis may link low birth weight with raised blood pressure in adult life.
Adult↗
Twins and the fetal origins hypothesis. Many variables differ between twins and singleton infants.
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Birth Weight↗
The insulin gene VNTR, type 2 diabetes and birth weight.
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Aged↗
Size at birth and plasma leptin concentrations in adult life.
OBJECTIVE: To determine whether low birthweight is associated with higher plasma leptin concentrations in adult life and whether leptin contributes to the metabolic alterations in adults that are associated with reduced foetal growth. DESIGN: Measurement of plasma leptin concentrations in a group of 502 men and women, aged 61-73, who were born in Hertfordshire and for whom records of birth and infant weight are available. Glucose tolerance was measured with a standard 75 g oral glucose tolerance test. MEASUREMENTS: Leptin concentrations were assayed in fasting plasma samples using a radioimmunoassay. RESULTS: Leptin concentrations ranged from 1.4 to 128.9 (mean 13.4) ng/ml and were higher in the 193 women than the 309 men (23.4 vs. 7.1 ng/ml). In both sexes leptin concentrations correlated positively with body mass index (r=0.65 in both men and women). Leptin concentration also correlated with fasting insulin (r=0.41) and with glucose and insulin concentrations 2 h after a glucose load (r=0.19 and 0.49). Adults with lower birth or infant weight had higher leptin concentrations than those of higher birthweight with similar degrees of obesity (P=0.02 and 0.06, respectively). Although both 2 h glucose and insulin concentrations negatively correlated with birthweight (r=-0.17, P<0.001 and r=-0.18, P<0.001, respectively), regression analysis suggested that the higher levels of leptin in adults who had low birthweight did not explain the association between low birthweight and glucose or insulin concentrations. CONCLUSION: These results suggest that adults who had had low birthweight had higher plasma concentrations of leptin than would be expected from their degree of obesity. The higher leptin concentrations, however, do not account for the association between birthsize and glucose tolerance. They may be a consequence of the altered body composition, hyperinsulinaemia, and other long-term endocrine changes associated with reduced foetal growth.
Aged↗
Reduced foetal growth and growth hormone secretion in adult life.
OBJECTIVES: Recent studies suggest that growth restriction or other adverse influences acting in utero or during early infancy lead to permanent alterations in growth hormone (GH) secretion. As GH secretion is known to predict cardiovascular risk, alterations in GH may contribute to the association between reduced foetal growth and cardiovascular disease. We have therefore assessed the relationship between birth size and GH secretion in a prospective study of young adults whose birth size was recorded and who have had their current blood pressure and glucose tolerance measured. DESIGN: Prospective cohort study PATIENTS: 153 healthy men and women, aged 20-21 years. MEASUREMENTS: Subjects carried out a timed overnight urinary collection for analysis of GH excretion. Insulin sensitivity and insulin secretion were measured using the intravenous glucose tolerance test with minimal model analysis. Blood pressure, height, weight, usual level of exercise, smoking habits, alcohol consumption, and socio-economic status were also recorded. RESULTS: GH excretion ranged from 0.01 to 41.8 microU per subject. It did not differ according to gender but was markedly reduced in obese subjects (P < 0.0001) Low birthweight was strongly associated with low GH excretion at age 20 years (P = 0.002). Low placental weight and short body length also predicted low GH (P = 0.02 and P = 0.04, respectively). These relationships were independent of other confounding factors including obesity. GH excretion was not independently related to current levels of blood pressure, insulin sensitivity or insulin secretion. CONCLUSIONS: Body size at birth predicts GH excretion in adult life. Low GH excretion in people who were small at birth may be one mechanism explaining their increased risk of cardiovascular disease.
Adult↗
The autonomic control of heart rate and insulin resistance in young adults.
The pathophysiology of insulin resistance is unclear. A link between increased heart rate (HR) and insulin resistance suggests an association with sympathetic nervous system activity. To further evaluate this, we examined autonomic activity using spectral analysis of HR variability (HRV), which provides a measure of cardiac sympathovagal modulation, and related this to insulin sensitivity (Si) in 137 men and women (20 yr old). The HRV spectrum displays 2 major peaks: a high-frequency peak, reflecting vagal activity, and a low-frequency peak caused by vagal and sympathetic activity. The high-to-low ratio (HLratio) reflects sympathovagal balance. Si was measured, using the i.v. glucose tolerance test with minimal modeling, and HR data was derived from a 15-min supine electrocardiogram. Women were more insulin resistant than men (Si, 3.94 vs. 5.09 10(4) min(-1)/per pmol x L; P = 0.002), had higher HR (59 vs. 56 beats/min, P = 0.019), but had a higher HLratio (2.04 vs. 1.31, P = 0.001). In men (but not women), Si correlated with HR (r = -0.410, P = 0.001) and measures of HRV: HLratio (r = 0.291, P = 0.002) independently of body mass index. In conclusion, Si correlates with cardiac sympathovagal balance in men, but not women, suggesting gender differences in the autonomic modulation of insulin resistance.
Adult↗
Natural antibody status in patients with Hashimoto's thyroiditis.
Raised levels of circulating natural antibodies (NABS) have been found in association with systemic lupus erythematosus (SLE) and chronic active hepatitis (CAH), indicative of polyclonal B-cell activation associated with these relatively non-organ specific autoimmune diseases. This study examined the natural antibody response in the organ-specific autoimmune disease Hashimoto's thyroiditis. Serum samples obtained from 69 women with newly diagnosed Hashimoto's thyroiditis together with 64 controls were analysed for IgG and IgM NABS directed at DNA, actin, myoglobin, myosin, trinitrophenyl hapten (TNP) and tubulin as the NAB antigen panel using an established ELISA. The same technique was also used to estimate thyroglobulin and thyroid microsomal autoantibody activities. Compared to a reference panel of normal serum samples, 31 of the Hashimoto's samples showed a greater than 2SD elevation of IgG and/or IgM NABS against one or more of the panel antigens together with elevated IgG thyroglobulin and thyroid microsomal antibody levels. The cases positive for one or more of the NAB panel also showed a greater incidence of active Hashimoto's thyroiditis as indicated by the presence of antibodies directed against the thyroid specific antigens. The above findings suggest that raised levels of NABS are also a feature of this organ-specific autoimmune disease. The wide ranging NAB specificities involved are consistent with an underlying or epiphenomenal state of polyclonal B-cell activation.
Antibodies, Antinuclear↗
A common mitochondrial DNA variant is associated with insulin resistance in adult life.
Mitochondrial DNA is maternally inherited. Mitochondrial DNA mutations could contribute to the excess of maternal over paternal inheritance of non-insulin-dependent diabetes mellitus (NIDDM). We therefore investigated the relationship between this variant, insulin resistance and other risk factors in a cohort which had been well characterised with respect to diabetes. Blood DNA was screened from 251 men born in Hertfordshire 1920-1930 in whom an earlier cohort study had shown that glucose tolerance was inversely related to birthweight. The 16189 variant (T--> C transition) in the first hypervariable region of mitochondrial DNA was detected using the polymerase chain reaction and restriction digestion. DNA analysis showed that 28 of the 251 men (11%) had the 16189 variant. The prevalence of the 16189 variant increased progressively with fasting insulin concentration (p < 0.01). The association was independent of age and body mass index and was present after exclusion of the patients with NIDDM or impaired glucose tolerance. We found that insulin resistance in adult life was associated with the 16189 variant. This study provides the first evidence that a frequent mitochondrial variant may contribute to the phenotype in patients with a common multifactorial disorder.
Adult↗
Does a common mitochondrial DNA polymorphism underlie susceptibility to diabetes and the thrifty genotype?
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DNA, Mitochondrial↗
Mortality from birth to adult life: a longitudinal study of twins.
We have examined mortality from birth through adult life in a cohort of 2562 twins born in Birmingham, UK, between 1950 and 1954. Their birthweights and obstetric details had been recorded as part of a longitudinal study of births in Birmingham. There were a total of 151 perinatal deaths (perinatal mortality rate = 116 per 1000 births) and 227 infant deaths (infant mortality rate = 94 per 1000 live births). 70 deaths occurred after the age of one year. In comparison with national mortality rates in the UK, overall mortality in the twins was high (standard mortality rate, SMR = 259, 95% CI 221-300). Mortality was highest in the first year of life and, although it then declined progressively, it remained significantly higher that that of the general population until age 5 years. The excess mortality was largely due to conditions originating in the perinatal period but there were excess rates of congenital abnormalities, diseases of the respiratory system, digestive system and nervous and sensory organs. A Cox proportional Hazards analysis showed that the risk of death was related to low birthweight, prematurity and male sex. Death of the co-twin was highly predictive of mortality throughout the period of follow up. These studies not only underline the excess mortality associated with twin birth but show for the first time that this excess mortality extends into childhood.
Adolescent↗
Reproducibility of the low dose dexamethasone suppression test: comparison between direct plasma and salivary cortisol assays.
BACKGROUND: The low dose dexamethasone suppression test (DST) has been used to detect subtle variations in the feedback suppression of the hypothalamic-pituitary-adrenal axis, which may contribute to the pathogenesis of several diseases including depression, the metabolic syndrome and coronary artery disease. Little is known about the reproducibility of this test, or whether the test can be combined with analysis of salivary cortisol which would offer a significant advantage over plasma in population studies. SUBJECTS AND DESIGN: A low dose DST was carried out in 29 healthy subjects (14 men, 15 women), aged 24-54 (mean 35.1) years, on two separate occasions 1-10 weeks apart. Following the administration of 0.25 mg dexamethasone (DXM) at 2200 h, plasma and saliva were sampled at 0830 h the next day. Cortisol was measured by radioimmunoassay in plasma and time-resolved immunofluorescent assay ('DELFIA') in saliva. Bland-Altman plots were produced for post-DXM plasma and salivary cortisol measures and used to derive a coefficient of repeatability for each measure, which describes the range of cortisol measurements within which 95% of repeated measurements will fall. RESULTS: The baseline, pre-DXM cortisol concentrations were far more variable for saliva (mean 16.5, range 4.4-34 nmol/l) than for plasma (mean 407.5; range 232-958 nmol/l). Following DXM both measurements showed an approximately 30% suppression from baseline but the variability of salivary cortisol was much greater. From the Bland-Altman plots the 95% range for the differences about their mean was calculated and used as an indication of repeatability. For plasma 95% of differences were within 0.78 log units, indicating that a repeated measurement was approximately half as small or twice as large as the first. For saliva 95% of differences were within 1.64, indicating that a repeated measurement was approximately five times as small or five times as large as the first. CONCLUSIONS: Assessment of dexamethasone suppression by salivary cortisol measurement is far less repeatable than the use of plasma cortisol. In the context of field studies of dexamethasone suppression, salivary cortisol measurements may only be appropriate for large numbers of subjects.
Adult↗
Long-term consequences of intrauterine growth retardation.
Recent studies in Europe, North America and the developing world have shown that low birth weight or other indices of abnormal fetal growth in babies born at term are linked with a higher prevalence of raised blood pressure, non-insulin-dependent diabetes and cardiovascular disease in late adult life. These findings have led to the 'fetal origins' hypothesis which proposes that fetal adaptations to an adverse intrauterine environment programme persistent physiological and metabolic changes which predispose to these diseases. The mechanisms are unknown, but evidence from animal studies and preliminary evidence in humans suggest that impaired fetal nutrient supply permanently alters neuroendocrine development in the offspring resulting in long-term changes in the set point of adrenocortical and sympathoadrenal hormonal activity.
Animals↗
Increased glucocorticoid activity in men with cardiovascular risk factors.
The association between hypertension and insulin resistance might be explained by increased activity of the principal glucocorticoid, cortisol. Recent data show that the intensity of dermal vasoconstriction after topical application of glucocorticoids is increased in patients with essential hypertension. In this report, we examine whether increased glucocorticoid sensitivity or secretion is associated with insulin resistance and is a cause or consequence of hypertension. We studied 32 men (aged 47 to 56 years) from a cross-sectional study and 105 men (aged 23 to 33 years) in whom predisposition to high blood pressure has been defined by their own blood pressure and the blood pressures of their parents. In both populations, increased dermal glucocorticoid sensitivity was associated with relative hypertension, insulin resistance, and hyperglycemia. In young men with higher blood pressure whose parents also had high blood pressure, enhanced glucocorticoid sensitivity was accompanied by enhanced secretion of cortisol, enhanced ligand-binding affinities for dexamethasone in leukocytes, and impaired conversion of cortisol to inactive metabolites (cortisone and 5beta-dihydrocortisol). Increased tissue sensitivity to cortisol, amplified by enhanced secretion of cortisol, is a feature of the familial predisposition to high blood pressure rather than a secondary effect of high blood pressure. It may be mediated by an abnormal glucocorticoid receptor, and it may contribute to the association between hypertension and insulin resistance.
Administration, Topical↗
Elevated plasma cortisol concentrations: a link between low birth weight and the insulin resistance syndrome?
Recent studies have shown that reduced fetal growth is associated with the development of the insulin resistance syndrome in adult life. The mechanisms are not known. However increased activity of the hypothalamic-pituitary-adrenal axis (HPAA) may underlie this association; the axis is known to be reset by fetal growth retardation in animals, and there is evidence in humans of an association between raised HPAA activity and the insulin resistance syndrome. We have, therefore, examined the relations among size at birth, plasma cortisol concentrations, and components of the insulin resistance syndrome in a sample of healthy men. We measured 0900 h fasting plasma cortisol and corticosteroid-binding globulin levels in 370 men who were born in Hertfordshire, UK, between 1920-1930 and whose birth weights were recorded. Fasting plasma cortisol concentrations varied from 112-702 nmol/L and were related to systolic blood pressure (P = 0.02), fasting and 2-h plasma glucose concentrations after an oral glucose tolerance test (P = 0.0002 and P = 0.04), plasma triglyceride levels (P = 0.009), and insulin resistance (P = 0.006). Plasma cortisol concentrations fell progressively (P = 0.007) from 408 nmol/L in men whose birth weights were 5.5 lb (2.50 kg) or less to 309 nmol/L among those who weighed 9.5 lb (4.31 kg) or more at birth, a trend independent of age and body mass index. These findings suggest that plasma concentrations of cortisol within the normal range could have an important effect on blood pressure and glucose tolerance. Moreover, this study provides the first evidence that intrauterine programming of the HPAA may be a mechanism underlying the association between low birth weight and the insulin resistance syndrome in adult life.
Aged↗