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Biomedical subjects

D I Phillips

Publications and source records attributed to D I Phillips.

At least 55 records · Page 3Linked to original sources
PubMed1998

Obesity and gender influence cortisol secretion and metabolism in man.

In obesity, urinary cortisol excretion is enhanced but plasma cortisol levels are not elevated, suggesting that metabolic clearance of cortisol is increased. Cortisol is metabolised in liver and fat by A-ring reductases but also regenerated from inactive cortisone in liver, fat, and skeletal muscle by 11 beta-reductase. These enzymes are regulated by estrogen. This study addressed whether there are differences in cortisol metabolism in obesity, and whether these differences are estrogen dependent. 31 men and 37 post-menopausal women (9 on estrogen replacement therapy) aged 47-53 y supplied 24 h urine for gas chromatography/mass spectrometry. Total cortisol metabolite excretion was higher in men than women, but weakly related to indices of obesity. By contrast, metabolism of cortisol favoured 5 alpha-rather than 5 beta-reduction in obese men and obese women, and favoured cortisol rather than cortisone in obese men. In women compared with men ratios of 5 alpha-/5 beta-reduced and cortisol/cortisone metabolites were also higher but these variables were not affected by estrogen replacement therapy. We conclude that in obesity, inactivation of cortisol by 5 alpha-reductase is enhanced but this is offset by impaired metabolism of cortisol by 5 beta-reductase in women and enhanced conversion of cortisone to cortisol by 11 beta-reductase in men. These observations suggest that cortisol clearance is altered in obesity, and this may account for activation of the hypothalamic-pituitary-adrenal axis. Moreover, these data predict that obese subjects will have higher concentrations of cortisol in key target tissues including liver and visceral fat. This may contribute to the adverse metabolic consequences of obesity.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1998

Birth weight and the future development of diabetes. A review of the evidence.

Recent studies in Europe, North America, and the developing world have shown that low birth weight and other indices of abnormal fetal growth in babies born at term are linked with a higher prevalence of glucose intolerance and NIDDM in adult life. Reduced fetal growth is also associated with a higher prevalence of the metabolic syndrome (in particular, hypertension and vascular disease) and with insulin resistance in adult life. Because birth size is determined largely by nongenetic factors, these findings have led to the "fetal origins" hypothesis, which proposes that fetal adaptations to an adverse intrauterine environment that reduces fetal growth program lifelong physiological changes. These changes in turn predispose to diabetes and the metabolic syndrome. The mechanisms are unknown, but evidence from animal studies and preliminary human evidence suggests that adverse events in early life may influence the neuroendocrine development of the fetus. This results in long-term alterations in the setpoint of several major hormonal axes, including an increase in adrenal glucocorticoid secretion. These hormonal alterations may contribute to the predisposition to diabetes and the metabolic syndrome in people who were small at birth.

Adult↗
PubMed1997

Fetal growth, length of gestation, and polycystic ovaries in adult life.

BACKGROUND: Polycystic ovaries are a common disorder associated with menstrual irregularities, subfertility, hirsutism, acne, and a range of endocrine abnormalities, including high concentrations of plasma luteinising hormone (LH) and excessive androgen production. The pathophysiology is not understood. We investigated whether the disorder originates during intrauterine life. METHODS: We examined 235 women aged 40-42 years who were born in Sheffield, UK. We related the prevalence of polycystic ovaries and the plasma concentrations of gonadotropin hormones and androgens to the women's body size at birth, and the length of gestation. FINDINGS: 49 (21%) of the women had polycystic ovaries. We defined two groups of women with the disorder, which correspond to the two groups that commonly present clinically. The first group comprised obese women who were androgenised, with higher than normal concentrations of plasma LH and testosterone. These women had above-average birthweight and were born to overweight mothers. The second group comprised women of normal weight who had high plasma LH, but normal testosterone concentrations. These women were born after term (40 weeks' gestation). INTERPRETATION: The two common forms of polycystic ovary syndrome have different origins in intrauterine life. Obese, hirsute women with polycystic ovaries have higher than normal ovarian secretion of androgens that are associated with high birthweight and maternal obesity. Thin women with polycystic ovaries have altered hypothalamic control of LH release resulting from prolonged gestation.

Adult↗
PubMed1997

Association between low birthweight and high resting pulse in adult life: is the sympathetic nervous system involved in programming the insulin resistance syndrome?

To test the hypothesis that elevated sympathetic nervous system (SNS) activity could be determined in utero and be one of the processes mediating the link between size at birth and insulin resistance and raised blood pressure in adult life, we have studied the resting pulse rate of 449 men and women aged 46 to 54 (mean 50) years born in Preston, Lancashire, England whose birth size was recorded in detail. The subjects were visited at home by trained fieldworkers who measured resting pulse rate and blood pressure using an automated recorder. The resting pulse rate ranged from 44 to 108 (mean 73) beats min(-1). It rose with increasing body mass index (r = 0.14, p = 0.003) and waist to hip ratio (adjusted for sex r = 0.10, p = 0.003) and correlated significantly with systolic and diastolic blood pressures (p = 0.001), fasting glucose (p = 0.02), split proinsulin (p = 0.001), and triglyceride concentrations (p = 0.02). The pulse rate fell progressively from 76 beats min(-1) among subjects who weighed 5.5 lb (2.5 kg) or less at birth to 71 beats min(-1) among those who weighed 7.5 lb (3.3 kg) or more (decline in pulse rate per kg increase in birthweight = 2.7, 95 % CI 0.6 to 4.8 beats min(-1). The association was independent of current body mass index, waist to hip ratio and of potential confounding variables including smoking, alcohol consumption, and social class. Although the resting pulse rate is an imperfect index of SNS activity, these findings are consistent with the hypothesis that elevated SNS activity established in utero is one mechanism linking small size at birth with the insulin resistance syndrome in adult life.

Adult↗
PubMed1997

Is an exaggerated postprandial triglyceride response associated with the component features of the insulin resistance syndrome?

To investigate whether individual component features of the insulin resistance syndrome were associated with the postprandial triglyceride response, 57 healthy Caucasian men between 57 and 70 years of age underwent a fat tolerance test lasting 8 h. Fasting triglyceride concentrations were associated with the total unfractionated postprandial triglyceride response (r(s) = 0.54, p < 0.001) and the triglyceride-rich lipoprotein (TGRLP) fraction (d < 1.006) at 8 h was associated with the maximum non-esterified fatty acid concentration (NEFA) (r(s) = 0.33, p = 0.01). Measures of obesity (BMI and WHR) were not associated with the postprandial triglyceride response but were inversely related to NEFA suppression (NEFA nadir and BMI, r(s) = 0.31, p = 0.02; and NEFA nadir and WHR, r(s) = 0.36, p = 0.006). Other component features of the IRS, including glucose tolerance and two proxy measures of insulin resistance (fasting insulin concentration and HOMA measurement) were not associated with the postprandial triglyceride response despite being strongly associated with fasting triglyceride concentration. Current smoking habit, chronic alcohol consumption and birth weight were also not associated with an altered postprandial triglyceride response. In conclusion these results show that although component features of the IRS were associated with increased fasting triglyceride concentrations many of these features, including two proxy measures of insulin sensitivity were not associated with an exaggerated postprandial triglyceride response.

Aged↗
PubMed1997

Fetal growth and insulin resistance in adult life: role of skeletal muscle morphology.

1. Thinness at birth is associated with insulin resistance in adult life and an apparent delay in activation of glycolysis/glycogenolysis in exercising skeletal muscle. As developmental abnormalities of skeletal muscle histology or metabolism may explain this association we examined muscle histology, biochemistry and blood flow in a group of 27 adult women whose birth details were known. 2. Subjects were examined by near-infrared spectroscopy to determine forearm muscle oxygen supply, and by muscle biopsy and forearm plethysmography. Those with a ponderal index at birth < 23 kg/m3 were insulin resistant (assessed by the short insulin-tolerance test-mean rate constants for glucose disappearance = 4.14 compared with 4.83%/min, P = 0.045) and had significantly more rapid muscle reoxygenation than the remainder of the subjects (13 compared with 22 s, P = 0.004). 3. Thinness at birth did not influence muscle capillary density, muscle glycogen content, glycogen synthase activity, citrate synthase activity or resting forearm blood flow. 4. Insulin resistance seen after fetal malnutrition was not associated with abnormal muscle histology, resting muscle blood flow, mitochondrial volume or glycogen content. 5. The increase in muscle reoxygenation rate in adult subjects who were thin at birth could occur to promote oxidative ATP synthesis in compensation for the delay in activation of glycolysis/glycogenolysis. It suggests altered regulation rather than structure of the muscle microcirculation. These changes appear to antedate the structural and biochemical changes seen in muscle from patients with established diabetes.

Embryonic and Fetal Development↗
PubMed1997

Iodine, milk, and the elimination of endemic goitre in Britain: the story of an accidental public health triumph.

OBJECTIVE: To determine how iodine deficiency and endemic goitre disappeared in Britain. DESIGN: Review of surveys of endemic goitre and iodine nutrition. MAIN RESULTS: Endemic goitre was widespread in Britain but has declined, most notably since the 1960's. Its disappearance was probably due to changes in farming practice, especially iodine supplementation in dairy herds which has resulted in iodine contamination of milk and dairy produce. CONCLUSIONS: Although iodization of dairy herds offers an indirect method of counteracting iodine deficiency, it is haphazard and there should be careful and continuous monitoring of iodine intakes in the population.

Animal Feed↗
PubMed1997

Proteinuria and progressive renal disease: birth weight and microalbuminuria.

BACKGROUND: Microalbuminuria and nephropathy in diabetic subjects has been linked to low birth weight or short stature in adulthood. We have explored the relationship of foetal growth and intrauterine starvation with microalbuminuria in non-diabetic subjects. METHODS: Albumin excretion rate was measured in an overnight sample in 236 men and women in Preston whose birth anthropometry had been recorded at the local maternity hospital. Albumin excretion rate was also measured in a 2-h and overnight sample in 98 subjects exposed to intrauterine maternal starvation during the Siege of Leningrad as well as in 124 subjects exposed in infancy and 62 born concurrently outside the Siege limits. RESULTS: In 236 men and women aged 46-54 years in Preston, 11 had microalbuminuria on an overnight urine collection. There were trends for these subjects to have lower birth weight (105.8 oz vs. 112.9 oz, P = 0.20) and lower ponderal index at birth (12.3 oz/in3 x 1000 vs. 13.4 oz/in3 x 1000, P = 0.09) than those who were normoalbuminuric. The albumin excretion rate of the subjects exposed in utero to maternal starvation (daytime sample 5.2 x/divided by 2.8 micrograms.min-1; overnight sample 2.9 x/divided by 2.5 micrograms.min-1) was not significantly different from those of the subjects exposed in infancy (5.5 x/divided by 2.7 micrograms.min-1 and 3.3 x/divided by 2.5 micrograms.min-1, respectively) or from those who were unexposed (5.1 x/divided by 3.0 micrograms.min-1 and 3.2 x/divided by 2.2 micrograms x min-1, respectively), (P = 0.99 for daytime and P = 0.73 for overnight rates controlling for sex, BMI, and systolic blood pressure). CONCLUSIONS: Consistent relationships of short stature with microalbuminuria and nephropathy in non-diabetic and diabetic subjects might suggest that more subtle anthropometric indices could relate to low nephron number at birth, or that postnatal or genetic influences could underlie the observed link.

Albuminuria↗
PubMed1996

The association between free fatty acid concentrations and triglyceride-rich lipoproteins in the post-prandial state is altered by a common deletion polymorphism of the apo B signal peptide.

To investigate whether there were associations between the free fatty acid (FFA) response during a fat tolerance test and changes in concentrations of triglyceride-rich lipoproteins 57 healthy Caucasian men between 57 and 70 years of age underwent a fat tolerance test lasting 8 h. FFA concentrations initially decreased from 0.75 +/- 0.03 to 0.64 +/- 0.03 mmol/l at 2 h and thereafter increased to 1.2 +/- 0.04 mmol/l at 8 h. Maximum FFA concentration was the only significant determinant of 8 h triglyceride-rich lipoprotein (TGRLP) concentrations (pooled chylomicron and VLDL fractions d < 1.006) (TGRLP-TG r = 0.33, P = 0.012; TGRLP apo B r = 0.37, P = 0.004; TGRLP cholesterol r = 0.38, P = 0.004). The strength of the association between FFA and TGRLP was affected by the apo B signal peptide genotype. Only in individuals who were homozygous for the 27 amino acid (SP27 or I) allele of the apo B signal peptide were there significant associations between maximum FFA concentration quartile and 8 h TGRLP concentration (P value for linear trend = 0.025). In this genotype group there were lower HDL cholesterol concentrations (1.16 mmol/l compared to 1.38 mmol/l in subjects either heterozygous or homozygous for the SP24 [D] allele; P = 0.005) and there was a trend toward increased 8 h TGRLP concentrations. We propose that the association between post-prandial FFA concentrations and post-prandial TGRLP concentrations in individuals who are homozygous for the SP27 allele may be linked to the increased prevalence of ischemic heart disease (IHD) in this genotypic group.

Aged↗
PubMed1996

Fetal growth and insulin resistance in adult life: relationship between glycogen synthase activity in adult skeletal muscle and birthweight.

Growth retardation during fetal life is associated with insulin insensitivity and an increased prevalence of impaired glucose tolerance in adult life. Because insulin-mediated stimulation of glycogen synthase may be an important rate-limiting step for insulin action at the cellular level, we have sought to determine whether impaired activation of muscle glycogen synthase is linked with early growth retardation. Postprandial glycogen synthase activity was therefore measured in muscle biopsies from a group of 27 women with normal glucose tolerance aged around 50 who were born in Preston, Lancashire, whose birthweight and body size at birth were recorded. Glycogen synthase activity measured at 0.1 mmol 1(-1) glucose-6-phosphate correlated with insulin sensitivity as measured by a short insulin tolerance test (r = 0.42, p < 0.05) and the waist to hip ratio (r = -0.48, p < 0.01), but not body mass index, body fat percentage or age. Within the group of women with normal glucose tolerance there was no relationship between intra-uterine growth as evidenced by birthweight or body size at birth and the response to insulin of skeletal muscle glycogen synthase in adult life. Thus we found no evidence for a direct link between fetal growth and insulin sensitivity in this pathway.

Biopsy↗
PubMed1996

Intramuscular triglyceride and muscle insulin sensitivity: evidence for a relationship in nondiabetic subjects.

Intracellular triglyceride (TG) is an important energy source for skeletal muscle. However, recent evidence suggests that if muscle contains abnormally high TG stores its sensitivity to insulin may be reduced, and this could predispose to type II diabetes. To test this hypothesis, we measured muscle lipid content in 27 women aged 47 to 55 years (mean, 52) and related it to their glucose tolerance, insulin resistance, and muscle insulin sensitivity as measured by insulin activation of glycogen synthase, an insulin-regulated enzyme that is rate-limiting for insulin action in muscle. Both muscle TG content and intracellular lipid determined by Oil red O staining of muscle fibers were negatively associated with glycogen synthase activation (r = .43, P = .03 and r = -.47, P = .02, respectively). In addition, intracellular lipid correlated with features of the insulin resistance syndrome, including an increased waist to hip ratio (r = .47, P = .01) and fasting nonesterified fatty acids ([NEFA] r = .44, P = .04). These data demonstrate that increased muscle TG stores are associated with decreased insulin-stimulated glycogen synthase activity. Intracellular fat may underlie a major part of the insulin resistance in normal subjects, as well as type II diabetics.

Body Constitution↗
PubMed1995

Weight gain in infancy and cancer of the ovary.

The geographic association between ovarian cancer and tall stature suggests a link with rapid growth in early childhood. Among 5585 women born in Hertfordshire, UK, 41 who died from ovarian cancer had had a high rate of weight gain in infancy. Whereas their mean birthweight was the same as that of the other women, their mean weight at 1 year was higher (22.3 pounds [10.1 kg] vs 21.4 pounds [9.7 kg], p = 0.01). These observations are consistent with the hypothesis that ovarian cancer is linked to altered patterns of gonadotropin release established in utero when the fetal hypothalamus is imprinted.

Adult↗
PubMed1995

A relationship between impaired fetal growth and reduced muscle glycolysis revealed by 31P magnetic resonance spectroscopy.

Thinness at birth is associated with insulin resistance and an increased prevalence of non-insulin-dependent diabetes mellitus in adult life. As muscle is an important site of insulin resistance, and because thin babies have reduced muscle mass, thinness at birth may affect muscle structure and function and impair carbohydrate metabolism. We have therefore used 31P magnetic resonance spectroscopy to investigate the bioenergetics of gastrocnemius and flexor digitorum superficialis muscles in 16 normoglycaemic women who had a low ( < or = 23 kg/m3) and 9 women who had a high (> 23 kg/m3) ponderal index at birth. In the flexor digitorum superficialis study anaerobic metabolism was stressed with a constant heavy workload. Low ponderal index subjects fatigued more rapidly (3.3 vs 5.8 min); as phosphocreatine decreased, the accompanying drop in muscle pH was less than in the high ponderal index group. In the first minute of exercise phosphocreatine fell and adenosine diphosphate rose more rapidly (p=0.04 and 0.03, respectively). Gastrocnemius showed a similar trend late in exercise (this exercise was more oxidative, becoming more anaerobic with increasing workload). These changes were not explained by differences in body composition, muscle mass or blood flow. The findings are consistent with a decreased lactic acid and glycolytic adenosine triphosphate production in the low ponderal index group and suggest the possibility that the mechanisms which control substrate utilisation and metabolism in adult life be programmed during prenatal life.

Adenosine Diphosphate↗
PubMed1995

Relation of fetal growth to adult muscle mass and glucose tolerance.

Recent studies show reduced fetal growth is associated with insulin resistance and a raised prevalence of glucose intolerance in adult life. Because early growth retardation in animal models leads to permanent changes in body composition and a reduction in the mass of muscle, a major insulin sensitive tissue, reduced adult muscle mass could explain the link between impaired fetal growth and glucose intolerance. To investigate this hypothesis, muscle mass has been determined in a group of men and women aged around 50 who were born in Preston, Lancashire and compared with their birthweight or body size at birth and their current insulin resistance and glucose tolerance. Subjects who had lower birthweights were shorter and lighter but their weight adjusted for height (BMI) was similar to that of other subjects. Much of the difference in weight was accounted for by a reduction in muscle mass. Muscle mass as estimated by the urinary creatinine excretion rose from 18.8% of body weight in women who had birthweights of 2.5 kg or less to 24.7% of bodyweight in those with birthweights of 3.4 kg or more. Trends in men were similar. Regression analysis showed that adult muscle mass was predicted by low birthweight (p = 0.004), low placental weight (p = 0.02), and small head circumference (p = 0.02) but not, however, by thinness at birth, the birth measurement most predictive of insulin resistance. In addition there were no significant relationships between muscle mass and insulin resistance or glucose tolerance in either men or women.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Fetal growth and insulin resistance in adult life: role of plasma triglyceride and non-esterified fatty acids.

Reduced fetal growth is associated with insulin resistance and a high prevalence of glucose intolerance in adult life. Because babies who are growth retarded have elevated levels of triglyceride and non-esterified fatty acids (NEFA), and because similar abnormalities are observed in subjects with the insulin resistance syndrome, impaired regulation of lipid metabolism could be one of the mechanisms explaining the link between reduced fetal growth and insulin resistance. We have, therefore, measured fasting plasma triglyceride and NEFA, and the insulin-mediated suppression of NEFA during an oral glucose tolerance test in 93 men and women aged 50, born in Preston, whose birthweight and body size at birth had been recorded. Elevated fasting plasma triglycerides and reduced NEFA suppression during the oral glucose tolerance test were associated with the male sex, glucose intolerance, central obesity as indicated by a high waist to hip ratio and insulin resistance as measured by a short insulin tolerance test. However there were no statistically significant relationships between the birth measurements and the circulating lipid levels. Moreover in regression analyses the relationships between thinness at birth and insulin resistance or glucose intolerance in adult life were unaffected by the addition of triglyceride or NEFA in the models. These results suggest that the link between reduced fetal growth and insulin resistance in the adult is not mediated by an abnormal regulation of lipid metabolism.

Administration, Oral↗